COMPOSITIONS AND METHODS FOR REGULATING MAPT

Abstract

The disclosure relates to small interfering RNA (siRNA) molecules targeting MAPT and adeno-associated viral (AAV) particles encoding the same for treating tauopathies.

Description

COMPOSITIONS AND METHODS FOR REGULATING MAPT RELATED ORDERS

[001] This application claims priority from U.S. Provisional Patent Application No. 63 / 477,736, filed December 29, 2022, the contents of which are incorporated herein by reference in their entirety. SEQUENCE LISTING

[002] This application is being filed together with a Sequence Listing in electronic format. The Sequence Listing file, titled V2071-3010PCT_SL.xml, was created on December 13, 2023, and is 2,478,152 bytes in size. The electronic information from the Sequence Listing is incorporated herein by reference in its entirety. FIELD OF THE INVENTION

[003] The present invention relates generally to compositions and methods for vectored delivery of an agent, for example, an RNA agent, that inhibits a mutant, variant or wild-type human microtubule-associated tau (MAPT) gene, mRNA and / or protein. BACKGROUND

[004] Tauopathies, which may also be referred to here as tau-associated diseases, are a heterogeneous group of neurodegenerative diseases characterized by dysfunction and / or aggregation of microtubule-associated tau protein (MAPT), which may also be referred to here as Tau, and which is encoded by the MAPT gene. Tau is normally a highly soluble protein known to associate with microtubules based on the extent of its phosphorylation. In tauopathies, tau becomes hyperphosphorylated, misfolds, and aggregates as neurofibrillary tangles (NFTs) of paired helical filaments (PHFs), twisted ribbons, or linear filaments. These NTFs are Petition 870260044145, dated 11 / 05 / 2026, page 6 / 1140 2 / 530 widely considered indicative of impending neuronal cell degeneration, which can contribute to widespread neuronal cell loss, leading to a variety of behavioral and cognitive deficits, and can also be fatal. Currently, treatment options available for tauopathies are very limited, often with only symptomatic relief and supportive therapies available. As such, there is a medical need for improved compositions and methods of prevention, treatment, and diagnosis for diseases associated with aberrant tau expression, including tauopathies and related neurodegenerative disorders. SUMMARY

[005] The present invention provides AAV particles encoding an agent to target MAPT, for example, an RNA agent to modulate, for example, inhibit, the expression of the MAPT gene and / or the production of the MAPT protein and methods of using the same. In some embodiments, the agent to target MAPT, for example, a MAPT gene, mRNA or protein (for example, a tau protein) is an RNA agent to target MAPT, for example, a MAPT-targeting siRNA duplex. In some embodiments, the agent to target MAPT comprises a modulating polynucleotide encoding a MAPT-targeting siRNA duplex. Methods for treating diseases associated with MAPT expression, for example, aberrant expression, such as tauopathies, including but not limited to Alzheimer's disease (AD), frontotemporal dementia (FTD) and / or Dravet syndrome (DS) in an individual who needs them.

[006] Thus, in one aspect, the present invention provides a short interfering ribonucleic acid (siRNA) to inhibit the expression of microtubule-associated tau protein (MAPT), comprising a sense strand sequence and an antisense strand sequence, wherein the antisense sequence is complementary to at least 15, 16, 17, 18, 19, Petition 870260044145, dated 11 / 05 / 2026, p. 7 / 1140 3 / 530 or 21 contiguous nucleotides comprising 0, 1, 2, or 3 mismatches of a MAPT sequence comprising the nucleotide sequence of SEQ ID NO: 5024 or a nucleotide sequence provided in Table 3 or 19. In some embodiments, the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides that differ by 3, 2, 1, or 0 nucleotides from any of the antisense strand sequences provided in Tables 3, 4, 5, 9A, or 9B; and the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, 21 contiguous nucleotides that differ by 3, 2, 1, or 0 nucleotides from any of the sense strand sequences provided in Tables 3, 4, 5, 9A, or 9B, wherein the sense strand sequence and the antisense strand sequence comprise a complementarity region of at least 15 nucleotides.In some embodiments, the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides from any of the antisense strand sequences provided in Tables 3, 4, 5, 9A, or 9B; and the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides from any of the sense strand sequences provided in Tables 3, 4, 5, 9A, or 9B, wherein the sense strand sequence and the antisense strand sequence comprise a complementarity region of at least 15 nucleotides.In some embodiments, the antisense strand sequence comprises the nucleotide sequence of any of the antisense strand sequences provided in Tables 3, 4, 5, 9A, or 9B; and the sense strand sequence comprises the nucleotide sequence of any of the sense strand sequences provided in Tables 3, 4, 5, 9A, or 9B, wherein the sense strand sequence and the antisense strand sequence comprise a complementarity region of at least 15 nucleotides.

[007] In another aspect, the present invention provides a short interfering ribonucleic acid (siRNA) to inhibit protein expression. Petition 870260044145, dated 11 / 05 / 2026, page 8 / 1140 4 / 530 microtubule-associated tau (MAPT) comprising a sense strand sequence and an antisense strand sequence, wherein: (i) the antisense strand sequence comprises at least 20 or 21 contiguous nucleotides of any of the following SEQ ID NOs: 4908, 4920, 4924, 5057, 4916, 4912, 5080, 5104 or 5128; and (ii) the sense strand sequence comprises at least 20 or 21 contiguous nucleotides of any of the following SEQ ID NOs: 4906, 4926, 4946, 4966, 4986, 5006, 4918, 4938, 4958, 4978, 4998, 4922, 4942, 4962, 4982, 5002, 5022, 5054, 5060, 5064, 5066, 5070, 5074, 4914, 4934, 4954, 4974, 4994, 5014, 4910, 4930, 4950, 4970, 4990, 5010, 5077, 5084, 5088, 5092, 5096, 5098, 5101, 5108, 5112, 5116, 5120, 5122, 5125, 5132, 5136, 5140, 5144 or 5146; wherein the sense strand sequence and the antisense strand sequence comprise a complementarity region of at least 15 nucleotides.

[008] In another aspect, the present invention provides an adeno-associated virus (AAV) viral genome comprising a nucleotide sequence positioned between two inverted terminal repeats (ITRs), wherein the nucleotide sequence encodes an siRNA to inhibit MAPT, wherein the siRNA comprises a sense strand sequence and an antisense strand sequence, wherein: (i) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of any of the SEQ ID NOs: 4908, 4920, 4924, 5057, 4916, 4912, 5080, 5104 or 5128; and (ii) the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of any of the following SEQ ID NOs: 4906, 4926, 4946, 4966, 4986, 5006, 4918, 4938, 4958, 4978, 4998, 4922, 4942, 4962, 4982, 5002, 5022, 5054, 5060, 5064, 5066, 5070, 5074, 4914, 4934, 4954, 4974, 4994, 5014, 4910, 4930, 4950, 4970, 4990, 5010, 5077, 5084, 5088, 5092, 5096, 5098, 5101, 5108, 5112, 5116, 5120, 5122, 5125, 5132, 5136, 5140, 5144 or 5146; wherein the sense tape sequence and the nonsense tape sequence Petition 870260044145, dated 11 / 05 / 2026, page 9 / 1140 5 / 530 comprise a complementarity region of at least 15 nucleotides.

[009] In another aspect, the present invention provides a modulating polynucleotide that encodes an siRNA to target the MAPT described herein. In some embodiments, the modulating polynucleotide further comprises a 5' flanking region, a loop region and / or a 3' flanking region.

[0010] In another aspect, the present invention provides an AAV particle comprising a promoter operatively linked to a nucleic acid encoding a modulating polynucleotide comprising an siRNA to target the MAPT described herein.

[0011] In another aspect, the present invention provides a method for producing an AAV particle comprising an AAV capsid protein, for example, an AAV capsid variant, encoding an siRNA to target the MAPT described herein. In some embodiments, the method comprises providing a host cell comprising a viral genome encoding an siRNA described herein and incubating the host cell under suitable conditions to enclose the viral genome in the AAV capsid protein, for example, an AAV capsid variant, thereby producing the AAV particle.

[0012] In another aspect, the present invention provides a method of administering an siRNA to inhibit MAPT to a cell. In some embodiments, the method comprises administering an effective amount of an siRNA or an AAV particle encoding an siRNA described herein.

[0013] In another aspect, the present invention provides a method of treating an individual who has or has been diagnosed with a genetic disorder, for example, a monogenic disorder or a polygenic disorder. The method comprises administering an effective amount of an AAV particle comprising a variant of Petition 870260044145, dated 11 / 05 / 2026, page 10 / 1140 6 / 530 AAV capsid described in this document.

[0014] In another aspect, the present invention provides a method of treating an individual who has or has been diagnosed with a neurological disorder, for example, a neurodegenerative disorder. The method comprises administering an effective amount of an AAV particle comprising a variant of the AAV capsid described in this document.

[0015] In another aspect, the present invention provides a method of treating an individual who has or has been diagnosed with a disorder associated with tau expression, for example, aberrant tau expression. The method comprises administering an effective amount of an AAV particle comprising an AAV capsid variant described in this document.

[0016] In another aspect, the present invention provides a method of treating an individual who has or has been diagnosed with a tauopathy. The method comprises administering an effective amount of an AAV particle comprising a variant of the AAV capsid described in this document.

[0017] In some modalities, the genetic disorder, neurological disorder (e.g., neurodegenerative disorder), disorder associated with tau expression (e.g., aberrant tau expression) and / or tauopathy is Alzheimer's disease, frontotemporal dementia (FTD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration (FTLD), Dravet syndrome, neurodegenerative disease, traumatic brain injury (CTE), chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), Down syndrome, Pick's disease, corticobasal degeneration (CBD), corticobasal syndrome, amyotrophic lateral sclerosis (ALS), prion diseases, CJD, multiple system atrophy, mild cognitive impairment, tangled dementia, or progressive subcortical gliosis. Petition 870260044145, dated 11 / 05 / 2026, page 11 / 1140 7 / 530 Listed Modalities

[0018] 1. A short interfering ribonucleic acid (siRNA) to inhibit the expression of microtubule-associated tau protein (MAPT), comprising a sense strand sequence and an antisense strand sequence, wherein the antisense sequence is complementary to at least 15, 16, 17, 18, 19, 20 or 21 contiguous nucleotides comprising 0, 1, 2 or 3 mismatches of a MAPT sequence comprising the nucleotide sequence of SEQ ID NO: 5024 or a nucleotide sequence provided in Table 3 or 19.

[0019] 2. The siRNA of embodiment 1, wherein the antisense strand is complementary to at least 15, 16, 17, 18, 19, 20 or 21 contiguous nucleotides with 0, 1, 2 or 3 mismatches with an exon of a MAPT sequence, wherein the exon comprises nucleotides 1277 to 1332 of SEQ ID NO: 5024, nucleotides 1712-1977 of SEQ ID NO: 5024 or nucleotides 2266-6644 of SEQ ID NO: 5024.

[0020] 3. The siRNA of embodiment 1 or 2, in which the antisense strand is complementary to at least 15, 16, 17, or 18 contiguous nucleotides with 0, 1, 2, or 3 mismatches with nucleotides 1300-1317, 1305-1322, 1860-1877, 2279-2297, 2286-2303, 2402-2419, 2581-2958, 2584-2601, 2633-2650, or 2634-2653 of SEQ ID NO: 5024.

[0021] 4. The siRNA of any of the modalities 1-3, in which the sense tape comprises: (i) at least 15, 16, 17, 18, 19, 20 or 21 contiguous nucleotides comprising 0, 1, 2 or 3 mismatches of a MAPT sequence comprising the nucleotide sequence of SEQ ID NO: 5024 or a nucleotide sequence provided in Table 3 or 19; (ii) at least 15, 16, 17, 18, 19, 20 or 21 contiguous nucleotides with 0, 1, 2 or 3 mismatches with an exon of a MAPT sequence, wherein the exon comprises nucleotides 1277 to 1332 of SEQ ID NO: 5024, nucleotides 1712-1977 of SEQ ID NO: Petition 870260044145, dated 11 / 05 / 2026, p. 12 / 1140 8 / 530 5024 or nucleotides 2266-6644 of SEQ ID NO: 5024; or (iii) at least 15, 16, 17 or 18 contiguous nucleotides with 0, 1, 2 or 3 mismatches with nucleotides 1300-1317, 1305-1322, 1860-1877, 2279-2297, 2286-2303, 2402-2419, 2581-2958, 2584-2601, 2633-2650 or 2634-2653 of SEQ ID NO: 5024.

[0022] 5. The siRNA of any of the embodiments 1-4, in which the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, 21 contiguous nucleotides differing by 3, 2, 1 or 0 nucleotides from any of the antisense strand sequences provided in Tables 3, 4, 5, 9A or 9B.

[0023] 6. The siRNA of any of the embodiments 1-5, wherein the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, 21 contiguous nucleotides differing by 3, 2, 1 or 0 nucleotides from any of the sense strand sequences provided in Table 4, 5, 9A or 9B.

[0024] 7. The siRNA of any of the embodiments 1-6, in which the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, 21 contiguous nucleotides that differ by 3, 2, 1 or 0 nucleotides from any of the antisense strand sequences provided in Tables 3, 4, 5, 9A or 9B; and the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, 21 contiguous nucleotides that differ by 3, 2, 1, or 0 nucleotides from any of the sense strand sequences provided in Tables 3, 4, 5, 9A, or 9B, wherein the sense strand sequence and the antisense strand sequence comprise a complementarity region of at least 15 nucleotides.

[0025] 8. The siRNA of embodiment 7, in which the complementarity region is 15-30, 19-21, or 25-30 nucleotides long, for example, 17, 18, 20, 21, 22, 25, or 30 nucleotides long.

[0026] 9. The siRNA of any of embodiments 1-8, in which: (i) the antisense tape sequence comprises at least Petition 870260044145, dated 11 / 05 / 2026, page 13 / 1140 9 / 530 15, 16, 17, 18, or 19 contiguous nucleotides that differ by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4700 and the sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides that differ by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any of the SEQ ID NOs: 4502-4505; (ii) the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20 or 21 contiguous nucleotides that differ by 3, 2, 1 or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4920 and the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20 or 21 contiguous nucleotides that differ by 3, 2, 1 or 0 nucleotides from the nucleotide sequence of any of the SEQ ID NOs: 4918, 4938, 4958, 4978 or 4998; (iii) the antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides that differ by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4697 and the sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides that differ by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any of the SEQ ID NOs: 4495-4499; (iv) the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides that differ by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4908 and the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides that differ by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any of the SEQ ID NOs: 4906, 4926, 4946, 4966, 4986, or 5006; (v) the antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides that differ by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4690 and the sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides that differ by 3, 2, 1, or 0 nucleotides from Petition 870260044145, dated 11 / 05 / 2026, page 14 / 1140 10 / 530 nucleotide sequence of any of the SEQ IDs: 44804484; (vi) the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20 or 21 contiguous nucleotides that differ by 3, 2, 1 or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4924 and the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20 or 21 contiguous nucleotides that differ by 3, 2, 1 or 0 nucleotides from the nucleotide sequence of any of the SEQ ID NOs: 4922, 4942, 4962, 4982, 5002 or 5022; (vii) the antisense strand sequence comprises at least 15, 16, 17, 18 or 19 contiguous nucleotides differing by 3, 2, 1 or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4694 and the sense strand sequence comprises at least 15, 16, 17, 18 or 19 contiguous nucleotides differing by 3, 2, 1 or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4492; (viii) the antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides that differ by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4691 and the sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides that differ by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any of the SEQ ID NOs: 4485-4489; (ix) the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides that differ by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4916 and the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides that differ by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any of the SEQ ID NOs: 4914, 4934, 4954, 4974, 4994, or 5014; (x) the antisense strand sequence comprises at least 15, 16, 17, 18 or 19 contiguous nucleotides that differ by 3, 2, 1 or Petition 870260044145, dated 11 / 05 / 2026, page 15 / 1140 11 / 530 nucleotides of the nucleotide sequence of SEQ ID NO: 4701 and the sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides that differ by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any of the SEQ ID NOs: 4506-4510; (xi) the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20 or 21 contiguous nucleotides that differ by 3, 2, 1 or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4912 and the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20 or 21 contiguous nucleotides that differ by 3, 2, 1 or 0 nucleotides from the nucleotide sequence of any of the SEQ ID NOs: 4910, 4930, 4950, 4970, 4990 or 5010; (xii) the antisense strand sequence comprises at least 15, 16, 17, 18 or 19 contiguous nucleotides differing by 3, 2, 1 or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4687 and the sense strand sequence comprises at least 15, 16, 17, 18 or 19 contiguous nucleotides differing by 3, 2, 1 or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4477; (xiii) the antisense strand sequence comprises at least 15, 16, 17, 18 or 19 contiguous nucleotides that differ by 3, 2, 1 or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4712 and the sense strand sequence comprises at least 15, 16, 17, 18 or 19 contiguous nucleotides that differ by 3, 2, 1 or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4521; (xiv) the antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4696 and the sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4494; or (xv) the antisense strand sequence comprises at least Petition 870260044145, dated 11 / 05 / 2026, page 16 / 1140 12 / 530 15, 16, 17, 18 or 19 contiguous nucleotides differing by 3, 2, 1 or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4718 and the sense strand sequence comprises at least 15, 16, 17, 18 or 19 contiguous nucleotides differing by 3, 2, 1 or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4527.

[0027] 10. The siRNA of any of claims 1-9, wherein: (i) the antisense strand sequence comprises at least 15, 16, 17, 18 or 19 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4700 and the sense strand sequence comprises at least 15, 16, 17, 18 or 19 contiguous nucleotides of the nucleotide sequence of any of the SEQ ID NOs: 4502-4505; (ii) the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20 or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4920 and the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20 or 21 contiguous nucleotides that differ from the nucleotide sequence of any of the SEQ ID NOs: 4918, 4938, 4958, 4978 or 4998; (iii) the antisense strand sequence comprises at least 15, 16, 17, 18 or 19 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4697 and the sense strand sequence comprises at least 15, 16, 17, 18 or 19 contiguous nucleotides of the nucleotide sequence of any of the SEQ ID NOs: 4495-4499; (iv) the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4908 and the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of any of the SEQ ID NOs: 4906, 4926, 4946, 4966, 4986 or 5006; (v) the antisense tape sequence comprises at least Petition 870260044145, dated 11 / 05 / 2026, page 17 / 1140 13 / 530 15, 16, 17, 18, or 19 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4690 and the sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides of the nucleotide sequence of any of the SEQ ID NOs: 4480-4484; (vi) the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4924 and the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of any of the SEQ ID NOs: 4922, 4942, 4962, 4982, 5002 or 5022; (vii) the antisense strand sequence comprises at least 15, 16, 17, 18 or 19 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4694 and the sense strand sequence comprises at least 15, 16, 17, 18 or 19 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4492; (viii) the antisense strand sequence comprises at least 15, 16, 17, 18 or 19 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4691 and the sense strand sequence comprises at least 15, 16, 17, 18 or 19 contiguous nucleotides of the nucleotide sequence of any of the SEQ ID NOs: 4485-4489; (ix) the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4916 and the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of any of the SEQ ID NOs: 4914, 4934, 4954, 4974, 4994 or 5014; (x) the antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4701 and the sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides of the sequence of Petition 870260044145, dated 11 / 05 / 2026, page 18 / 1140 14 / 530 nucleotides of any of the following SEQ IDs: 4506-4510; (xi) the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4912 and the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of any of the SEQ ID NOs: 4910, 4930, 4950, 4970, 4990 or 5010; (xii) the antisense strand sequence comprises at least 15, 16, 17, 18 or 19 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4687 and the sense strand sequence comprises at least 15, 16, 17, 18 or 19 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4477; (xiii) the antisense strand sequence comprises at least 15, 16, 17, 18 or 19 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4712 and the sense strand sequence comprises at least 15, 16, 17, 18 or 19 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4521; (xiv) the antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4696 and the sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4494; or (xv) the antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4718 and the sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4527. 11. A short interfering ribonucleic acid (siRNA) to inhibit microtubule-associated tau protein (MAPT) expression, characterized in that it comprises a sense strand sequence and Petition 870260044145, dated 11 / 05 / 2026, page 19 / 1140 15 / 530 a nonsensical tape sequence, in which: (i) the antisense strand sequence comprises at least 20 or 21 contiguous nucleotides of any of the following SEQ ID NOs: 4908, 4920, 4924, 5057, 4916, 4912, 5080, 5104, or 5128; and (ii) the sense strand sequence comprises at least 20 or 21 contiguous nucleotides of any of the following SEQ ID NOs: 4906, 4926, 4946, 4966, 4986, 5006, 4918, 4938, 4958, 4978, 4998, 4922, 4942, 4962, 4982, 5002, 5022, 5054, 5060, 5064, 5066, 5070, 5074, 4914, 4934, 4954, 4974, 4994, 5014, 4910, 4930, 4950, 4970, 4990, 5010, 5077, 5084, 5088, 5092, 5096, 5098, 5101, 5108, 5112, 5116, 5120, 5122, 5125, 5132, 5136, 5140, 5144, or 5146; wherein the sense strand sequence and the antisense strand sequence comprise a region of complementarity of at least 15 nucleotides.

[0028] 12. An adeno-associated virus (AAV) viral genome comprising a nucleotide sequence positioned between two inverted terminal repeats (ITRs), wherein the nucleotide sequence encodes a MAPT-inhibiting siRNA, wherein the siRNA comprises a sense strand sequence and an antisense strand sequence, wherein: (i) the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of any of the following SEQ ID NOs: 4908, 4920, 4924, 5057, 4916, 4912, 5080, 5104, or 5128; and (ii) the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of any of the following SEQ ID NOs: 4906, 4926, 4946, 4966, 4986, 5006, 4918, 4938, 4958, 4978, 4998, 4922, 4942, 4962, 4982, 5002, 5022, 5054, 5060, 5064, 5066, 5070, 5074, 4914, 4934, 4954, 4974, 4994, 5014, 4910, 4930, 4950, 4970, 4990, 5010, 5077, 5084, 5088, 5092, 5096, 5098, 5101, 5108, 5112, 5116, 5120, 5122, 5125, 5132, 5136, 5140, 5144, or 5146; Petition 870260044145, dated 11 / 05 / 2026, p. 20 / 1140 16 / 530 wherein the sense strand sequence and the antisense strand sequence comprise a complementarity region of at least 15 nucleotides.

[0029] 13. The siRNA of any of the embodiments 8-11 or the AAV viral genome of embodiment 12, in which the complementarity region comprises at least 18, 19 or 20 nucleotides.

[0030] 14. The siRNA of any of the embodiments 1-10 or the AAV viral genome of embodiment 12 or 13, wherein the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of any of the SEQ ID NOs: 4908, 4920, 4924 or 4912.

[0031] 15. The siRNA of any of embodiments 1-10 or the AAV viral genome of any of embodiments 12-14, wherein the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of any of the following SEQ ID NOs: 4906, 4926, 4946, 4966, 4986, 5006, 4918, 4938, 4958, 4978, 4998, 4922, 4942, 4962, 4982, 5002, 5022, 4910, 4930, 4950, 4970, 4990, or 5010.

[0032] 16. The siRNA of any of the embodiments 1-10 or the AAV viral genome of any of the embodiments 12-15, where: (i) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4908 and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of any of the SEQ ID NOs: 4906, 4926, 4946, 4966, 4986 or 5006; (ii) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4920 and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of any of the SEQ ID NOs: 4918, 4938, 4958, 4978 or 4998; (iii) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of Petition 870260044145, dated 11 / 05 / 2026, page 21 / 1140 17 / 530 SEQ ID NO: 4924 and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from any of the SEQ ID NOs: 4922, 4942, 4962, 4982, 5002, or 5022; (iv) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4912 and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of any of the SEQ ID NOs: 4910, 4930, 4950, 4970, 4990 or 5010; (v) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4916 and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of any of the SEQ ID NOs: 4914, 4934, 4954, 4974, 4994 or 5014; (vi) the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of any of the SEQ ID NOs: 5101, 5108, 5112, 5116, 5120, or 5122; (vii) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of any of the SEQ ID NOs: 5125, 5132, 5136, 5140, 5144 or 5146; (viii) the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of any of the SEQ ID NOs: 5077, 5084, 5088, 5092, 5096, or 5098; ​​or (ix) the antisense strand sequence comprises at least Petition 870260044145, dated 11 / 05 / 2026, page 22 / 1140 18 / 530 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of any of the SEQ ID NOs: 5054, 5060, 5064, 5066, 5070, or 5074.

[0033] 17. The siRNA of any of the embodiments 1-10 or the AAV viral genome of any of the embodiments 12 to 16, wherein the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4908 and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4906.

[0034] 18. The siRNA of any of embodiments 1-10 or the AAV viral genome of any of embodiments 12-16, wherein the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4920 and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4918.

[0035] 19. The siRNA of any embodiment 1-10 or the AAV viral genome of any embodiment 12-16, wherein the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4924 and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4922.

[0036] 20. The siRNA of any embodiment 1-10 or the AAV viral genome of any embodiment 12 to 16, wherein the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4908 and the sense strand sequence comprises at least 19, 20, or 21 Petition 870260044145, dated 11 / 05 / 2026, p. 23 / 1140 19 / 530 contiguous nucleotides of the nucleotide sequence SEQ ID NO: 4966.

[0037] 21. The siRNA of any of embodiments 1-10 or the AAV viral genome of any of embodiments 12-16, wherein the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4912 and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4970.

[0038] 22. The siRNA of any embodiment 1-10 or the AAV viral genome of any embodiment 12-16, wherein the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4920 and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4978.

[0039] 23. The siRNA of any embodiment 1-10 or the AAV viral genome of any embodiment 12-16, wherein the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4924 and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4982.

[0040] 24. The siRNA of any of the embodiments 1-10 or the AAV viral genome of any of the embodiments 12-16, where: (i) the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4910; Petition 870260044145, dated 11 / 05 / 2026, page 24 / 1140 20 / 530 (ii) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4914; (iii) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5054; (iv) the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4908; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4926; (v) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4930; (vi) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4934; (vii) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4938; Petition 870260044145, dated 11 / 05 / 2026, page 25 / 1140 21 / 530 (viii) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4924; and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4942; (ix) the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5060; (x) the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4908; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4946; (xi) the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4950; (xii) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4954; (xiii) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4958; Petition 870260044145, dated 11 / 05 / 2026, page 26 / 1140 22 / 530 (xiv) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4924; and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4962; (xv) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5064; (xvi) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4974; (xvii) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5066; (xviii) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4908; and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4986; (xix) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4990; Petition 870260044145, dated 11 / 05 / 2026, page 27 / 1140 23 / 530 (xx) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4994; (xxi) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4998; (xxii) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4924; and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5002; (xxiii) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5070; (xxiv) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4908; and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5006; (xxv) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5010; Petition 870260044145, dated 11 / 05 / 2026, page 28 / 1140 24 / 530 (xxvi) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5014; (xxvii) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4958; (xxviii) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4924; and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5022; (xxvii) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5074; (xxix) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5077; (xxx) the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5084; Petition 870260044145, dated 11 / 05 / 2026, page 29 / 1140 25 / 530 (xxxi) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5088; (xxxii) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5092; (xxxiii) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5096; (xxxiv) the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5098; (xxxv) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5101; (xxxvi) the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5108; Petition 870260044145, dated 11 / 05 / 2026, page 30 / 1140 26 / 530 (xxxvii) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5112; (xxxviii) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5116; (xxxix) the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5120; (xl) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5122; (xli) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5125; (xlii) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5132; Petition 870260044145, dated 11 / 05 / 2026, page 31 / 1140 27 / 530 (xliii) the antisense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5136; (xliv) the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5140; (xlv) the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5144; or (xlvi) the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5146.

[0041] 25. The siRNA of any of embodiments 1-11 or 13 or the AAV viral genome of any of embodiments 12-24, wherein the antisense strand sequence comprises at least 20 contiguous nucleotides of any of the SEQ ID NOs: 4908, 4920, 4924 or 4912.

[0042] 26. The siRNA of any of embodiments 1-11, 13 or the AAV viral genome of any of embodiments 12-25, wherein the sense strand sequence comprises at least 20 contiguous nucleotides of any of the following SEQ ID NOs: 4906, 4926, 4946, 4966, 4986, 5006, 4918, 4938, 4958, 4978, 4998, 4922, 4942, 4962, 4982, Petition 870260044145, dated 11 / 05 / 2026, p. 32 / 1140 28 / 530 5002, 5022, 4910, 4930, 4950, 4970, 4990 or 5010.

[0043] 27. The siRNA of any of the embodiments 1-11, 13, 25 or 26 or the AAV viral genome of any of the embodiments 12-26, where: (i) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4908 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any of the SEQ ID NOs: 4906, 4926, 4946, 4966, 4986, or 5006; (ii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4920 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any of the SEQ ID NOs: 4918, 4938, 4958, 4978 or 4998; (iii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4924 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any of the SEQ ID NOs: 4922, 4942, 4962, 4982, 5002, or 5022; (iv) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4912 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any of the SEQ ID NOs: 4910, 4930, 4950, 4970, 4990, or 5010; (v) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4916 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any of the SEQ ID NOs: 4914, 4934, 4954, 4974, 4994 or 5014; (vi) the nonsense tape sequence comprises at least Petition 870260044145, dated 11 / 05 / 2026, page 33 / 1140 29 / 530 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of any of the SEQ ID NOs: 5101, 5108, 5112, 5116, 5120 or 5122; (vii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any of the SEQ ID NOs: 5125, 5132, 5136, 5140, 5144 or 5146; (viii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any of the SEQ ID NOs: 5077, 5084, 5088, 5092, 5096 or 5098; ​​or (ix) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5057 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any of the SEQ ID NOs: 5054, 5060, 5064, 5066, 5070 or 5074.

[0044] 28. The siRNA of any of the modalities 1-11, 13 or 25-27 or the AAV viral genome of either embodiment 11-17 or 25-27, wherein the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4908 and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4906.

[0045] 29. The siRNA of any of the modalities 1-11, 13 or 25-27 or the AAV viral genome of any of the embodiments 11-16, 18, or 25-27, wherein the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of Petition 870260044145, dated 11 / 05 / 2026, p. 34 / 1140 30 / 530 SEQ ID NO: 4920 and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4918.

[0046] 30. The siRNA of any of the modalities 1-11, 13 or 25-27 or the AAV viral genome of any of the embodiments 11-16, 19, or 25-27, wherein the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4924 and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4922.

[0047] 31. The siRNA of any of the modalities 1-11, 13 or 25-27 or the AAV viral genome of any of the embodiments 11-16, 20, or 25-27, wherein the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4908 and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4966.

[0048] 32. The siRNA of any of the modalities 1-11, 13 or 25-27 or the AAV viral genome of any of the embodiments 11-16, 21, or 25-27, wherein the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4912 and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4970.

[0049] 33. The siRNA of any of the modalities 1-11, 13 or 25-27 or the AAV viral genome of any of the embodiments 11-16, 22, or 25-27, wherein the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4920 and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID Petition 870260044145, dated 11 / 05 / 2026, p. 35 / 1140 31 / 530 NO: 4978.

[0050] 34. The siRNA of any of the modalities 1-11, 13 or 25-27 or the AAV viral genome of any of the embodiments 11-16, 23, or 25-27, wherein the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4924 and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4982.

[0051] 35. The siRNA of any of the modalities 1-11, 13 or 25-27 or the AAV viral genome of either 11-16 or 24-27 modalities, where: (i) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4910; (iii) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4914; (iii) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5054; (iv) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4908; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: Petition 870260044145, dated 11 / 05 / 2026, page 36 / 1140 32 / 530 4926; (v) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4930; (vi) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4934; (vii) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4938; (vii i) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4924; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4942; (ix) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5060; (x) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4908; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: Petition 870260044145, dated 11 / 05 / 2026, page 37 / 1140 33 / 530 4946; (xi) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4950; (xii) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4954; (xiii) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4958; (xiv) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4924; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4962; (xv) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5064; (xvi) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: Petition 870260044145, dated 11 / 05 / 2026, page 38 / 1140 34 / 530 4974; (xvii) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5066; (xvii i) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4908; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4986; (xix) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4990; (xx) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4994; (xxi) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4998; (xxii) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4924; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: Petition 870260044145, dated 11 / 05 / 2026, page 39 / 1140 35 / 530 5002; (xxiii) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5070; (xxiv) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4908; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5006; (xxv) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5010; (xxvi) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5014; (xxvii) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4958; (xxvii i) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4924; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: Petition 870260044145, dated 11 / 05 / 2026, page 40 / 1140 36 / 530 5022; (xxvii) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5074; (xxix) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5077; (xxx) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5084; (xxxi) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5088; (xxxii) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5092; (xxxiii) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: Petition 870260044145, dated 11 / 05 / 2026, page 41 / 1140 37 / 530 5096; (xxxiv) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5098; (xxxv) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5101; (xxxvi) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5108; (xxxvii) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5112; (xxxvii i) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5116; (xxx ix) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: Petition 870260044145, dated 11 / 05 / 2026, page 42 / 1140 38 / 530 5120; (xl) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5122; (xli) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5125; (xlii) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5132; (xliii) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5136; (xliv) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5140; (xlv) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: Petition 870260044145, dated 11 / 05 / 2026, page 43 / 1140 39 / 530 5144; or (xlvi) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence SEQ ID NO: 5128; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5146.

[0052] 36. The siRNA of any of the modalities 1-11, 13 or 25-35 or the AAV viral genome of any of the 12-35 embodiments, wherein the antisense strand sequence comprises the nucleotide sequence of any of the SEQ ID NOs: 4908, 4920, 4924 or 4912.

[0053] 37. The siRNA of any of the modalities 1-11, 13 or 25-36 or the AAV viral genome of any of the embodiments 12-36, wherein the sense strand sequence comprises the nucleotide sequence of any of the SEQ ID NOs: 4906, 4926, 4946, 4966, 4986, 5006, 4918, 4938, 4958, 4978, 4998, 4922, 4942, 4962, 4982, 5002, 5022, 4910, 4930, 4950, 4970, 4990 or 5010.

[0054] 38. The siRNA of any of the modalities 1-11, 13 or 25-37 or the AAV viral genome of any of the modalities 12-37, where: (i) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908 and the sense strand sequence comprises the nucleotide sequence of any of the SEQ ID NOs: 4906, 4926, 4946, 4966, 4986 or 5006; (ii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920 and the sense strand sequence comprises the nucleotide sequence of any of the SEQ ID NOs: 4918, 4938, 4958, 4978 or 4998; (iii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924 and the sense strand sequence Petition 870260044145, dated 11 / 05 / 2026, p. 44 / 1140 40 / 530 comprises the nucleotide sequence of any of the following SEQ ID numbers: 4922, 4942, 4962, 4982, 5002 or 5022; (iv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912 and the sense strand sequence comprises the nucleotide sequence of any of the SEQ ID NOs: 4910, 4930, 4950, 4970, 4990 or 5010; (v) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916 and the sense strand sequence comprises the nucleotide sequence of any of the SEQ ID NOs: 4914, 4934, 4954, 4974, 4994 or 5014; (vi) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises the nucleotide sequence of any of the SEQ ID NOs: 5101, 5108, 5112, 5116, 5120 or 5122; (vii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises the nucleotide sequence of any of the SEQ ID NOs: 5125, 5132, 5136, 5140, 5144 or 5146; (viii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises the nucleotide sequence of any of the SEQ ID NOs: 5077, 5084, 5088, 5092, 5096 or 5098; ​​or (ix) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises the nucleotide sequence of any of the SEQ ID NOs: 5054, 5060, 5064, 5066, 5070 or 5074.

[0055] 39. The siRNA of any of the embodiments 1-11, 13, 25-28 or 36-39 or the AAV viral genome of any of the embodiments 11-17, 25-28 or 36-39, wherein the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908 and the sequence Petition 870260044145, dated 11 / 05 / 2026, p. 45 / 1140 41 / 530 of the sense strand comprises the nucleotide sequence of SEQ ID NO: 4906.

[0056] 40. The siRNA of any of the modalities 1-11, 13, 25- 27, 29 or 36-39 or the AAV viral genome of any of the embodiments 11-16, 18, 25-27, 29 or 36-39, wherein the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4918.

[0057] 41. The siRNA of any of the modalities 1-11, 13, 25- 27, 30 or 36-39 or the AAV viral genome of any of the embodiments 11-16, 19, 25-27, 30 or 36-39, wherein the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4922.

[0058] 42. The siRNA of any of the modalities 1-11, 13, 25- 27, 31 or 36-39 or the AAV viral genome of any of the embodiments 11-16, 19, 25-27, 31 or 36-39, wherein the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4966.

[0059] 43. The siRNA of any of the modalities 1-11, 13, 25- 27, 32 or 36-39 or the AAV viral genome of any of the embodiments 11-16, 19, 25-27, 62 or 36-39, wherein the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4970.

[0060] 44. The siRNA of any of the modalities 1-11, 13, 25- 27, 33 or 36-39 or the AAV viral genome of any of the embodiments 11-16, 19, 25-27, 33 or 36-39, wherein the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920 Petition 870260044145, dated 11 / 05 / 2026, p. 46 / 1140 42 / 530 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4978.

[0061] 45. The siRNA of any of the modalities 1-11, 13, 25- 27, 34 or 36-39 or the AAV viral genome of any of the embodiments 11-16, 19, 25-27, 34 or 36-39, wherein the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4982.

[0062] 46. The siRNA of any of the modalities 1-11, 13, 25- 27, 35 or 36-39 or the AAV viral genome of any of the modalities 11-16, 19, 25-27, 35 or 36-39, where: (i) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4910; (ii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4914; (iii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5054; (iv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4926; (v) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4930; (vi) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4934; (vii) the antisense tape sequence comprises the sequence Petition 870260044145, dated 11 / 05 / 2026, page 47 / 1140 43 / 530 of the nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4938; (viii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4942; (ix) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5060; (x) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4946; (xi) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4950; (xii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4954; (xiii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4958; (xiv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4962; (xv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5064; (xvi) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4974; (xvii) the nonsense tape sequence comprises the Petition 870260044145, dated 11 / 05 / 2026, page 48 / 1140 44 / 530 nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5066; (xviii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4986; (xix) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4990; (xx) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4994; (xxi) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4998; (xxii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5002; (xxiii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5070; (xxiv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5006; (xxv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5010; (xxvi) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5014; (xxvii) the antisense tape sequence comprises the Petition 870260044145, dated 11 / 05 / 2026, page 49 / 1140 45 / 530 nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4958; (xxviii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5022; (xxvii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5074; (xxix) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5077; (xxx) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5084; (xxxi) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5088; (xxxii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5092; (xxxiii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5096; (xxxiv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5098; (xxxv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5101; (xxxvi) the nonsense tape sequence comprises the Petition 870260044145, dated 11 / 05 / 2026, page 50 / 1140 46 / 530 nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5108; (xxxvii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5112; (xxxviii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5116; (xxxix) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5120; (xl) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5122; (xli) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5125; (xlii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5132; (xliii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5136; (xlv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5140; (xliv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5144; or (xlvi) the antisense strand sequence comprises the Petition 870260044145, dated 11 / 05 / 2026, page 51 / 1140 47 / 530 nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5146.

[0063] 47. The siRNA of any of the embodiments 1-11 or 1346 or the AAV viral genome of any of the embodiments 12-46, where: (i) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4700 and the sense strand sequence comprises the nucleotide sequence of any of the SEQ ID NOs: 4502-4505; (ii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920 and the sense strand sequence comprises the nucleotide sequence of any of the SEQ ID NOs: 4918, 4938, 4958, 4978 or 4998; (iii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4697 and the sense strand sequence comprises the nucleotide sequence of any of the SEQ ID NOs: 4495-4499; (iv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908 and the sense strand sequence comprises the nucleotide sequence of any of the SEQ ID NOs: 4906, 4926, 4946, 4966, 4986 or 5006; (v) the antisense strand sequence comprises at least 15, 16, 17, 18 or 19 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4690 and the sense strand sequence comprises at least 15, 16, 17, 18 or 19 contiguous nucleotides of the nucleotide sequence of any of the SEQ ID NOs: 4480-4484; (vi) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924 and the sense strand sequence comprises the nucleotide sequence of any of the SEQ ID NOs: 4922, 4942, 4962, 4982, 5002 or 5022; Petition 870260044145, dated 11 / 05 / 2026, page 52 / 1140 48 / 530 (vii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4694 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4492; (viii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4691 and the sense strand sequence comprises the nucleotide sequence of any of the SEQ ID NOs: 4485-4489; (ix) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916 and the sense strand sequence comprises the nucleotide sequence of any of the SEQ ID NOs: 4914, 4934, 4954, 4974, 4994 or 5014; (x) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4701 and the sense strand sequence comprises the nucleotide sequence of any of the SEQ ID NOs: 4506-4510; (xi) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912 and the sense strand sequence comprises the nucleotide sequence of any of the SEQ ID NOs: 4910, 4930, 4950, 4970, 4990 or 5010; (xii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4687; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4477; (xiii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4712; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4521; (xiv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4696; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4494; or (xv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4718; and the sense strand sequence Petition 870260044145, dated 11 / 05 / 2026, p. 53 / 1140 49 / 530 comprises the nucleotide sequence of SEQ ID NO: 4527.

[0064] 48. The siRNA of any of the embodiments 1-11 or 1347 or the AAV viral genome of any of the embodiments 12-47, where: (i) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4420 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4434; (ii) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4905 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4907; (iii) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4421 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4435; (iv) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4909 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4911; (v) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4422 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4436; (vi) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4913 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4915; (vii) the nucleotide sequence that codes for the sequence Petition 870260044145, dated 11 / 05 / 2026, page 54 / 1140 The 50 / 530 sense strand comprises the nucleotide sequence of SEQ ID NO: 4423, and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4437. (viii) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4917 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4919; (ix) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4424 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4438; (x) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4921 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4923; (xi) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4410 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4434; (xii) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4925 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4907; (xiii) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4411 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4435; ((xiv) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4929 and the nucleotide sequence encoding the antisense strand Petition 870260044145, dated 11 / 05 / 2026, page 55 / 1140 51 / 530 comprises the nucleotide sequence of SEQ ID NO: 4911; (xv) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4412 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4436; (xvi) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4933 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4915; (xvii) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4413 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4437; (xviii) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4937 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4419; (xix) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4414 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4438; (xx) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4941 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4923; (xxi) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4415 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4434; (xxii) the nucleotide sequence that codes for the sequence Petition 870260044145, dated 11 / 05 / 2026, page 56 / 1140 The 52 / 530 sense strand comprises the nucleotide sequence of SEQ ID NO: 4945, and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4907. (xxiii) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4416 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4435; (xxiv) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4949 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4911; (xxv) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4417 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4436; (xxvi) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4953 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4915; (xxvii) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4418 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4437; (xxviii) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4957 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4919; (xxix) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4419 and the nucleotide sequence encoding the antisense strand Petition 870260044145, dated 11 / 05 / 2026, page 57 / 1140 53 / 530 comprises the nucleotide sequence of SEQ ID NO: 4438; (xxx) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4961 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4923; (xxxi) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4420 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4434; (xxxii) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4965 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4907; (xxxii) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4421 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4435; (xxxiii) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4969 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4911; (xxxiv) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4422 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4436; (xxxv) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4973 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4915; (xxvi) the nucleotide sequence that codes for the sequence Petition 870260044145, dated 11 / 05 / 2026, page 58 / 1140 The 54 / 530 sense strand comprises the nucleotide sequence of SEQ ID NO: 4423, and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4437. (xxvii) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4977 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4919; (xxxvii i) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4424 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4438; (xxx ix) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4981 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4923; (xl) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4425 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4434; (xli) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4985 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4907; (xlii) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4426 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4435; (xliii) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4989 and the nucleotide sequence encoding the antisense strand Petition 870260044145, dated 11 / 05 / 2026, page 59 / 1140 55 / 530 comprises the nucleotide sequence of SEQ ID NO: 4911; (xliv) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4427 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4436; (xlv) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4993 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4915; (xlvi) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4428 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4437; (xlvii) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4997 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4919; (xlviii) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4429 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4438; (xlix) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 5001 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4923; (l) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4430 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4434; (li) the nucleotide sequence that codes for the sequence of Petition 870260044145, dated 11 / 05 / 2026, pp. 60 / 1140 The 56 / 530 sense strand comprises the nucleotide sequence of SEQ ID NO: 5005 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4907; (lii) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4431 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4435; (liii) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 5009 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4911; (liv) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4432 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4436; (lv) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 5013 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4915; (lvi) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4433 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4438; (lvii) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 5021 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4923; (lviii) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5053 and the nucleotide sequence encoding the antisense strand Petition 870260044145, dated 11 / 05 / 2026, page 61 / 1140 57 / 530 comprises the nucleotide sequence of SEQ ID NO: 5056; (lix) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 5059 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5056; (lx) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 5063 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5056; (lxi) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 5065 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5056; (lxii) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 5069 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5056; (lxiii) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 5073 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5056; (lxiv) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 5076 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5079; (lxv) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 5083 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5079; (lxvi) the nucleotide sequence that codes for the sequence Petition 870260044145, dated 11 / 05 / 2026, page 62 / 1140 The 58 / 530 sense strand comprises the nucleotide sequence of SEQ ID NO: 5087, and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5079. (lxvii) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 5091 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5079; (lxviii) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 5095 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5079; (lxix) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 5097 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5079; (lxx) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 5100 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5103; (lxxi) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 5107 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5103; (lxxii) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 5111 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5103; (lxxiii) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5115 and the nucleotide sequence encoding the antisense strand Petition 870260044145, dated 11 / 05 / 2026, page 63 / 1140 59 / 530 comprises the nucleotide sequence of SEQ ID NO: 5103; (Ixxiv) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 5119 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5103; (lxxv) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 5121 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5103; (lxxvi) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 5124 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5127; (lxxvii) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 5131 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5127; (lxxviii) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 5135 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5127; (lxxix) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 5139 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5127; (lxxx) the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 5143 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5127; or (lxxxi) the nucleotide sequence encoding the sequence Petition 870260044145, dated 11 / 05 / 2026, page 64 / 1140 The 60 / 530 sense strand comprises the nucleotide sequence of SEQ ID NO: 5145, and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5127.

[0065] 49. The siRNA of any of the embodiments 1-11, 13, 25-28, 36-39, 47 or 48, or the AAV viral genome of any of the embodiments 11-17, 25-28, 36-39 or 47 or 48, wherein the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4907 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4905.

[0066] 50. The siRNA of any of the embodiments 1-11, 13, 25-27, 29, 36-39, 47 or 48 or the AAV viral genome of any of the embodiments 11-16, 18, 25-27, 29, 36-39, 47 or 48, wherein the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4919 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4917.

[0067] 51. The siRNA of any of the embodiments 1-11, 13, 25-27, 30, 36-39, 47 or 48 or the AAV viral genome of any of the embodiments 11-16, 19, 25-27, 30, 36-39, 47 or 48, wherein the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4923 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4921.

[0068] 52. The siRNA of any of embodiments 1-11, 13, 25-27, 31, 36-39, 47 or 48 or the AAV viral genome of any of embodiments 11-16, 19, 25-27, 31, 36-39, 47 or 48, wherein the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4907 and the nucleotide sequence encoding the sense strand sequence comprises the Petition 870260044145, dated 11 / 05 / 2026, p. 65 / 1140 61 / 530 nucleotide sequence of SEQ ID NO: 4965.

[0069] 53. The siRNA of any of the embodiments 1-11, 13, 25-27, 32, 36-39, 47 or 48 or the AAV viral genome of any of the embodiments 11-16, 19, 25-27, 62, 36-39, 47 or 48, wherein the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4911 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4969.

[0070] 54. The siRNA of any of the embodiments 1-11, 13, 25-27, 33, 36-39, 47 or 48 or the AAV viral genome of any of the embodiments 11-16, 19, 25-27, 33, 36-39, 47 or 48, wherein the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4919 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4977.

[0071] 55. The siRNA of any of the embodiments 1-11, 13, 25-27, 34, 36-39, 47 or 48 or the AAV viral genome of any of the embodiments 11-16, 19, 25-27, 34, 36-39, 47 or 48, wherein the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4923 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4981.

[0072] 56. The siRNA of any embodiment 1-11 or 1355, or the AAV viral genome of any embodiment 12-55, wherein the sense strand sequence, the antisense strand sequence, or both the sense strand sequence and the antisense strand sequence, comprise at least 15-30, 19-21 or 25-30 nucleotides in length, for example, 17, 18, 20, 21, 22, 25 or 30 nucleotides in length.

[0073] 57. The siRNA of any of the modalities 1-11 or 13 Petition 870260044145, of 11 / 05 / 2026, p. 66 / 1140 62 / 530 or the AAV viral genome of any of the embodiments 12-56, wherein the sense strand sequence, the antisense strand sequence, or both the sense strand sequence and the antisense strand sequence, comprise an overhang, for example, an overhang at the 5' end of the sense strand sequence and / or at the 3' end of the antisense strand sequence, of 1 or 2 nucleotides.

[0074] 58. The siRNA of any of the embodiments 1-11 or 1357 or the AAV viral genome of any of the embodiments 12-57, where: (i) the sense tape and the antisense tape comprise an incompatibility; and / or (ii) the antisense tape and the target sequence comprise an incompatibility.

[0075] 59. A modulating polynucleotide comprising siRNA of either embodiment 1-12 or 13-58.

[0076] 60. The AAV viral genome of any of the modalities 13-58, in which the nucleotide sequence further encodes a modulating polynucleotide comprising the sense strand sequence and the antisense strand sequence.

[0077] 61. The modulating polynucleotide of modality 59, or the AAV viral genome of modality 60, wherein the modulating polynucleotide further comprises one, two, three, or all of the following: (i) a flanking region 5'; (ii) a loop region; and (iii) a flanking region 3'.

[0078] 62. The modulating polynucleotide of modality 61, or the AAV viral genome of modality 61, wherein: (i) the 5' flanking region comprises the nucleotide sequence of any of the SEQ ID NOs: 4878-4886; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% Petition 870260044145, dated 11 / 05 / 2026, page 67 / 1140 63 / 530 96%, 97%, 98%, 99% identical to it; a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of any of the SEQ ID NOs: 4878-4886; or a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from the nucleotide sequence of any of the SEQ ID NOs: 4878-4886; (ii) the loop region comprises the nucleotide sequence of any of the SEQ ID NOs: 4887-4896; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to it; a nucleotide sequence comprising one, two, three or four, but not more than five nucleotides different from the nucleotide sequence of any of the SEQ ID NOs: 4887-4896; or a nucleotide sequence comprising one, two, three or four, but not more than five modifications from the nucleotide sequence of any of the SEQ ID NOs: 4887-4896; and / or (iii) the 3' flanking region comprises the nucleotide sequence of any of the SEQ ID NOs: 4897-4904; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to it;a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications with respect to the nucleotide sequence of any of the SEQ ID Nos: 4897-4904; or a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications with respect to the nucleotide sequence of any of the SEQ ID Nos: 4897-4904.

[0079] 63. The modulating polynucleotide of modality 61 or 62 or the AAV viral genome of modality 61 or 62, where: (i) the nucleotide sequence that codes for the region of Petition 870260044145, dated 11 / 05 / 2026, p. 68 / 1140 64 / 530 5' flanking comprises the nucleotide sequence of any of the SEQ ID NOs: 4353-4361, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to it; a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of any of the SEQ ID NOs: 4353-4361; or a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from the nucleotide sequence of any of the SEQ ID NOs: 4353-4361; (ii) the nucleotide sequence encoding the loop region comprises the nucleotide sequence of any of the SEQ ID NOs: 4362-4371; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to it; a nucleotide sequence comprising one, two, three or four, but not more than five nucleotides different from the nucleotide sequence of any of the SEQ ID NOs: 4362-4371; or a nucleotide sequence comprising one, two, three or four, but not more than five modifications from the nucleotide sequence of any of the SEQ ID NOs: 4362-4371; and / or (iii) the nucleotide sequence encoding the 3' flanking region comprises the nucleotide sequence of any of the SEQ ID NOs: 4372-4379; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to it;a nucleotide sequence comprising one, two, three, four, five, six, or seven, but not more than ten nucleotides different from the nucleotide sequence of any of the SEQ ID Nos: 4372-4379; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but not more than ten modifications from the nucleotide sequence of; Petition 870260044145, dated 11 / 05 / 2026, p. 69 / 1140 65 / 530 any of the SEQ ID Nos: 4372-4379.

[0080] 64. The modulating polynucleotide of either embodiment 59 or 61-63 or the AAV viral genome of either embodiment 60-63, wherein the modulating polynucleotide comprises: (i) a 5' flanking region comprising the nucleotide sequence of SEQ ID NO: 4879, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4879, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4879; or a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4879; (ii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4887, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4887, a nucleotide sequence comprising one, two, three or four, but not more than five nucleotides different from the nucleotide sequence of SEQ ID NO: 4887; or a nucleotide sequence comprising one, two, three or four, but not more than five nucleotides different from the nucleotide sequence of SEQ ID NO: 4887;and (iii) a 3' flanking region of SEQ ID NO: 4898, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six or; Petition 870260044145, dated 11 / 05 / 2026, pp. 70 / 1140 66 / 530 seven, but no more than ten modifications in relation to the nucleotide sequence of SEQ ID NO: 4898.

[0081] 65. The modulating polynucleotide of either embodiment 59 or 61-63 or the AAV viral genome of either embodiment 60-63, wherein the modulating polynucleotide comprises: (i) a 5' flanking region of SEQ ID NO: 4879, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4879, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4879, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from the nucleotide sequence of SEQ ID NO: 4879; (ii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4888, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4888, a nucleotide sequence comprising one, two, three or four, but not more than five nucleotides different from the nucleotide sequence of SEQ ID NO: 4888; or a nucleotide sequence comprising one, two, three or four, but not more than five modifications from the nucleotide sequence of SEQ ID NO: 4888;and (iii) a 3' flanking region of SEQ ID NO: 4898, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six or; Petition 870260044145, dated 11 / 05 / 2026, p. 71 / 1140 67 / 530 seven, but no more than ten modifications in relation to the nucleotide sequence of SEQ ID NO: 4898.

[0082] 66. The modulating polynucleotide of either embodiment 59 or 61-63 or the AAV viral genome of either embodiment 60-63, wherein the modulating polynucleotide comprises: (i) a 5' flanking region of SEQ ID NO: 4879, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4879, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4879, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from the nucleotide sequence of SEQ ID NO: 4879; (ii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4887, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4887, a nucleotide sequence comprising one, two, three or four, but not more than five nucleotides different from the nucleotide sequence of SEQ ID NO: 4887; or a nucleotide sequence comprising one, two, three or four, but not more than five modifications from the nucleotide sequence of SEQ ID NO: 4887;and (iii) a 3' flanking region of SEQ ID NO: 4899, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4899, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4899, a nucleotide sequence comprising one, two, three, four, five, six or; Petition 870260044145, dated 11 / 05 / 2026, p. 72 / 1140 68 / 530 seven, but no more than ten modifications in relation to the nucleotide sequence of SEQ ID NO: 4899.

[0083] 67. The modulating polynucleotide of either embodiment 59 or 61-63 or the AAV viral genome of either embodiment 60-63, wherein the modulating polynucleotide comprises: (i) a 5' flanking region comprising the nucleotide sequence of SEQ ID NO: 4880, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4880, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4880; or a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from the nucleotide sequence of SEQ ID NO: 4880; (ii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4891, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4891, a nucleotide sequence comprising one, two, three or four, but not more than five nucleotides different from the nucleotide sequence of SEQ ID NO: 4891; or a nucleotide sequence comprising one, two, three or four, but not more than five modifications from the nucleotide sequence of SEQ ID NO: 4891; and (iii) a 3' flanking region of SEQ ID NO: 4900, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4900, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4900, or a Petition 870260044145, dated 11 / 05 / 2026, page 73 / 1140 69 / 530 nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications with respect to SEQ ID NO: 4900.

[0084] 68. The modulating polynucleotide of either embodiment 59 or 61-67 or the AAV viral genome of either embodiment 62-67, wherein the modulating polynucleotide comprises in the order of 5' to 3': (i) the 5' flanking region, sense tape sequence, loop region, antisense tape sequence and 3' flanking region; or (i) the 5' flanking region, antisense tape sequence, loop region, sense tape sequence and 3' flanking region.

[0085] 69. The modulating polynucleotide of any of the embodiments 59, 61-63, 67, 68 or the AAV viral genome of any of the embodiments 60-63, 67, 68, wherein the modulating polynucleotide comprises: (i) a 5' flanking region comprising the nucleotide sequence of SEQ ID NO: 4880, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4880, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4880, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from the nucleotide sequence of SEQ ID NO: 4880; (ii) the sense tape sequence of SEQ ID NO: 4906; (ii i) a loop region comprising the nucleotide sequence of SEQ ID NO: 4891; a nucleotide sequence by Petition 870260044145, dated 11 / 05 / 2026, page 74 / 1140 70 / 530 minus 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4891; a nucleotide sequence comprising one, two, three or four, but not more than five nucleotides different from the nucleotide sequence of SEQ ID NO: 4891; or a nucleotide sequence comprising one, two, three or four, but not more than five modifications from the nucleotide sequence of SEQ ID NO: 4891; (iv) the antisense strand sequence of SEQ ID NO: 4908; and (v) a 3' flanking region comprising the nucleotide sequence of SEQ ID NO: 4900; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4900; a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4900; or a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from SEQ ID NO: 4900.

[0086] 70. The modulating polynucleotide of any of the 59, 61-63 or 67-69 embodiments, or the AAV viral genome of any of the 60-63 or 67-69 embodiments, wherein the nucleotide sequence encoding the modulating polynucleotide comprises: (i) a 5' flanking region comprising the nucleotide sequence of SEQ ID NO: 4355; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4355; a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4355; or a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from the nucleotide sequence Petition 870260044145, dated 11 / 05 / 2026, page 75 / 1140 71 / 530 of SEQ ID NO: 4355; (ii) the sense tape sequence of SEQ ID NO: 4905; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4366; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4366; a nucleotide sequence comprising one, two, three or four, but not more than five nucleotides different from the nucleotide sequence of SEQ ID NO: 4366; or a nucleotide sequence comprising one, two, three or four, but not more than five modifications from the nucleotide sequence of SEQ ID NO: 4366; (iv) the antisense strand sequence of SEQ ID NO: 4907; and (v) a 3' flanking region comprising the nucleotide sequence of SEQ ID NO: 4375; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4375; a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4375; or a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from SEQ ID NO: 4375.

[0087] 71. The modulating polynucleotide of any of the embodiments 59, 61-63, 67 or 68 or the AAV viral genome of any of the embodiments 60-63, 67 or 68, wherein the modulating polynucleotide comprises: (i) a 5' flanking region comprising the nucleotide sequence of SEQ ID NO: 4880, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4880, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not Petition 870260044145, dated 11 / 05 / 2026, page 76 / 1140 72 / 530 more than ten different nucleotides in relation to the nucleotide sequence of SEQ ID NO: 4880, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications in relation to the nucleotide sequence of SEQ ID NO: 4880; (ii) the sense tape sequence of SEQ ID NO: 4918; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4891; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4891; a nucleotide sequence comprising one, two, three or four, but not more than five nucleotides different from the nucleotide sequence of SEQ ID NO: 4891; or a nucleotide sequence comprising one, two, three or four, but not more than five modifications from the nucleotide sequence of SEQ ID NO: 4891; (iv) the antisense strand sequence of SEQ ID NO: 4920; and (v) a 3' flanking region comprising the nucleotide sequence of SEQ ID NO: 4900; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4900; a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4900; or a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from SEQ ID NO: 4900.

[0088] 72. The modulating polynucleotide of any of the embodiments 59, 61-63, 67, 68 or 71 or the AAV viral genome of any of the embodiments 60-63, 67, 68 or 71, wherein the nucleotide sequence encoding the modulating polynucleotide comprises: (i) a flanking region 5' comprising the Petition 870260044145, dated 11 / 05 / 2026, p. 77 / 1140 73 / 530 nucleotide sequence of SEQ ID NO: 4355; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4355; a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4355; or a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from the nucleotide sequence of SEQ ID NO: 4355; (ii) the sense tape sequence of SEQ ID NO: 4917; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4366; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4366; a nucleotide sequence comprising one, two, three or four, but not more than five nucleotides different from the nucleotide sequence of SEQ ID NO: 4366; or a nucleotide sequence comprising one, two, three or four, but not more than five modifications from the nucleotide sequence of SEQ ID NO: 4366; (iv) the antisense strand sequence of SEQ ID NO: 4919; and (v) a 3' flanking region comprising the nucleotide sequence of SEQ ID NO: 4375; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4375; a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4375; or a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from SEQ ID NO: 4375.

[0089] 73. The modulating polynucleotide of any of the Petition 870260044145, dated 11 / 05 / 2026, p. 78 / 1140 74 / 530 modalities 59, 61-63, 67 or 68 or the AAV viral genome of any of the modalities 60-63, 67 or 68, wherein the modulating polynucleotide comprises: (i) a 5' flanking region comprising the nucleotide sequence of SEQ ID NO: 4880, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4880, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4880, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from the nucleotide sequence of SEQ ID NO: 4880; (ii) the sense tape sequence of SEQ ID NO: 4922; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4891; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4891; a nucleotide sequence comprising one, two, three or four, but not more than five nucleotides different from the nucleotide sequence of SEQ ID NO: 4891; or a nucleotide sequence comprising one, two, three or four, but not more than five modifications from the nucleotide sequence of SEQ ID NO: 4891; (iv) the antisense strand sequence of SEQ ID NO: 4924; and (v) a 3' flanking region comprising the nucleotide sequence of SEQ ID NO: 4900; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4900; a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the sequence of Petition 870260044145, dated 11 / 05 / 2026, p. 79 / 1140 75 / 530 nucleotides of SEQ ID NO: 4900; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but not more than ten modifications with respect to SEQ ID NO: 4900.

[0090] 74. The modulating polynucleotide of any of the embodiments 59, 61-63, 67, 68 or 73 or the AAV viral genome of any of the embodiments 60-63, 67, 68 or 73, wherein the nucleotide sequence encoding the modulating polynucleotide comprises: (i) a 5' flanking region comprising the nucleotide sequence of SEQ ID NO: 4355; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4355; a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4355; or a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from the nucleotide sequence of SEQ ID NO: 4355; (ii) the sense tape sequence of SEQ ID NO: 4921; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4366; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4366; a nucleotide sequence comprising one, two, three or four, but not more than five nucleotides different from the nucleotide sequence of SEQ ID NO: 4366; or a nucleotide sequence comprising one, two, three or four, but not more than five modifications from the nucleotide sequence of SEQ ID NO: 4366; (iv) the antisense strand sequence of SEQ ID NO: 4923; and (v) a 3' flanking region comprising the nucleotide sequence of SEQ ID NO: 4375; a sequence of Petition 870260044145, dated 11 / 05 / 2026, pages 80 / 1140 76 / 530 nucleotides at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4375; a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4375; or a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from SEQ ID NO: 4375.

[0091] 75. The modulating polynucleotide of any of the embodiments 59, 60-63, 65 or 68 or the AAV viral genome of any of the embodiments 60-63, 65 or 68, wherein the modulating polynucleotide comprises: (i) a 5' flanking region of SEQ ID NO: 4879, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4879, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4879, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from the nucleotide sequence of SEQ ID NO: 4879; (ii) the sense tape sequence of SEQ ID NO: 4966; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4888; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4888; a nucleotide sequence comprising one, two, three or four, but not more than five nucleotides different from the nucleotide sequence of SEQ ID NO: 4888; or a nucleotide sequence comprising one, two, three or four, but not more than five modifications from the nucleotide sequence of SEQ ID NO: 4888; Petition 870260044145, dated 11 / 05 / 2026, page 81 / 1140 77 / 530 (iv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908; and (v) a 3' flanking region of SEQ ID NO: 4898, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from the nucleotide sequence of SEQ ID NO: 4898.

[0092] 76. The modulating polynucleotide of any of the embodiments 59, 61-63, 65, 68 or 76 or the AAV viral genome of any of the embodiments 60-63, 65, 68 or 76, wherein the nucleotide sequence encoding the modulating polynucleotide comprises: (i) a 5' flanking region comprising the nucleotide sequence of SEQ ID NO: 4354; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4354; a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4354; or a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from the nucleotide sequence of SEQ ID NO: 4354; (ii) the sense tape sequence of SEQ ID NO: 4965; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4363; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4363; a nucleotide sequence comprising Petition 870260044145, dated 11 / 05 / 2026, page 82 / 1140 78 / 530 one, two, three or four, but not more than five different nucleotides in relation to the nucleotide sequence of SEQ ID NO: 4363; or a nucleotide sequence comprising one, two, three or four, but not more than five modifications in relation to the nucleotide sequence of SEQ ID NO: 4363; (iv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4907; and (v) a 3' flanking region of SEQ ID NO: 4373, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from the nucleotide sequence of SEQ ID NO: 4373.

[0093] 77. The modulating polynucleotide of any of the embodiments 59, 61-63, 65 or 68 or the AAV viral genome of any of the embodiments 60-63, 65 or 68, wherein the modulating polynucleotide comprises: (i) a 5' flanking region of SEQ ID NO: 4879, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4879, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4879, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from the nucleotide sequence of SEQ ID NO: 4879; (ii) the sense tape sequence of SEQ ID NO: 4970; Petition 870260044145, dated 11 / 05 / 2026, p. 83 / 1140 79 / 530 (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4888; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4888; a nucleotide sequence comprising one, two, three or four, but not more than five nucleotides different from the nucleotide sequence of SEQ ID NO: 4888; or a nucleotide sequence comprising one, two, three or four, but not more than five modifications from the nucleotide sequence of SEQ ID NO: 4888; (iv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912; and (v) a 3' flanking region of SEQ ID NO: 4898, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from the nucleotide sequence of SEQ ID NO: 4898.

[0094] 78. The modulating polynucleotide of any of the embodiments 59, 61-63, 65, 68 or 77 or the AAV viral genome of any of the embodiments 60-63, 65, 68 or 77, wherein the nucleotide sequence encoding the modulating polynucleotide comprises: (i) a 5' flanking region comprising the nucleotide sequence of SEQ ID NO: 4354; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4354; a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the sequence of Petition 870260044145, dated 11 / 05 / 2026, page 84 / 1140 80 / 530 nucleotides of SEQ ID NO: 4354; or a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications with respect to the nucleotide sequence of SEQ ID NO: 4354; (ii) the sense tape sequence of SEQ ID NO: 4969; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4363; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4363; a nucleotide sequence comprising one, two, three or four, but not more than five nucleotides different from the nucleotide sequence of SEQ ID NO: 4363; or a nucleotide sequence comprising one, two, three or four, but not more than five modifications from the nucleotide sequence of SEQ ID NO: 4363; (iv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4911; and (v) a 3' flanking region of SEQ ID NO: 4373, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from the nucleotide sequence of SEQ ID NO: 4373.

[0095] 79. The modulating polynucleotide of any of the embodiments 59, 61-63, 65 or 68 or the AAV viral genome of any of the embodiments 60-63, 65 or 68, wherein the modulating polynucleotide comprises: (i) a flanking region 5' of SEQ ID NO: 4879, Petition 870260044145, dated 11 / 05 / 2026, page 85 / 1140 81 / 530 a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4879, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4879, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from the nucleotide sequence of SEQ ID NO: 4879; (ii) the sense tape sequence of SEQ ID NO: 4978; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4888; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4888; a nucleotide sequence comprising one, two, three or four, but not more than five nucleotides different from the nucleotide sequence of SEQ ID NO: 4888; or a nucleotide sequence comprising one, two, three or four, but not more than five modifications from the nucleotide sequence of SEQ ID NO: 4888; (iv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920; and (v) a 3' flanking region of SEQ ID NO: 4898, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from the nucleotide sequence of SEQ ID NO: 4898.

[0096] 80. The modulating polynucleotide of any of the Petition 870260044145, dated 11 / 05 / 2026, p. 86 / 1140 82 / 530 embodiments 59, 61-63, 65, 68 or 79 or the AAV viral genome of any of the embodiments 60-63, 65, 68 or 79, wherein the nucleotide sequence encoding the modulating polynucleotide comprises: (i) a 5' flanking region comprising the nucleotide sequence of SEQ ID NO: 4354; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4354; a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4354; or a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from the nucleotide sequence of SEQ ID NO: 4354; (ii) the sense tape sequence of SEQ ID NO: 4977; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4363; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4363; a nucleotide sequence comprising one, two, three or four, but not more than five nucleotides different from the nucleotide sequence of SEQ ID NO: 4363; or a nucleotide sequence comprising one, two, three or four, but not more than five modifications from the nucleotide sequence of SEQ ID NO: 4363; (iv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4919; and (v) a 3' flanking region of SEQ ID NO: 4373, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten different nucleotides in relation to Petition 870260044145, dated 11 / 05 / 2026, p. 87 / 1140 83 / 530 to the nucleotide sequence of SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications to the nucleotide sequence of SEQ ID NO: 4373.

[0097] 81. The modulating polynucleotide of any of the embodiments 59, 61-63, 65 or 68 or the AAV viral genome of any of the embodiments 60-63, 65 or 68, wherein the modulating polynucleotide comprises: (i) a 5' flanking region of SEQ ID NO: 4879, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4879, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4879, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from the nucleotide sequence of SEQ ID NO: 4879; (ii) the sense tape sequence of SEQ ID NO: 4982; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4888; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4888; a nucleotide sequence comprising one, two, three or four, but not more than five nucleotides different from the nucleotide sequence of SEQ ID NO: 4888; or a nucleotide sequence comprising one, two, three or four, but not more than five modifications from the nucleotide sequence of SEQ ID NO: 4888; (iv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924; and (v) a 3' flanking region of SEQ ID NO: 4898, Petition 870260044145, dated 11 / 05 / 2026, page 88 / 1140 84 / 530 a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from the nucleotide sequence of SEQ ID NO: 4898.

[0098] 82. The modulating polynucleotide of any of the embodiments 59, 61-63, 65, 68 or 81 or the AAV viral genome of any of the embodiments 60-63, 65, 68 or 81, wherein the nucleotide sequence encoding the modulating polynucleotide comprises: (i) a 5' flanking region comprising the nucleotide sequence of SEQ ID NO: 4354; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4354; a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4354; or a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from the nucleotide sequence of SEQ ID NO: 4354; (ii) the sense tape sequence of SEQ ID NO: 4981; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4363; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4363; a nucleotide sequence comprising one, two, three or four, but not more than five nucleotides different from the nucleotide sequence of SEQ ID NO: 4363; or a nucleotide sequence comprising one, two, three or Petition 870260044145, dated 11 / 05 / 2026, page 89 / 1140 85 / 530 four, but no more than five modifications in relation to the nucleotide sequence of SEQ ID NO: 4363; (iv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4923; and (v) a 3' flanking region of SEQ ID NO: 4373, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from the nucleotide sequence of SEQ ID NO: 4373.

[0099] 83. The modulating polynucleotide of any embodiment 59 or 61-82 or the AAV viral genome of any embodiment 62-82, wherein the nucleotide sequence encoding the modulating polynucleotide comprises the nucleotide sequence of any SEQ ID NOs: 43804409 or 5027-5050, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical thereto.

[00100] 84. The modulating polynucleotide of any of the embodiments 59, 61-63, 67-70 or 83, or the AAV viral genome of any of the embodiments 60-63, 67-70 or 83, wherein the nucleotide sequence encoding the modulating polynucleotide comprises the nucleotide sequence of the nucleotide sequence of SEQ ID NO: 4405, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical thereto.

[00101] 85. The modulating polynucleotide of any of the modalities 59, 61-63, 67, 68, 71, 72 or 83, or the AAV viral genome of Petition 870260044145, dated 11 / 05 / 2026, pp. 90 / 1140 86 / 530 any of the embodiments 60-63, 67, 68, 71, 72 or 83, wherein the nucleotide sequence encoding the modulating polynucleotide comprises the nucleotide sequence of SEQ ID NO: 4408, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to it.

[00102] 86. The modulating polynucleotide of any of the embodiments 59, 61-63, 67, 68, 73, 74 or 83, or the AAV viral genome of any of the embodiments 60-63, 67, 68, 73, 74 or 83, wherein the nucleotide sequence encoding the modulating polynucleotide comprises the nucleotide sequence of SEQ ID NO: 4409, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical thereto.

[00103] 87. The modulating polynucleotide of any of the embodiments 59, 61-63, 65, 68, 75, 76 or 83, or the AAV viral genome of any of the embodiments 60-63, 65, 68, 75, 76 or 83, wherein the nucleotide sequence encoding the modulating polynucleotide comprises the nucleotide sequence of SEQ ID NO: 4390, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical thereto.

[00104] 88. The modulating polynucleotide of any of the embodiments 59, 61-63, 65, 68, 77, 78 or 83, or the AAV viral genome of any of the embodiments 60-63, 65, 68, 77, 78 or 83, wherein the nucleotide sequence encoding the modulating polynucleotide comprises the nucleotide sequence of SEQ ID NO: 4391, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical thereto.

[00105] 89. The modulating polynucleotide of any of the embodiments 59, 61-63, 65, 68, 79, 80 or 83, or the AAV viral genome of any of the embodiments 60-63, 65, 68, 79, 80 or 83, wherein the nucleotide sequence encoding the modulating polynucleotide Petition 870260044145, dated 11 / 05 / 2026, pp. 91 / 1140 87 / 530 comprises the nucleotide sequence of SEQ ID NO: 4393, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to it.

[00106] 90. The modulating polynucleotide of any of the embodiments 59, 61-63, 65, 68, 81, 82 or 83, or the AAV viral genome of any of the embodiments 60-63, 65, 68, 81, 82 or 83, wherein the nucleotide sequence encoding the modulating polynucleotide comprises the nucleotide sequence of SEQ ID NO: 4394, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical thereto.

[00107] 91. An adeno-associated virus (AAV) viral genome comprising a nucleic acid-coupled promoter encoding either the modulating polynucleotide of any of the 59-90 embodiments or the siRNA of any of the 1-11 or 1358 embodiments.

[00108] 92. The AAV viral genome of any of the modalities 12-58 or 60-90, in which the AAV viral genome further comprises a promoter operatively linked to the nucleotide sequence encoding the sense strand sequence and the antisense strand sequence or the modulating polynucleotide.

[00109] 93. The AAV viral genome of modality 92, in which the promoter is a ubiquitous promoter.

[00110] 94. The AAV viral genome of modality 92, in which the promoter is a cell- or tissue-specific promoter.

[00111] 95. The AAV viral genome of any of the modalities 92-94, where the promoter is chosen from the α subunit of human elongation factor 1 (EF^), immediate-early enhancer and / or promoter of cytomegalovirus (CMV), chicken β-actin (CBA) and its derivative CAG, β-glucuronidase (GUSB) or ubiquitin C (UBC), neuron-specific enolase (NSE), growth factor derived from Petition 870260044145, dated 11 / 05 / 2026, page 92 / 1140 88 / 530 platelets (PDGF), platelet-derived growth factor B chain (PDGF-β), intercellular adhesion molecule 2 (ICAM-2), synapsin (Syn), methyl-CpG binding protein 2 (MeCP2), calcium-dependent / calmodulin-dependent protein kinase II (CaMKII), metabotropic glutamate receptor 2 (mGluR2), neurofilament light chain (NFL) or neurofilament heavy chain (NFH), β-globin minigene nβ2, preproenkephalin (PPE), enkephalin (Enk) and excitatory amino acid transporter 2 (EAAT2), glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), a cardiovascular promoter (e.g., αMHC, cTnT, and CMV-MLC2k), a hepatic promoter (e.g., hAAT, TBG), a skeletal muscle promoter (e.g., for example, desmin, MCK, C512) or a functional fragment, for example, a truncation or a functional variant thereof.

[00112] 96. The AAV viral genome of any of the modalities 92-95, where the promoter comprises a CBA promoter or a variant thereof.

[00113] 97. The AAV viral genome of any of the modalities 92-95, wherein the promoter comprises the nucleotide sequence of any of the nucleotide sequences provided in Table 2; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to any of the nucleotide sequences provided in Table 2; or a nucleotide sequence with at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% sequence identity with any of the nucleotide sequences provided in Table 2.

[00114] 98. The AAV viral genome of any of the modalities 92-97, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising Petition 870260044145, dated 11 / 05 / 2026, p. 93 / 1140 89 / 530 at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 5199; or a nucleotide sequence with at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% sequence identity with SEQ ID NO: 5199.

[00115] 99. The AAV viral genome of any of the 92-97 embodiments, wherein the AAV viral genome further comprises a polyA signal sequence.

[00116] 100. The AAV viral genome of modality 99, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4476.

[00117] 101. The AAV viral genome of any of the 26-32 embodiments, wherein the AAV viral genome further comprises an inverted terminal repeat (ITR) sequence.

[00118] 102. The AAV viral genome of embodiment 101, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5197, 5200, 4469 or 4470; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 5197, 5200, 4469 or 4470; or a nucleotide sequence with at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% sequence identity with SEQ ID NO: 5197, 5200, 4469 or 4470.

[00119] 103. The AAV viral genome of any of the modalities 12-58 or 60-102, in which the AAV viral genome comprises a Petition 870260044145, dated 11 / 05 / 2026, p. 94 / 1140 90 / 530 ITR sequence positioned 5' relative to the nucleic acid encoding the modulating polynucleotide or siRNA.

[00120] 104. The AAV viral genome of embodiment 103, in which the ITR positioned 5' relative to the nucleic acid encoding the modulating polynucleotide or siRNA comprises the nucleotide sequence of SEQ ID NO: 5197 or 4469; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, relative to SEQ ID NO: 5197 or 4469; or a nucleotide sequence with at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% sequence identity with SEQ ID NO: 5197 or 4469.

[00121] 105. The AAV viral genome of any of the modalities 12-58 or 60-104, in which the AAV viral genome comprises an ITR sequence positioned 3' relative to the nucleic acid encoding the modulating polynucleotide or siRNA.

[00122] 106. The AAV viral genome of embodiment 103, in which the ITR positioned 3' relative to the nucleic acid encoding the modulating polynucleotide or siRNA comprises the nucleotide sequence of SEQ ID NO: 5200 or 4470; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, relative to SEQ ID NO: 5200 or 4470; or a nucleotide sequence with at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% sequence identity with SEQ ID NO: 5200 or 4470.

[00123] 107. The AAV viral genome particle of either embodiment 12-58 or 60-106, wherein the AAV viral genome comprises an ITR sequence positioned 5' relative to the nucleic acid encoding the modulating polynucleotide or siRNA and an ITR sequence Petition 870260044145, dated 11 / 05 / 2026, pp. 95 / 1140 91 / 530 positioned 3' relative to the nucleic acid that encodes the modulating polynucleotide or siRNA.

[00124] 108. The AAV viral genome of any of the modalities 105-107, where: (i) the ITR positioned 5' relative to the nucleic acid encoding the modulating polynucleotide or siRNA comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, relative to SEQ ID NO: 5197; and (ii) the ITR positioned 3' relative to the nucleic acid encoding the modulating polynucleotide or siRNA comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200;or a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 5200.;

[00125] 109. The AAV viral genome of any of the modalities 105-107, where: (i) the ITR positioned 5' relative to the nucleic acid encoding the modulating polynucleotide or siRNA comprises the nucleotide sequence of SEQ ID NO: 4469; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4469; or a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, relative to SEQ ID NO: 4469; and Petition 870260044145, dated 11 / 05 / 2026, p. 96 / 1140 92 / 530 (ii) the ITR positioned 3' relative to the nucleic acid encoding the modulating polynucleotide or siRNA comprises the nucleotide sequence of SEQ ID NO: 4470; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4470; or a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, relative to SEQ ID NO: 4470.

[00126] 110. The AAV viral genome of either embodiment 12-58 or 60-109, wherein the AAV viral genome further comprises an enhancer, a Kozak sequence, an intron region and / or an exon region.

[00127] 111. The AAV viral genome of modality 110, in which the enhancer comprises: (i) a CMVie enhancer or a variant thereof; or (ii) the nucleotide sequence of SEQ ID NO: 4471 or 4472; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 4471 or 4472; or a nucleotide sequence with at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% sequence identity with SEQ ID NO: 4471 or 4472.

[00128] 112. The AAV viral genome of embodiment 110 or 111, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 4471; or a nucleotide sequence with at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% sequence identity with SEQ ID NO: 4471. Petition 870260044145, dated 11 / 05 / 2026, p. 97 / 1140 93 / 530

[00129] 113. The AAV viral genome of any of the modalities 12-58 or 60-112, comprising a CMVie enhancer or variant thereof; and a CBA promoter or variant thereof; optionally where the CMVie enhancer or variant thereof is present 5' relative to the CBA promoter or variant thereof.

[00130] 114. The AAV viral genome of any of the modalities 110-113, wherein the enhancer and promoter comprise the nucleotide sequence of SEQ ID NO: 4473 or 4474; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 4473 or 4474; or a nucleotide sequence with at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% sequence identity with SEQ ID NO: 4473 or 4474.

[00131] 115. The AAV viral genome of any of the modalities 110-114, where the intron comprises: (i) a human beta-globin intron (hBG intron) or variant thereof; or (ii) the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 4475; or a nucleotide sequence with at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% sequence identity with SEQ ID NO: 4475.

[00132] 116. The AAV viral genome of either embodiment 12-58 or 60-115, wherein the AAV viral genome further comprises a nucleotide sequence encoding an miR binding site, for example, an miR binding site that modulates, for example, reduces the expression of the payload encoded by the viral genome in a Petition 870260044145, dated 11 / 05 / 2026, pp. 98 / 1140 94 / 530 cell or tissue where the corresponding miRNA is expressed.

[00133] 117. The AAV viral genome of modality 116, in which the miR-encoded binding site modulates, for example, reduces the expression of the encoded payload in a DRG cell or tissue, liver, heart, hematopoietic lineage, or a combination thereof.

[00134] 118. The AAV viral genome of either embodiment 12-58 or 60-117, wherein the AAV viral genome comprises at least 1-5 copies of the encoded miR binding site, for example, at least 1, 2, 3, 4 or 5 copies, optionally wherein the at least 1-5 copies are continuous (e.g., not separated by a spacer) or the at least 1-5 copies are separated by a spacer.

[00135] 119. The AAV viral genome of any of the modalities 12-58 or 60-118, where the AAV viral genome is self-complementary.

[00136] 120. The AAV viral genome of any of the modalities 12-58 or 60-118, where the AAV viral genome is single-stranded.

[00137] 121. The AAV viral genome of either 12-58 or 60-120 embodiment, wherein the AAV viral genome further comprises a nucleotide sequence encoding a Rep protein, for example, a non-structural protein, wherein the Rep protein comprises a Rep78 protein, a Rep68 protein, a Rep52 protein and / or a Rep40 protein (for example, a Rep78 protein and a Rep52 protein).

[00138] 122. The AAV viral genome of either embodiment 12-58 or 60-121, where the AAV viral genome comprises approximately 5' to 3': (i) an ITR; (ii) an enhancer (for example, a CMVie enhancer or variant thereof); (iii) a promoter (for example, a CBA promoter or variant thereof); (iv) an intron (for example, an hBG intron or variant of Petition 870260044145, dated 11 / 05 / 2026, pp. 99 / 1140 95 / 530 same); (v) a nucleic acid sequence that encodes a modulating polynucleotide (for example, the modulating polynucleotide of any of the 59-90 embodiments); (vi) a polyA signal sequence; and (vii) an ITR.

[00139] 123. The viral genome of AAV of either the 12-58 or 60-122 embodiments, where the viral genome of AAV comprises on the order of 5' to 3': (i) an ITR, where the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 5197; (ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4471; (iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5199; Petition 870260044145, dated 11 / 05 / 2026, pp. 100 / 1140 96 / 530 (iv) an intron, whereintro comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4475; (v) a nucleotide sequence encoding a modulating polynucleotide, wherein the nucleotide sequence comprises any of the SEQ ID NOs: 4380-4409 or 5027-5050, or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to it; (vi) a polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4476; and (vii) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven, but not more than ten modifications, for example, substitutions, insertions, or deletions, in relation to SEQ ID NO: 5200.

[00140] 124. The viral genome of AAV of either the 12-58 or 60-122 embodiments, where the viral genome of AAV comprises on the order of 5' to 3': Petition 870260044145, dated 11 / 05 / 2026, pp. 101 / 1140 97 / 530 (i) an ITR, where the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 5197; (ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4471; (iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5199; (iv) an intron, whereintro comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4475; (v) a nucleotide sequence encoding a modulating polynucleotide, wherein the nucleotide sequence comprises Petition 870260044145, dated 11 / 05 / 2026, pp. 102 / 1140 98 / 530 any of the SEQ ID NOS: 4405, 4408, 4409, 4390, 4391, 4393 or 4394, or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to it; (vi) a polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4476; and (vii) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven, but not more than ten modifications, for example, substitutions, insertions, or deletions, in relation to SEQ ID NO: 5200.

[00141] 125. The viral genome of AAV of either the 12-58 or 60-122 embodiments, where the viral genome of AAV comprises on the order of 5' to 3': (i) an ITR, where the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 5197; (ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471; a sequence of Petition 870260044145, dated 11 / 05 / 2026, pp. 103 / 1140 99 / 530 nucleotides comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4471; (iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5199; (iv) an intron, whereintro comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4475; (v) a nucleotide sequence encoding a modulating polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4405, or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical thereto; (vi) a polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to Petition 870260044145, dated 11 / 05 / 2026, pp. 104 / 1140 100 / 530 SEQ ID NO: 4476; and (vii) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 5200.

[00142] 126. The viral genome of AAV of either the 12-58 or 60-122 embodiments, where the viral genome of AAV comprises on the order of 5' to 3': (i) an ITR, where the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 5197; (ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4471; (iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 5199; or a Petition 870260044145, dated 11 / 05 / 2026, pp. 105 / 1140 101 / 530 nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5199; (iv) an intron, whereintro comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4475; (v) a nucleotide sequence encoding a modulating polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4408, or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical thereto; (vi) a polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4476; and (vii) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven, but not more than ten modifications, for example, substitutions, insertions, or deletions, in relation to SEQ ID NO: 5200.

[00143] 127. The AAV viral genome of either embodiment 12-58 or 60-122, wherein the AAV viral genome comprises Petition 870260044145, dated 11 / 05 / 2026, pp. 106 / 1140 102 / 530 order of 5 ' to 3': (i) an ITR, where the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 5197; (ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4471; (iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5199; (iv) an intron, whereintro comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4475; (v) a nucleotide sequence that codes for a Petition 870260044145, dated 11 / 05 / 2026, pp. 107 / 1140 103 / 530 polynucleotide modulator, wherein the nucleotide sequence comprises SEQ ID NO: 4409, or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical thereto; (vi) a polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4476; and (vii) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven, but not more than ten modifications, for example, substitutions, insertions, or deletions, in relation to SEQ ID NO: 5200.

[00144] 128. The viral genome of AAV of either the 12-58 or 60-122 embodiments, where the viral genome of AAV comprises on the order of 5' to 3': (i) an ITR, where the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 5197; (ii) an intensifier, wherein the intensifier comprises the Petition 870260044145, dated 11 / 05 / 2026, pp. 108 / 1140 104 / 530 nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4471; (iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5199; (iv) an intron, whereintro comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4475; (v) a nucleotide sequence encoding a modulating polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4390, or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical thereto; (vi) a polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 4476; or a nucleotide sequence comprising Petition 870260044145, dated 11 / 05 / 2026, pp. 109 / 1140 105 / 530 less 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4476; and (vii) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 5200.

[00145] 129. The viral genome of AAV of either the 12-58 or 60-122 embodiments, where the viral genome of AAV comprises on the order of 5' to 3': (i) an ITR, where the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 5197; (ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4471; (iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, Petition 870260044145, dated 11 / 05 / 2026, pp. 110 / 1140 106 / 530 substitutions, insertions, or deletions, in relation to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5199; (iv) an intron, whereintro comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4475; (v) a nucleotide sequence encoding a modulating polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4391, or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical thereto; (vi) a polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4476; and (vii) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven, but not more than ten modifications, for example, substitutions, insertions, or deletions, in relation to SEQ ID NO: 5200.

[00146] 130. The viral genome of AAV from any of the Petition 870260044145, dated 11 / 05 / 2026, pp. 111 / 1140 107 / 530 modalities 12-58 or 60-122, in which the AAV viral genome comprises, on the order of 5' to 3': (i) an ITR, where the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 5197; (ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4471; (iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5199; (iv) an intron, whereintro comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4475; Petition 870260044145, dated 11 / 05 / 2026, pp. 112 / 1140 108 / 530 (v) a nucleotide sequence encoding a modulating polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4393, or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to it; (vi) a polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4476; and (vii) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven, but not more than ten modifications, for example, substitutions, insertions, or deletions, in relation to SEQ ID NO: 5200.

[00147] 131. The viral genome of AAV of either 12-58 or 60-122 embodiments, wherein the viral genome of AAV comprises on the order of 5' to 3': (i) an ITR, where the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 5197; (ii) an intensifier, wherein the intensifier comprises the Petition 870260044145, dated 11 / 05 / 2026, pp. 113 / 1140 109 / 530 nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4471; (iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5199; (iv) an intron, whereintro comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4475; (v) a nucleotide sequence encoding a modulating polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4394, or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical thereto; (vi) a polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 4476; or a nucleotide sequence comprising Petition 870260044145, dated 11 / 05 / 2026, pp. 114 / 1140 110 / 530 less 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4476; and (vii) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 5200.

[00148] 132. The viral genome of AAV of either the 12-58 or 60-122 embodiments, where the viral genome of AAV comprises on the order of 5' to 3': (i) an ITR, where the ITR comprises the nucleotide sequence of SEQ ID NO: 4469; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4469; or a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 4469; (ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4472; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 4472; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4472; (iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, Petition 870260044145, dated 11 / 05 / 2026, pp. 115 / 1140 111 / 530 substitutions, insertions or deletions, in relation to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5199; (iv) an intron, whereintro comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4475; (v) a nucleotide sequence encoding a modulating polynucleotide, wherein the nucleotide sequence comprises any of the SEQ ID NOs: 4380-4409 or 5027-5050, or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to it; (vi) a polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4476; and (vii) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 4470; a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4470; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven, but not more than ten modifications, for example, substitutions, insertions, or deletions, in relation to SEQ ID NO: 4470. Petition 870260044145, dated 11 / 05 / 2026, pp. 116 / 1140 112 / 530

[00149] 133. The AAV viral genome of any of the modalities 12-58 or 60-132, comprising the nucleotide sequence of any of the SEQ ID NOs: 4439-4468 or 5149-5196, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to any of the SEQ ID NOs: 4439-4468 or 5149-5196.

[00150] 134. The AAV viral genome of any of the modalities 12-58, 60-96, 98-108 or 110-133, comprising the nucleotide sequence of any of the SEQ ID NOs: 5149-5196, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to any of the SEQ ID NOs: 5149-5196.

[00151] 135. The AAV viral genome of any of the modalities 12-58, 60-96, 98-108, 110-133 or 134, comprising the nucleotide sequence of any of the SEQ ID NOs: 5173, 5195, 5196, 5182, 5183, 5184 or 5185, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to any of the SEQ ID NOs: 5173, 5195, 5196, 5182, 5183, 5184 or 5185.

[00152] 136. The AAV viral genome of any of the modalities 12-58, 60-96, 98-108, 110-125 or 133-135, comprising the nucleotide sequence of SEQ ID NO: 5173, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5173.

[00153] 137. The AAV viral genome of any of the modalities 12-58, 60-96, 98-108, 110-124, 126 or 133-135, comprising the nucleotide sequence of SEQ ID NO: 5195, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5195.

[00154] 138. The AAV viral genome of any of the modalities Petition 870260044145, dated 11 / 05 / 2026, pp. 117 / 1140 113 / 530 12-58, 60-96, 98-108, 110-124, 127 or 133-135, comprising the nucleotide sequence of SEQ ID NO: 5196, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5196.

[00155] 139. The AAV viral genome of any of the modalities 12-58, 60-96, 98-108, 110-124, 128 or 133-135, comprising the nucleotide sequence of SEQ ID NO: 5182, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5182.

[00156] 140. The AAV viral genome of any of the modalities 12-58, 60-96, 98-108, 110-124, 129 or 133-135, comprising the nucleotide sequence of SEQ ID NO: 5183, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5183.

[00157] 141. The AAV viral genome of any of the modalities 12-58, 60-96, 98-108, 110-124, 130 or 133-135, comprising the nucleotide sequence of SEQ ID NO: 5184, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5184.

[00158] 142. The AAV viral genome of any of the modalities 12-58, 60-96, 98-108, 110-124, 131 or 133-135, comprising the nucleotide sequence of SEQ ID NO: 5185, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5185.

[00159] 143. The AAV viral genome of any of the modalities 12-58, 60-96, 98-107, 109-122 or 133, comprising the nucleotide sequence of any of the SEQ ID NOs: 4439-4468, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to any of the SEQ ID NOs: 4439-4468. Petition 870260044145, dated 11 / 05 / 2026, pp. 118 / 1140 114 / 530

[00160] 144. An AAV particle comprising the AAV viral genome of either embodiment 12-58 or 60-143, an AAV viral genome encoding the modulating polynucleotide of either embodiment 59-90, or an AAV viral genome encoding the siRNA of either embodiment 11 or 13-58, and an AAV capsid protein.

[00161] 145. The AAV particle of embodiment 48, wherein the AAV capsid protein comprises an AAV5 capsid protein, an AAV9 capsid protein, a VOY101 capsid protein, a PHPeB capsid protein, a PHP.B capsid protein, a PHP.N capsid protein, an AAV1 capsid protein, a VOY9P39 capsid protein, an AAV2 capsid protein, an AAVrh10 capsid protein or a variant thereof (for example, an AAV9 capsid protein or a variant thereof or an AAV5 capsid protein or a variant thereof).

[00162] 146. The AAV particle of embodiment 144 or 145, wherein the AAV capsid protein comprises an AAV9 capsid or a variant thereof.

[00163] 147. The AAV particle of embodiment 144 or 145, wherein the AAV capsid protein comprises an AAV5 capsid or a variant thereof.

[00164] 148. The particle AAV of any of the modalities 144- 147, where: (i) the AAV capsid protein comprises an amino acid sequence given in Table 1 or an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% identical to it; or (ii) the nucleotide sequence encoding the AAV capsid protein comprises any of the nucleotide sequences in Table 1, or a nucleotide sequence that is at least Petition 870260044145, dated 11 / 05 / 2026, pp. 119 / 1140 115 / 530 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98% or 99% identical to it.

[00165] 149. A vector comprising the AAV viral genome of either embodiment 12-58 or 60-143, a nucleotide sequence encoding the modulating polynucleotide of either embodiment 59-90, or a nucleotide sequence encoding the siRNA of either embodiment 11 or 13-58.

[00166] 150. A cell comprising the AAV particle of any of the embodiments 144-148, the AAV viral genome of any of the embodiments 12-58 or 60-143, the modulating polynucleotide of any of the embodiments 59-90, or the siRNA of any of the embodiments 11 or 13-58.

[00167] 151. The cell of modality 150, in which the cell is a mammalian cell or an insect cell.

[00168] 152. The cell of modality 150 or 151, wherein the cell is a cell from a region of the brain or a region of the spinal cord (e.g., a CNS cell).

[00169] 153. The cell of any of the modalities 150-152, wherein the cell is a cell of the cortex, hippocampus, thalamus, or brainstem.

[00170] 154. The cell of any of the modalities 150-153, in which the cell is a neuron, a glial cell, or an oligodendrocyte.

[00171] 155. A method for producing an AAV particle, comprising: (i) provide a host cell comprising the AAV viral genome of either embodiment 12-58 or 60-143, an AAV viral genome encoding the modulating polynucleotide of either embodiment 59-90, or a viral genome encoding the siRNA of either embodiment 11 or 13-58; (ii) incubate the host cell under suitable conditions Petition 870260044145, dated 11 / 05 / 2026, pages 120 / 1140 116 / 530 to enclose the AAV viral genome in an AAV capsid protein; thus forming the AAV particle.

[00172] 156. The embodiment 155 method, further comprising, before step (i), the introduction of a first nucleic acid molecule comprising the viral genome into the host cell.

[00173] 157. The embodiment 155 or 156 method, in which the host cell comprises a second nucleic acid encoding the AAV capsid protein.

[00174] 158. The embodiment modality method 157, in which the second nucleic acid molecule is introduced into the host cell before, simultaneously with, or after the first nucleic acid molecule.

[00175] 159. A pharmaceutical composition comprising the AAV particle of any of the embodiments 144-148, an AAV particle comprising the AAV viral genome of any of the embodiments 12-58 or 60-143, the modulating polynucleotide of any of the embodiments 59-90, or the siRNA of any of the embodiments 11 or 13-58, and a pharmaceutically acceptable excipient.

[00176] 160. A method of administering an siRNA to inhibit MAPT expression (e.g., MAPT gene, mRNA, or protein expression) to a cell, comprising administering an effective amount of the pharmaceutical composition of embodiment 159, of the AAV particle of any of embodiments 144-159, of an AAV particle comprising the AAV viral genome of any of embodiments 12-58 or 60-143, of the modulating polynucleotide of any of embodiments 59-90, or of the siRNA of any of embodiments 11 or 13-58, thereby administering the siRNA to inhibit MAPT expression to the cell.

[00177] 161. The method of implementation modality 160, in which the Petition 870260044145, dated 11 / 05 / 2026, pp. 121 / 1140 117 / 530 cell is a cell from a region of the brain or a region of the spinal cord.

[00178] 162. The method of modality 160 or 161, in which the cell is a cell of the cortex, hippocampus, thalamus or brainstem.

[00179] 163. The method of any of the modalities 160-162, in which the cell is a neuron, an astrocyte, a glial cell or an oligodendrocyte.

[00180] 164. The method of any of the embodiments 160-163, wherein administration decreases (e.g., inhibits) MAPT mRNA levels, for example, by at least 40%, 44%, 45%, 50%, 55%, 60%, 64%, 65%, 70%, 75%, 76%, 79%, 80%, 84%, 85%, 87% or 90%, for example, in a cell of a brain region (e.g., cortex, hippocampus or brainstem), for example, compared to a reference level (e.g., mRNA levels in a cell that was not administered or before administration of the AAV particle, modulating polynucleotide, siRNA or pharmaceutical composition), for example, when measured by an assay (e.g., an assay as described in Example 6).

[00181] 165. The method of any of the embodiments 160-164, in which administration decreases (e.g., inhibits) MAPT protein levels, for example, by at least 15%, 17%, 20%, 25%, 30%, 35%, 37%, 40%, 44%, 45%, 46%, 50%, 53%, 55%, 60%, 63%, 64%, 65%, 70%, 72%, 74% or 75%, for example, in a cell of a brain region (e.g., cortex, hippocampus, thalamus or brainstem), for example, compared to a reference level (e.g., protein levels in a cell that was not administered or before administration of the AAV particle, modulating polynucleotide, siRNA or pharmaceutical composition), for example, when measured by a test (for example, a test as described in Example 6). Petition 870260044145, dated 11 / 05 / 2026, pp. 122 / 1140 118 / 530

[00182] 166. The method of any of the modalities 160-165, in which the cell is in an individual.

[00183] 167. The method of modality 166, in which the individual has or has been diagnosed with a genetic disorder (for example, a monogenic disorder or a polygenic disorder).

[00184] 168. The method of modality 166 or 167, in which the individual has or has been diagnosed with a neurological disorder (e.g., a neurodegenerative disorder).

[00185] 169. The method of any of the modalities 166-168, in which the individual has or has been diagnosed with a disorder associated with tau expression, for example, aberrant tau expression.

[00186] 170. The method of any of the modalities 166-169, in which the individual has or has been diagnosed with a tauopathy.

[00187] 171. A method for treating an individual who has or has been diagnosed with a genetic disorder, for example, a monogenic disorder or a polygenic disorder, comprising administering to the individual an effective amount of the pharmaceutical composition of embodiment 159, the AAV particle of any of embodiments 144159, an AAV particle comprising the AAV viral genome of any of embodiments 12-58 or 60-143, the modulating polynucleotide of any of embodiments 59-90, or the siRNA of any of embodiments 11 or 13-58, thereby treating the individual who has or has been diagnosed with the genetic disorder, for example, the monogenic disorder or the polygenic disorder.

[00188] 172. A method for treating an individual who has or has been diagnosed with a neurological disorder (e.g., a neurodegenerative disorder), comprising administering to the individual an effective amount of the pharmaceutical composition of embodiment 159, the AAV particle of any of embodiments 144-159, an AAV particle comprising the viral genome of AAV of any of Petition 870260044145, dated 11 / 05 / 2026, pp. 123 / 1140 119 / 530 of the 12-58 or 60-143 modalities, the modulating polynucleotide of either 59-90 modalities, or the siRNA of either 11 or 13-58 modalities, thus treating the individual who has or has been diagnosed with the neurological disorder (e.g., neurodegenerative disorder).

[00189] 173. A method for treating an individual who has or has been diagnosed with a disorder associated with tau expression, for example, aberrant tau expression, comprising administering to the individual an effective amount of the pharmaceutical composition of embodiment 159, the AAV particle of any of embodiments 144-159, an AAV particle comprising the AAV viral genome of any of embodiments 12-58 or 60-143, the modulating polynucleotide of any of embodiments 59-90, or the siRNA of any of embodiments 11 or 13-58, thereby treating the individual who has or has been diagnosed with the disorder associated with tau expression, for example, aberrant tau expression.

[00190] 174. A method for treating an individual who has or has been diagnosed with a tauopathy, comprising administering to the individual an effective amount of the pharmaceutical composition of embodiment 159, the AAV particle of any of embodiments 144-159, an AAV particle comprising the AAV viral genome of any of embodiments 12-58 or 60-143, the modulating polynucleotide of any of embodiments 59-90, or the siRNA of any of embodiments 11 or 13-58, thereby treating the individual who has or has been diagnosed with the tauopathy.

[00191] 175. The method of any of the modalities 167-174, in which genetic disorder, neurological disorder (e.g., neurodegenerative disorder), disorder associated with tau expression (e.g., aberrant tau expression) and / or tauopathy is Alzheimer's disease (AD), frontotemporal dementia (FTD), frontotemporal dementia Petition 870260044145, dated 11 / 05 / 2026, pp. 124 / 1140 120 / 530 and parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration (FTLD), Dravet syndrome (DS), neurodegenerative disease, traumatic brain injury (TBI), chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), Down syndrome, Pick's disease, corticobasal degeneration (CBD), corticobasal syndrome, amyotrophic lateral sclerosis (ALS), prion diseases, CJD, multiple system atrophy, mild cognitive impairment, entangled dementia only, or progressive subcortical gliosis.

[00192] 176. The method of any of the modalities 171-175, in which the treatment comprises preventing the progression of the genetic disorder, neurological disorder (e.g., neurodegenerative disorder), disorder associated with tau expression (e.g., aberrant tau expression) and / or tauopathy in the individual.

[00193] 177. The method of any of the modalities 171-176, further comprising the performance of a blood test, an imaging examination (e.g., positron emission tomography or positron emission tomography in combination with a biomarker, e.g., serum biomarker staining), a CNS biopsy sample or an aqueous cerebrospinal fluid biopsy, optionally wherein the blood test, imaging examination, biopsy sample or aqueous cerebrospinal fluid biopsy are performed before, during or after treatment with the AAV particle, modulating polynucleotide, siRNA or pharmaceutical composition.

[00194] 178. The method of any of the modalities 160-177, in which administration decreases, for example, reduces or inhibits, the expression of a MAPT gene, mRNA and / or protein.

[00195] 179. The method of embodiments 178, in which the MAPT gene, mRNA and / or protein is a wild-type MAPT gene, mRNA or protein.

[00196] 180. The method of modality 178 or 179, in which the gene, Petition 870260044145, dated 11 / 05 / 2026, pages 125 / 1140 121 / 530 mRNA and / or MAPT protein is a mutated MAPT gene, mRNA, or protein (e.g., it comprises at least 1 mutation).

[00197] 181. The method of any of the modalities 171-180, in which administration of the AAV particle, modulating polynucleotide, siRNA or pharmaceutical composition results in a reduction and / or prevention of tau pathology, for example, a decrease in a biomarker of tau pathology (e.g., 18F-flortaucipir, plasma ptau 181 or 18F-PM-PBB3), for example, as measured by a PET scan or PET scan in combination with Braak neuropathological staging and / or serum biomarker staining, for example, compared to a reference (e.g., an individual who did not receive the AAV particle, modulating polynucleotide, siRNA or pharmaceutical composition).

[00198] 182. The method of any of the embodiments 171-181, whereby administration decreases MAPT mRNA levels in the individual, for example, by at least 40%, 44%, 45%, 50%, 55%, 60%, 64%, 65%, 70%, 75%, 76%, 79%, 80%, 84%, 85%, 87% or 90%, for example, in a cell of a brain region (for example, cortex, hippocampus or brainstem), for example, compared to a reference level (for example, mRNA levels in an individual who has not received or before receiving the AAV particle, modulating polynucleotide, siRNA or pharmaceutical composition), for example, when measured by an assay (for example, an assay as described in Example 6).

[00199] 183. The method of any of the modalities 171-182, in which administration decreases MAPT protein levels in the individual, for example, by at least 15%, 17%, 20%, 25%, 30%, 35%, 37%, 40%, 44%, 45%, 46%, 50%, 53%, 55%, 60%, 63%, 64%, 65%, 70%, 72%, 74% or 75%, for example, in a cell of a brain region (e.g., cortex, hippocampus, thalamus or brainstem), Petition 870260044145, dated 11 / 05 / 2026, pp. 126 / 1140 122 / 530 for example, compared to a reference level (e.g., protein levels in an individual who has not received or before receiving the AAV particle, modulating polynucleotide, siRNA, or pharmaceutical composition), for example, when measured by an assay (e.g., an assay as described in Example 6).

[00200] 184. The method of any of the modalities 166-183, in which the individual is a human.

[00201] 185. The method of any of the modalities 166-184, in which the pharmaceutical composition, AAV particle, modulating polynucleotide or siRNA is administered to the individual intravenously, intramuscularly, via intraparenchymal administration, intracerebroventricularly, via intracystinal magna injection (ICM), intrathecally, via focused ultrasound (FUS), for example, coupled with intravenous microbubble administration (FUS-MB) or magnetic resonance-guided FUS coupled with intravenous administration.

[00202] 186. The method of any of the modalities 166-185, in which the pharmaceutical composition, AAV particle, modulating polynucleotide or siRNA is administered to the individual intravenously.

[00203] 187. The method of any of the embodiments 166-186, in which the pharmaceutical composition, AAV particle, modulating polynucleotide or siRNA is administered to the individual by means of intracystinal magna injection (ICM).

[00204] 188. The method of any of the modalities 166-187, in which the pharmaceutical composition, AAV particle, modulating polynucleotide or siRNA is administered to the individual via intrathecal route.

[00205] 189. The pharmaceutical composition of embodiment 159, the AAV particle of any of the embodiments 144-159, an AAV particle comprising the AAV viral genome of any of the embodiments 12-58 or 60-143, the modulating polynucleotide of any Petition 870260044145, dated 11 / 05 / 2026, pp. 127 / 1140 123 / 530 one of the embodiments 59-90, or the siRNA of either embodiment 11 or 13-58 for use in a method of delivering an siRNA to inhibit MAPT expression to a cell.

[00206] 190. The pharmaceutical composition of embodiment 159, the AAV particle of any of the embodiments 144-159, an AAV particle comprising the AAV viral genome of any of the embodiments 12-58 or 60-143, the modulating polynucleotide of any of the embodiments 59-90, or the siRNA of any of the embodiments 11 or 13-58, for use in the manufacture of a medicament.

[00207] 191. The pharmaceutical composition of embodiment 159, the AAV particle of any of the embodiments 144-159, an AAV particle comprising the AAV viral genome of any of the embodiments 12-58 or 60-143, the modulating polynucleotide of any of the embodiments 59-90, or the siRNA of any of the embodiments 11 or 13-58, for use in the treatment of a genetic disorder, neurological disorder (e.g., neurodegenerative disorder), disorder associated with tau expression (e.g., aberrant tau expression) and / or tauopathy.

[00208] 192. Use of the pharmaceutical composition of embodiment 159, of the AAV particle of any of embodiments 144-159, of an AAV particle comprising the AAV viral genome of any of embodiments 12-58 or 60-143, of the modulating polynucleotide of any of embodiments 59-90, or of the siRNA of any of embodiments 11 or 13-58, in the manufacture of a medicament to deliver an siRNA to inhibit MAPT expression to a cell.

[00209] 193. Use of the pharmaceutical composition of embodiment 159, of the AAV particle of any of the embodiments 144-159, of an AAV particle comprising the AAV viral genome of any of the embodiments 12-58 or 60-143, of the modulating polynucleotide of any of the embodiments 59-90, or of the siRNA of any of Petition 870260044145, dated 11 / 05 / 2026, pp. 128 / 1140 124 / 530 of embodiments 11 or 13-58, in the manufacture of a medicament.

[00210] 194. Use of the pharmaceutical composition of embodiment 159, of the AAV particle of any of embodiments 144-159, of an AAV particle comprising the AAV viral genome of any of embodiments 12-58 or 60-143, of the modulating polynucleotide of any of embodiments 59-90, or of the siRNA of any of embodiments 11 or 13-58, in the manufacture of a medicament to treat a genetic disorder, neurological disorder (e.g., neurodegenerative disorder), disorder associated with tau expression (e.g., aberrant tau expression) and / or tauopathy. BRIEF DESCRIPTION OF THE DRAWINGS

[00211] FIG. Figure 1 depicts the relative R / F activity as a percentage over the non-target control (NTC) on the Y-axis after transfection with the MAPT-targeted modulating polynucleotide constructs indicated on the X-axis (from left to right: VOYTaumiR-102-556 (SEQ ID NO: 4381), VOYTaumiR-102-579 (SEQ ID NO: 4383), VOYTaumiR-102-586 (SEQ ID NO: 4384), VOYTaumiR-104-530 (SEQ ID NO: 4385), VOYTaumiR-104-556 (SEQ ID NO: 4386), VOYTaumiR-104-579 (SEQ ID NO: 4388), VOYTaumiR-104-586 (SEQ ID NO: 4389), VOYTaumiR-109-530 (SEQ ID NO: 4390), VOYTaumiR-109-556 (SEQ ID NO: 4391), VOYTaumiR109-579 (SEQ ID NO: 4393), VOYTaumiR-109-586 (SEQ ID NO: 4394), VOYTaumiR-114-530 (SEQ ID NO: 4395), VOYTaumiR-114-556 (SEQ ID NO: 4396), VOYTaumiR-114-579 (SEQ ID NO: 4398), VOYTaumiR114-586 (SEQ ID NO: 4399), VOYTaumiR-116-530 (SEQ ID NO: 4400), VOYTaumiR-116-556 (SEQ ID NO: 4401), VOYTaumiR-116-579 (SEQ ID NO: 4403), VOYTaumiR-116-586 (SEQ ID NO: 4404),VOYTaumiR127-530 (SEQ ID NO: 4405), VOYTaumiR-127-556 (SEQ ID NO: 4406), VOYTaumiR-127-579 (SEQ ID NO: 4408) and VOYTaumiR-127-586 (SEQ ID NO: 4409)). Petition 870260044145, dated 11 / 05 / 2026, pp. 129 / 1140 125 / 530

[00212] FIG. Figure 2 shows the change in times in the remaining MAPT mRNA for each vectored modulating polynucleotide relative to the non-target control (change in times relative to the NTC) on the Y-axis after transfection, with the MAPT-targeted modulating polynucleotide constructs indicated on the X-axis (from left to right: simulation, non-target control (NTC), VOYTaumiR127-530 (SEQ ID NO: 4405), VOYTaumiR-127-556 (SEQ ID NO: 4406), VOYTaumiR-127-579 (SEQ ID NO: 4408), VOYTaumiR-127-586 (SEQ ID NO: 4409), VOYTaumiR-116-530 (SEQ ID NO: 4400), VOYTaumiR116-556 (SEQ ID NO: 4401), VOYTaumiR-116-579 (SEQ ID NO: 4403), VOYTaumiR-116-586 (SEQ ID NO: 4404), VOYTaumiR-114-530 (SEQ ID NO: 4395), VOYTaumiR-114-556 (SEQ ID NO: 4396), VOYTaumiR114-579 (SEQ ID NO: 4398), VOYTaumiR-114-586 (SEQ ID NO: 4399), VOYTaumiR-109-530 (SEQ ID NO: 4390), VOYTaumiR-109-556 (SEQ ID NO: 4391), VOYTaumiR-109-579 (SEQ ID NO: 4393), VOYTaumiR109-586 (SEQ ID NO: 4394),VOYTaumiR-104-530 (SEQ ID NO: 4385), VOYTaumiR-104-556 (SEQ ID NO: 4386), VOYTaumiR-104-579 (SEQ ID NO: 4388), VOYTaumiR-104-586 (SEQ ID NO: 4389), VOYTaumiR102-530 (SEQ ID NO: 4380), VOYTaumiR-102-556 (SEQ ID NO: 4381), VOYTaumiR-102-579 (SEQ ID NO: 4383) and VOYTaumiR-102-586 (SEQ ID NO: 4384)).

[00213] FIG. 3 is a graph showing the change in times in remaining MAPT mRNA for each vectored modulating polynucleotide relative to the non-target control (change in times relative to NTC) on the Y-axis after transfection with increasing concentrations (0.05 μg, 0.16 μg, 0.50 μg, or 1.50 μg per well) of the modulating polynucleotides on the X-axis (from left to right: simulation, non-target control (NTC), VOYTaumiR-127-530 (SEQ ID NO: 4405), VOYTaumiR127-556 (SEQ ID NO: 4406), VOYTaumiR-127-579 (SEQ ID NO: 4408), VOYTaumiR-127-586 (SEQ ID NO: 4409), VOYTaumiR-109-530 (SEQ Petition 870260044145, dated 11 / 05 / 2026, pp. 130 / 1140 126 / 530 ID NO: 4390), VOYTaumiR-109-556 (SEQ ID NO: 4391), VOYTaumiR109-579 (SEQ ID NO: 4393), VOYTaumiR-109-586 (SEQ ID NO: 4394), VOYTaumiR-116-579 (SEQ ID NO: 4403), VOYTaumiR-104-556 (SEQ ID NO: 4386) e VOYTaumiR-104-586 (SEQ ID NO: 4389)).

[00214] FIG. Figure 4 is a graph depicting the change in times in the remaining MAPT mRNA for each vectored modulating polynucleotide relative to the non-target control (change in times relative to NTC) on the Y-axis after transfection with the indicated concentrations (0.5 μg or 1.0 μg) of the modulating polynucleotides on the X-axis (from left to right: simulation, GFP, NTC, positive antisense oligonucleotide (ASO) control MAPT, VOYTaumiR-127-530 (SEQ ID NO: 4405), VOYTaumiR-109-530 (SEQ ID NO: 4390), VOYTaumiR102-582 (SEQ ID NO: 5027), VOYTaumiR-104-582 (SEQ ID NO: 5031), VOYTaumiR-109-582 (SEQ ID NO: 5035), VOYTaumiR-114-582 (SEQ ID NO: 5039), VOYTaumiR-127-582 (SEQ ID NO: 5047), VOYTaumiR102-587 (SEQ ID NO: 5028), VOYTaumiR-109-587 (SEQ ID NO: 5036), VOYTaumiR-114-587 (SEQ ID NO: 5040), VOYTaumiR-104-552 (SEQ ID NO: 5033), VOYTaumiR-104-549 (SEQ ID NO: 5034) and VOYTaumiR116-549 (SEQ ID NO: 5046).

[00215] FIGS. 5A-5E are a series of graphs representing vector genome copies per diploid cell in the cortex (FIG. 5A), hippocampus (FIG. 5B), brainstem (FIG. 5C), thalamus (FIG. 5D), or liver (FIG. 5E) of mice after intravenous injection of vehicle control or AAV particles comprising the VOY9P39 capsid encoding the modulating polynucleotide VOYTaumiR-127-530 (VOY9P39_127-530) at a dose of 3e12 vg / kg, 1e13 vg / kg, or 3e13 vg / kg. Statistical significance was assessed using one-way ANOVA with Tukey's post-hoc multiple comparisons test; *, **, ***, and **** indicate p < 0.05, 0.005, 0.0005, and 0.0001, respectively. Data are presented as group mean ± SEM. Numbers above the Petition 870260044145, dated 11 / 05 / 2026, pp. 131 / 1140 127 / 530 bars indicate the group average in vg / dg (biodistribution).

[00216] FIGS. 6A-6D are a series of graphs representing the change in times in remaining MAPT mRNA levels after treatment in each treatment group relative to the vehicle on the Y-axis, in the cortex (FIG. 6A), hippocampus (FIG. 6B), thalamus (FIG. 6C) or brainstem (FIG. 6D).Figure 6D) of mice after intravenous injection of AAV particles comprising the payload and capsid combinations indicated on the X-axis, which are, from left to right: vehicle control, VOY9P39 capsid and mCherry reporter control at 3e13 vg / kg, VOY9P39 capsid and non-target control (NTC) at 3e13 vg / kg, VOY9P39 capsid and modulating polynucleotide VOYTaumiR-127-530 (127-530) at 3e12 vg / kg, VOY9P39 capsid and modulating polynucleotide VOYTaumiR-127-530 (127-530) at 1e13 vg / kg, VOY9P39 capsid and modulating polynucleotide VOYTaumiR-127-530 (127-530) at 3e13 vg / kg, VOY101 capsid and mCherry reporter control at 3e13 vg / kg and VOY101 capsid and VOYTaumiR-127-530 modulating polynucleotide (127-530) at 3e13 vg / kg. Statistical significance was assessed using one-way ANOVA with Tukey's multiple comparison with p-value, as shown in the graphs.

[00217] FIGS. 7A-7D are a series of graphs depicting the remaining MAPT protein levels after treatment in each treatment group relative to the vehicle in the cortex (FIG. 7A), hippocampus (FIG. 7B), thalamus (FIG. 7C), or brainstem (FIG. 7D) of mice after intravenous injection of the vehicle control (vehicle); or AAV particles comprising the VOY9P39 capsid encoding the modulating polynucleotide VOYTaumiR-127-530 (127-530) administered at a dose of 3e12 vg / kg, 1e13 vg / kg, or 3e13 vg / kg. The percentages above the bars represent the percentage reduction in tau protein after treatment. Statistical significance was assessed using a one-way ANOVA with Tukey's multiple comparison. Petition 870260044145, dated 11 / 05 / 2026, pp. 132 / 1140 128 / 530

[00218] FIGS. 8A-8D are a series of graphs representing the remaining MAPT mRNA levels after treatment in each treatment group relative to the vehicle in the cortex (FIG. 8A), hippocampus (FIG. 8B), thalamus (FIG. 8C) or brainstem (FIG. 8D) of mice after intravenous injection of the vehicle control (vehicle); AAV particles comprising the VOY9P39 capsid encoding the non-target control (NTC) at a dose of 1e13 vg / kg (C9P39-NTC_1E13); AAV particles comprising the VOY9P39 capsid encoding the modulating polynucleotide VOYTaumiR-127-530 at a dose of 1e12 vg / kg (C9P39-127.530_1E12) or 1e13 vg / kg (C9P39-127.530_1E13); or AAV particles comprising the VOY9P39 capsid encoding the modulating polynucleotide VOYTaumiR-127-579 at a dose of 1e13 vg / kg (C9P39-127.579_1E13). Statistical significance was assessed using one-way ANOVA with Tukey's multiple comparisons, with p-values ​​as shown in the graphs. DETAILED DESCRIPTION

[00219] Here are described, among other things, compositions comprising isolated viral particles, for example, recombinants, for example, AAV particles, for administration, for example, vectored administration, of an RNA agent to target MAPT (for example, a siRNA duplex to target MAPT) and methods for producing and using the same. In some embodiments, the RNA agent to target MAPT is a siRNA duplex that modulates, for example, inhibits MAPT expression, for example, a siRNA duplex to target MAPT as described herein. Generally, recombinant AAV particles will include a viral genome comprising a nucleotide sequence, for example, encoding a transgene that encodes an RNA agent to target MAPT (for example, a siRNA duplex to target MAPT) and an AAV capsid protein, for example, an AAV capsid variant described herein. Petition 870260044145, dated 11 / 05 / 2026, pp. 133 / 1140 129 / 530

[00220] Mutations in the MAPT gene have been identified in autosomally dominant inherited frontotemporal tauopathy dementia and chromosome 17-linked parkinsonism (FTDP-17), demonstrating that mutations in the MAPT gene and / or tau protein can lead to neurodegenerative changes in the brain. Mutant tau is considered more amyloidogenic than wild-type tau, meaning it is more likely to become hyperphosphorylated and aggregate as NFTs (Hutton, M. et al., 1998, Nature 393(6686):702-5), and these NFTs may be composed of pathological forms of tau, including, but not limited to, hyperphosphorylated, misfolded, and aggregated tau species, each of which has produced a set of avidly pursued targets. Hyperphosphorylation of tau depresses its binding to microtubules and its microtubule assembly / stability activity. Furthermore, hyperphosphorylation of tau makes it prone to misfolding and aggregation.Without wanting to be limited by theory, it is believed in some modalities that the administration of a siRNA targeting MAPT (e.g., a mutated MAPT gene or a wild-type MAPT gene), for example, a MAPT-targeting siRNA described here, and vectored forms thereof, can reduce tau protein expression, e.g., pathological tau, aggregation, hyperphosphorylation, and / or misfolding, thus modulating, for example, reducing or delaying, the pathology associated with aberrant tau expression and / or tauopathies (e.g., Alzheimer's disease (AD), frontotemporal dementia (FTD), and / or Dravet syndrome (DS)).

[00221] Without wanting to get bogged down in theory, it is believed in some embodiments that the use of an AAV particle or plurality of AAV particles for the vectored delivery of an RNA agent to target MAPT (e.g., a siRNA duplex to target MAPT) described herein would lead to increased exposure in the central nervous system (CNS) and robust expression of the RNA agent for Petition 870260044145, dated 11 / 05 / 2026, pp. 134 / 1140 130 / 530 targets MAPT in the individual, for example, an individual who has or has been diagnosed with a disease associated with tau expression or a neurological disorder described here (e.g., a tauopathy). I. COMPOSITIONS

[00222] According to the present invention, compositions are provided to supply a functional RNA agent for targeting MAPT by adeno-associated virus (AAV) particles, for example, an AAV particle comprising an AAV capsid polypeptide. In some embodiments, an AAV particle, for example, an AAV particle comprising an AAV capsid polypeptide as described herein, or a plurality of particles, may be supplied, for example, delivered, via any of several routes of administration (e.g., via intravenous administration), to a cell, tissue, organ or organism, in vivo, ex vivo, or in vitro. Adeno-associated viruses (AAVs) and AAV particles

[00223] Here are described, among other things, compositions comprising isolated viral particles, for example, recombinants, for example, AAV particles, for administration, for example, vectored administration, of a polynucleotide, for example, a siRNA targeting MAPT, and methods for producing and using the same.

[00224] In some embodiments, an adeno-associated virus (AAV) comprises a small, non-enveloped icosahedral capsid virus of the family Parvoviridae and is characterized by a single-stranded DNA viral genome. Parvoviruses and other members of the family Parvoviridae are generally described in Kenneth I. Berns, Parvoviridae: The Viruses and Their Replication, Chapter 69 in FIELDS VIROLOGY (3rd edition, 1996), the contents of which are incorporated by reference in their entirety. In some embodiments, AAVs have the ability to replicate in vertebrate hosts, including, but not limited to, Petition 870260044145, dated 11 / 05 / 2026, pages 135 / 1140 131 / 530 species: humans, primates, cattle, dogs, horses, and sheep.

[00225] In some embodiments, an AAV particle is used as a biological tool due to its relatively simple structure, its ability to infect a wide range of cells (including quiescent and dividing cells) without integration into the host genome and without replication, and its relatively benign immunogenic profile. The virus genome can be manipulated to contain a minimum of components for the assembly of a functional recombinant virus, or viral particle, which is loaded or designed to target a specific tissue and express or deliver a desired payload, for example, a polynucleotide encoding an siRNA to target MAPT.

[00226] In some embodiments, the AAV particle is either a naturally occurring AAV (e.g., wild-type) or a recombinant AAV. In some embodiments, the wild-type AAV viral genome is a linear single-stranded DNA (ssDNA) molecule approximately 5,000 nucleotides (nt) in length.In some embodiments, inverted terminal repeats (ITRs) cover the viral genome at the 5' and 3' ends, providing origins of replication for the viral genome. In some embodiments, an AAV viral genome typically comprises two ITR sequences. These ITRs have a characteristic T-shaped hairpin structure, defined by a self-complementary region (145 nt in wild-type AAV) at the 5' and 3' ends of the ssDNA, forming an energetically stable double-stranded region. The double-stranded hairpin structures comprise multiple functions, including, but not limited to, acting as an origin for DNA replication, functioning as primers for the host viral cell's endogenous DNA polymerase complex.

[00227] In some embodiments, the AAV particle, for example, an AAV particle (e.g., ssAAVs) described herein comprises a viral genome that is self-complementary (scAAV). In some Petition 870260044145, dated 11 / 05 / 2026, pp. 136 / 1140 In 132 / 530 embodiments, ssAAV comprises nucleic acid molecules, for example, DNA strands, that bind together to form double-stranded DNA. In some embodiments, a scAAV allows rapid expression in a transduced cell because it bypasses the synthesis of the second strand.

[00228] In some embodiments, the wild-type AAV viral genome further comprises nucleotide sequences for two open reading frames, one for the four non-structural Rep proteins (Rep78, Rep68, Rep52, Rep40, encoded by the Rep genes) and one for the three capsid, or structural, proteins (VP1, VP2, VP3, encoded by the capsid genes or Cap genes). The Rep proteins are used for replication and packaging, while the capsid proteins are assembled to create the AAV protein coat, or AAV capsid polypeptide, for example, an AAV capsid variant. Alternative splicing and alternative initiation codons and promoters result in the generation of four different Rep proteins from a single open reading frame and the generation of three capsid proteins from a single open reading frame.Although it varies according to the AAV serotype, as a non-limiting example, for AAV9 (SEQ ID NO: 138) VP1 refers to amino acids 1-736, VP2 refers to amino acids 138-736, and VP3 refers to amino acids 203-736. In other words, VP1 is the complete capsid sequence, while VP2 and VP3 are shorter components of the whole. As a result, sequence changes in the VP3 region are also changes in VP1 and VP2; however, the percentage difference relative to the precursor sequence will be greater for VP3, as it is the shortest sequence of the three. Although described in this document in relation to the amino acid sequence, the nucleic acid sequence encoding these proteins can be described similarly. Together, the three capsid proteins assemble to create the AAV capsid protein. While not wishing to be limited by theory, the protein of... Petition 870260044145, dated 11 / 05 / 2026, pp. 137 / 1140 The 133 / 530 AAV capsid typically comprises a molar ratio of 1:1:10 of VP1:VP2:VP3. In some embodiments, a viral genome of a wild-type AAV, for example, a naturally occurring one, can be modified to replace the rep / cap sequences with a nucleic acid comprising a transgene encoding a payload, for example, an antibody molecule, wherein the genetic element comprises at least one ITR region. In some embodiments, the viral genome of a recombinant AAV comprises two ITR regions, for example, a 5'ITR or a 3'ITR. In some embodiments, the rep / cap sequences can be provided in trans during production to generate AAV particles.In some embodiments, the viral genome of an AAV is comprised in an AAV vector, which further encodes a capsid protein, for example, a structural protein, wherein the capsid protein comprises a VP1 polypeptide, a VP2 polypeptide and / or a VP3 polypeptide; and / or a Rep protein, for example, a non-structural protein, wherein the Rep protein comprises a Rep78 protein, a Rep68 protein, a Rep52 protein and / or a Rep40 protein.

[00229] In some embodiments, the AAV particles of the present invention are recombinant AAV particles that have replication defects and lack the nucleotide sequences that encode the functional Rep and Cap proteins. In some embodiments, these defective AAV particles may lack most or all of the parental coding sequences and carry only one or two AAV ITR sequences and the nucleic acid of interest for delivery to a cell, tissue, organ, or organism.

[00230] The methods for producing and / or modifying AAV particles are disclosed in the art, such as pseudotyped AAV particles (Patent Publications No. PCT W0200028004; WO200123001; WO2004112727; W02005005610; and WO2005072364, the contents of which are incorporated herein by way of Petition 870260044145, dated 11 / 05 / 2026, pp. 138 / 1140 134 / 530 reference in its entirety).

[00231] As described herein, the AAV particles of the invention comprising an AAV capsid polypeptide and a viral genome are capable of providing, for example, delivering, a transgene to a cell, for example, a mammalian cell and / or to an individual. In some embodiments, the recombinant AAV particles of the present invention are capable of vectored delivery of an siRNA (for example, an siRNA to target MAPT). AAV Capsids and Variants thereof

[00232] In some embodiments, an AAV particle, for example, an AAV particle for the vectored delivery of an siRNA described herein (e.g., an siRNA to target MAPT), may comprise an AAV capsid polypeptide, for example, an AAV capsid variant.

[00233] In some embodiments, the AAV capsid polypeptide, for example, the AAV capsid variant, allows penetration of the blood-brain barrier after intravenous administration. In some embodiments, the AAV capsid, for example, the AAV capsid variant, allows penetration of the blood-brain barrier after focused ultrasound (FUS), for example, coupled with intravenous microbubble administration (FUS-MB), or magnetic resonance-guided FUS coupled with intravenous administration. In some embodiments, the AAV capsid, for example, the AAV capsid variant, allows greater distribution to a brain region. In some embodiments, the brain region comprises a frontal cortex, sensory cortex, motor cortex, caudate nucleus, dentate nucleus, cerebellar cortex, cerebral cortex, brainstem, hippocampus, thalamus, putamen, or a combination thereof.In some modalities, the AAV capsid, for example, the AAV capsid variant, allows preferential transduction in one region of the brain relative to transduction. Petition 870260044145, dated 11 / 05 / 2026, pages 139 / 1140 135 / 530 in the dorsal root ganglia (DRG).

[00234] In some embodiments, the AAV capsid polypeptide, for example, the AAV capsid variant, allows for greater distribution to a region of the spinal cord. In some embodiments, the spinal region comprises a region of the cervical spinal cord, a region of the thoracic spinal cord, and / or a region of the lumbar spinal cord.

[00235] In some embodiments, the AAV capsid polypeptide, for example, an AAV capsid variant, comprises a VOY101 capsid polypeptide, a PHPeB capsid polypeptide, an AAVPHP.B (PHP.B) capsid polypeptide, an AAVPHP.N (PHP.N) capsid polypeptide, an AAV1 capsid polypeptide, an AAV2 capsid polypeptide, an AAV5 capsid polypeptide, an AAV9 capsid polypeptide, an AAV9 K449R capsid polypeptide, an AAVrh10 capsid polypeptide, or a functional variant thereof. In some embodiments, the AAV capsid polypeptide, for example, the AAV capsid variant, comprises an amino acid sequence from any of the AAV capsid polypeptides in Table 1, or a substantially identical amino acid sequence (for example, having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98% or 99% sequence identity) to it.In some embodiments, the nucleotide sequence encoding the AAV capsid polypeptide comprises any of the nucleotide sequences in Table 1, or a substantially identical nucleotide sequence (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to it. Petition 870260044145, dated 11 / 05 / 2026, pages 140 / 1140 136 / 530 Table 1: Specimen full-length capsid sequences Description SEQ ID NO: Sequence Information VOY101 1 MAADGYLPDWLEDNLSEGIREWWALKPGAPQ PKANQQHQDNARGLVLPGYKYLGPGNGLDKG EPVNAADAAALEHDKAYDQQLKAGDNPYLKY NHADAEFQERLKEDTSFGGNLGRAVFQAKKR LLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSS AGIGKSGAQPAKRLNFGQTGDTESVPDPQPI GEPPAAPSGVGSLTMASGGGAPVADNNEGAD GVGSSSGNWHCDSQLGGGAPVADNNEGAD TYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKR LNFKLFNIQVKEVTDNNGVKTIANNLTSTVQVF TDSDYQLPYVLGSAHEGCLPPFPADVFMIPQY GYLTLNDGSQAVGRSSFYFGYFGRFQMLG NNFQFSYEFENVPFHSYAHSQSLDRLMNPLI DQYLYLSKTINGSGQNQQTLKFSVAGPSNMA VQGRNYIPGPSYRQRVSTTVTQNNNSEFAW PGASSWALNGRNSLMNPGPAMASHKEGEDR FFPLSGSLIFGKQGTGRDNVDADKVMITNEEI KTTNPVATESYGQVATNHQSDGTLAVPFKAQA QTGWVQNQGILPGMVWQDRDVYLQGPIWAKI PHTDGNFHPSPLMGGFGMKHPPPQILIKNTPV PADPPTAFNKDKLNSFITQYSTGQVSVEIEWEL QKENSKRWNPEQNYEFNYEFNYVNNAV GVYSEPRPIGTRYLTRNL AAV9 / hu.14 K449R 11 MAADGYLPDWLEDNLSEGIREWWALKPGAPQ PKANQQHQDNARGLVLPGYKYLGPGNGLDKG EPVNAADAAALEHDKAYDQQLKAGDNPYLKY NHADAEFQERLKEDTSFGGNLGRAVFQAKKR LLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSS AGIGKSGAQPAKKRLNFGQTGDTESVPDPQPI GEPPAAPSGVGSLTMASGGGAPVADNNEGAD GVGSSSGNWHCDSQWLGDRVITTSTRTWALP TYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKR LNFKLFNIQVKEVTDNNGVKTIANNLTSTVQVF TDSDYQLPYVLGSAHEGCLPPFPADVFMIPQY GYLTLNDGSQAVGRSSFYCLEYFPSQMLRTG NNFQFSYEFENVPFHSSYAHSQSLDRLMNPLI DQYLYYLSRTINGSGQNQQTLKFSVAGPSNMA VQGRNYIPGPSYRQQRVSTTVTQNNNSEFAW. Petição 870260044145, de 11 / 05 / 2026, pág. 141 / 1140 137 / 530 PGASSWALNGRNSLMNPGPAMASHKEGEDR FFPLSGSLIFGKQGTGRDNVDADKVMITNEEEI KTTNPVATESYGQVATNHQSAQAQAQTGWVQ NQGILPGMVWQDRDVYLQGPIWAKIPHTDGNF HPSPLMGGFGMKHPPPQILIKNTPVPADPPTA FNKDKLNSFITQYSTGQVSVEIEWELQKENSK RWNPEIQYTSNYYKSNNVEFAVNTEGVYSEPR PIGTRYLTRNL AAV9 / hu.14 WT (amino acid) 138 MAADGYLPDWLEDNLSEGIREWWALKPGAPQ PKANQQHQDNARGLVLPGYKYLGPGNGLDKG EPVNAADAAAALEHDKAYDQQLKAGDNPYLKY NHADAEFQERLKEDTSFGGNKLKFQKRGR LLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSS AGIGKSGAQPAKRLNFGQTGDTESVPDPQPI GEPPAAPSGVGSLTMASGGGAPVADNNEGAD GVGSSSGNWHCDSQWLGDRVITTSTRTWALP TYNNHLYKQISNSTSGGSSNDNAYFGYFGYF GYFDFNRFHCHFSPRDWQRLINNNWGFRPKR LNFKLFNIQVKEVTDNNGVKTIANNLTSTVQVF TDSDYQLPYVLGSAHEGCLPPFPADVFMIPQY GYLTLNDGSQAVGRSSFYCLEYFPSQMLRTG NNFQFSYEFENVPFHSLSLMQSLQML DQYLYLSKTINGSGQNQQTLKFSVAGPSNMA VQGRNYIPGPSYRQRVSTTVTQNNNSEFAW PGASSWALNGRNSLMNPGPAMASHKEGEDR FFPLSGSLIFGKQGTGRDNVDADKVMITNEEI KTTNPVATESYGQVATNHQSAQQAQGWQ NQGILPGMVWQDRDVYLQGPIWAKIPHTDGNF HPSPLMGGFGMKHPPPQILIKNTPVPADPPTA FNKDKLNSFITQYSTGQVSVEIEWELQKENSK RWNPEIQYTSNYKSNNVEFAVNTEGVYSEPR PIGTRYLTRNL AAV9 / hu.14 WT (DNA) 137 ATGGCTGCCGATGGTTATCTTCCAGATTGGC TCGAGGACAACCTTAGTGAAGGAATTCGCGA GTGGTGGGC 1 1 1 GAAACCTGGAGCCCCTCA ACCCAAGGCAAATCAACAACATCAAGACAAC GCTCGAGGTCTTGTGACTCATCCATC ACCTTGGACCCGGCAACGGACTCCGACAAGG GGGAGCCGGTCAACGCAGCAGACGCGGCG GCCCTCGAGCACGACAAGGCCTACGACCAG CAGCTCAAGGCCGGACAACCCGTACCTC AAGTACAACCACGCCGACGCCGAGTTCCAG GAGCGGCTCAAAGAAGATACGTC 1 III GCACCAGGGCCGGCCGCCGTC AAAAAGAGGCTTCTTGAACCTCTTGGTCTGG. Petition 870260044145, of 11 / 05 / 2026, p. 142 / 1140 138 / 530 TTGAGGAAGCGGCTAAGACGGCTCCTGGAA AGAAGAGGCCTGTAGAGCAGTCTCCTCAGG AACCGGACTCCTCCGCGGGTATTGGCAAAT CGGGTGCACAGCCCGCTAAAAAGAGACTCA ATTTCGGTCAGACTGGCGACACAGAGTCAGT CCCAGACCCTCAACCAATCGGAGAACCTCC CGCAGCCCCCTCAGGTGTGGGATCTCTTAC AATGGCTTCAGGTGGTGGCGCACCAGTGGC AGACAATAACGAAGGTGCCGATGGAGTGGG TAGTTCCTCGGGAAATTGGCATTGCGATTCC CAATGGCTGGGGGACAGAGTCATCACCACC AGCACCCGAACCTGGGCCCTGCCCACCTAC AACAATCACCTCTACAAGCAAATCTCCAACA GCACATCTGGAGGATCTTCAAATGACAACGC CTACTTCGGCTACAGCACCCCCTGGGGGTA TT TT GACTTCAACAGATTCCACTGCCACTTCT CACCACGTGACTGGCAGCGACTCATCAACAA CAACTGGGGATTCCGGCCTAAGCGACTCAA CTTCAAGCTCTTCAACATTCAGGTCAAAGAG GTTACGGACAACAATGGAGTCAAGACCATCG CCAATAACCTTACCAGCACGGTCCAGGTCTT CACGGACTCAGACTATCAGCTCCCGTACGTG CTCGGGTCGGCTCACGAGGGCTGCCTCCCG CCGTTCCCAGCGGACG TT TT CATGATTCCTC AGTACGGGTATCTGACGCTTAATGATGGAAG CCAGGCCGTGGGTCGTTCGTCCT T T TACTGC CTGGAATA T T T CCCGTCGCAAATGCTAAGAA CGGGTAACAACTTCCAGTTCAGCTACGAGTT TGAGAACGTACC T T T CCATAGCAGCTACGCT CACAGCCAAAGCCTGGACCGACTAATGAATC CACTCATCGACCAATACTTGTACTATCTCTCAAAGACTATTAACGGTTCTGGACAGAATCAAC AAACGCTAAAATTCAGTGGCCGGACCCAG CAACATGGCTGTCCAGGGAAGAAACTACATA CCTGGACCCAGCTACCGACAACAGGTGTCT CAACCACTGTGACTCAAAACAACAACAGCCGA ATTT GCTTGGCCTGGAGTTGGCTTCTT CTCAATGGACGTAATAGCTTGATGAATCCTG GACCTGCTATGGCCAGCCACAAAGAAGGAG AGGACCG TTTCTTTCCTTTGTCT GGA TCTTTA ATTTTT GGCAAACAAGGAACTGGAAGAGACA ACGTGGATGCGGACAAAGTCATGATAACCAA CGAAGAAGAAACCTACCTACCTA GCAACGGAGTCCTATGGACAAGTGGCCACA AACCACCAGAGTGCCCAAGCACAGGCGCAG Petition 870260044145, of 11 / 05 / 2026, p. 143 / 1140 139 / 530 ACCGGCTGGGTTCAAAACCAAGGAATACTTC CGGGTATGG 1 1 1 GGCAGGACAGAGATGTGT ACCTGCAAGGACCCA1 1 1 GGGCCAAAATTCC TCACACGGACGGCAAC 1 1 1 CACCCTTCTCCG CTGATGGGAGGG 1 1 1 GGAATGAAGCACCCG CCTCCTCAGATCCTCATCAAAAACACACCTG TACCTGCGGATCCTCCAACGGCCTTCAACAA GGACAAGCTGAACTC1 1 1 CATCACCCAGTAT TCTACTGGCCAAGTCAGCGTGGAGATCGAG TGGGAGCTGCAGAAGGAAAACAGCAAGCGC TGGAACCCGGAGATCCAGTACACTTCCAACT ATTACAAGTCTAATAATGTTGAA1 1 1 GCTGTT AATACTGAAGGTGTATATAGTGAACCCCGCC CCATTGGCACCAGATACCTGACTCGTAATCT GTAA PHP.eB (amino acid) 3 MAADGYLPDWLEDNLSEGIREWWALKPGAPQ PKANQQHQDNARGLVLPGYKYLGPGNGLDKG EPVNAADAAAALEXDKAYDQQLKAGDNPYLKY NHADAEFQERLKEDTSFGGNLGRAVFQKKR LLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSS AGIGKSGAQPAKRLNFGQTGDTESVPDPQPI GEPPAAPSGVGSLTMASGGGAPVADNNEGAD GVGSSSGNWHCDSQWLGDRVITTSTRTWALP TYNNHLYKQISNSTSGGSSNDNAYFGYFGYF GYFDFNRFHCHFSPRDWQRLINNNWGFRPKR LNFKLFNIQVKEVTDNNGVKTIANNLTSTVQVF TDSDYQLPYVLGSAHEGCLPPFPADVFMIPQY GYLTLNDGSQAVGRSSFYCLEYFPSQMLRTG NNFQFSYEFENVPFHSLSLMQSLQML DQYLYYLSRTINGSGQNQQTLKFSVAGPSNMA VQGRNYIPGPSYRQQRVSTTVTQNNNSEFAW PGASSWALNGRNSLMNPGPAMASHKEGEDR FFPLSGSLIFGKQGTGRDNVDADKVMITNEEI KTTNPVATESYGQVATNHQSDGTTFKAVPQQA QTGWVQNQGILPGMVWQDRDVYLQGPIWAKI PHTDGNFHPSPLMGGFGMKHPPPQILIKNTPV PADPPTAFNKDKLNSFITQYSTGQVSVEIEWEL QKENSKRWNPEIQYTSNYYKSNNVEFAVNTE GVYSEPRPIGTRYLTRILTRIGLRNAMi PHP MAADGYLPDWLEDNLSEGIREWWALKPGAPQ PKANQQHQDNARGLVLPGYKYLGPGNGLDKG EPVNAADAAALEHDKAYDQQLKAGDNPYLKY NHADAEFQERLKEDTSFGGNLGRAVFQAKKR LLEPLGLVERPKERPQEPQEPQEPQE AGIGKSGAQPAKRLNFGQTGDTESVPDPQPI. Petition 870260044145, dated 11 / 05 / 2026, pp. 144 / 1140 140 / 530 GEPPAAPSGVGSLTMASGGGAPVADNNEGAD GVGSSSGNWHCDSQWLGDRVITTSTRTWALP TYNNHLYKQISNSTSGGSSNDNAYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKR LNFKLFNIQVKEVTDNNGVKTIANNLTSTVQVF TDSDYQLPYVLGSAHEGCLPPFPADVFMIPQY GYLTLNDGSQAVGRSSFYCLEYFPSQMLRTG NNFQFSYEFENVPFHSSYAHSQSLDRLMNPLI DQYLYYLSRTINGSGQNQQTLKFSVAGPSNMA VQGRNYIPGPSYRQQRVSTTVTQNNNSEFAW PGASSWALNGRNSLMNPGPAMASHKEGEDR FFPLSGSLIFGKQGTGRDNVDADKVMITNEEEI KTTNPVATESYGQVATNHQSAQTLAVPFKAQA QTGWVQNQGILPGMVWQDRDVYLQGPIWAKI PHTDGNFHPSPLMGGFGMKHPPPQILIKNTPV PADPPTAFNKDKLNSFITQYSTGQVSVEIEWEL QKENSKRWNPEIQYTSNYYKSNNVEFAVNTE GVYSEPRPIGTRYLTRNL PHP.N (amino acid) 13 MAADGYLPDWLEDNLSEGIREWWALKPGAPQ PKANQQHQDNARGLVLPGYKYLGPGNGLDKG EPVNAADAAAALEHDKAYDQQLKAGDNPYLKY NHADAEFQERLKEDTSFGGNLGRAVFQKKR LLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSS AGIGKSGAQPAKRLNFGQTGDTESVPDPQPI GEPPAAPSGVGSLTMASGGGAPVADNNEGAD GVGSSSGNWHCDSQWLGDRVITTSTRTWALP TYNNHLYKQISNSTSGGSSNDNAYFGYFGYF GYFDFNRFHCHFSPRDWQRLINNNWGFRPKR LNFKLFNIQVKEVTDNNGVKTIANNLTSTVQVF TDSDYQLPYVLGSAHEGCLPPFPADVFMIPQY GYLTLNDGSQAVGRSSFYCLEYFPSQMLRTG NNFQFSYEFENVPFHSLSLMQSLQML DQYLYYLSRTINGSGQNQQTLKFSVAGPSNMA VQGRNYIPGPSYRQQRVSTTVTQNNNSEFAW PGASSWALNGRNSLMNPGPAMASHKEGEDR FFPLSGSLIFGKQGTGRDNVDADKVMITNEEI KTTNPVATESYGQVATNHPFSNQSAQTLAV QTGWVQNQGILPGMVWQDRDVYLQGPIWAKI PHTDGNFHPSPLMGGFGMKHPPPQILIKNTPV PADPPTAFNKDKLNSFITQYSTGQVSVEIEWEL QKENSKRWNPEIQYTSNYYKSNNVEFAVNTE GVYSEPRPIGTRYLTRNL AAVrh10 (aminoácido) 14 MAADGYLPDWLEDNLSEGIREWWDLKPGAPK PKANQQKQDDGRGLVLPGYKYLGPFNGLDKG EPVNAADAAALEHDKAYDQQLKAGDNPYLRY. Petition 870260044145, of 11 / 05 / 2026, p. 145 / 1140 141 / 530 NHADAEFQERLQEDTSFGGNLGRAVFQAKKR VLEPLGLVEEGAKTAPGKKRPVEPSPQRSPDS STGIGKKGQQPAKKRLNFGQTGDSESVPDPQ PIGEPPAGPSGLGSGTMAAGGGAPMADNNEG ADGVGSSSGNWHCDSTWLGDRVITTSTRTWA LPTYNNHLYKQISNGTSGGSTNDNTYFGYSTP WGYFDFNRFHCHFSPRDWQRLINNNWGFRP KRLNFKLFNIQVKEVTQNEGTKTIANNLTSTIQV FTDSEYQLPYVLGSAHQGCLPPFPADVFMIPQ YGYLTLNNGSQAVGRSSFYCLEYFPSQMLRT GNNFEFSYQFEDVPFHSSYAHSQSLDRLMNPL IDQYLYYLSRTQSTGGTAGTQQLLFSQAGPNN MSAQAKNWLPGPCYRQQRVSTTLSQNNNSNF AWTGATKYHLNGRDSLVNPGVAMATHKDDEE RFFPSSGVLMFGKQGAGKDNVDYSSVMLTSE EEIKTTNPVATEQYGVVADNLQQQNAAPIVGA VNSQGALPGMVWQNRDVYLQGPIWAKIPHTD GNFHPSPLMGGFGLKHPPPQILIKNTPVPADPP TTFSQAKLASFITQYSTGQVSVEIEWELQKENS KRWNPEIQYTSNYYKSTNVDFAVNTDGTYSEP RPIGTRYLTRNL AAVrhIO (DNA) 15 ATGGCTGCCGATGGTTATCTTCCAGATTGGC TCGAGGACAACCTCTCTGAGGGCATTCGCG AGTGGTGGGACTTGAAACCTGGAGCCCCGA AACCCAAAGCCAACCAGCAAAAGCAGGACG ACGGCCGGGGTCTGGTGCTTCCTGGCTACA AGTACCTCGGACCCTTCAACGGACTCGACAA GGGGGAGCCCGTCAACGCGGCGGACGCAG CGGCCCTCGAGCACGACAAGGCCTACGACC AGCAGCTCAAAGCGGGTGACAATCCGTACC TGCGGTATAACCACGCCGACGCCGAG IIICAGGAGCGTCTGCAAGAAGATACGTC iijiGG GGGCAACCTCGGGCGAGCAGTCTTCCAGGC CAAGAAGCGGGTTCTCGAACCTCTCGGTCT GGTTGAGGAAGGCGCTAAGACGGCTCCTGG AAAGAAGAGACCGGTAGAGCCATCACCCCA GCGTTCTCCAGACTCCTCGAGAGAGCAGACCAGCCGAGACCAGCCGACCAGCA ACTCAAC TTT GGGCAGACTGGCGACTCAGA GTCAGTGCCCGACCCTCAACCAATCGGAGA ACCCCCCGCAGGCCCCTCTGGTCTGGGATC TGGTACAATGGCTGCAGGCGGTGGCGCTCC AATGGCAGACAATAACGAAGGCGCCGACGG AGTGGGTAGTTCCGACTGAGGTT GATTCCACATGGCTGGGCGACAGAGTCATC Petition 870260044145, of 11 / 05 / 2026, p. 146 / 1140 142 / 530 ACCACCAGCACCCGAACCTGGCCCTCCCC ACCTACAACAACAACCACCTTACAAGCAAATCT CCAACGGGACTTCGGGAGGAAGCACCAACG ACAACACCACTACTTCGGCTACAGCACCCCCT GGGGTATTTTGACTTTAACAGATTCCACTGC CACTTCTCACCACGTGACTGGCAGCACTCA TCAACAACAACTGGGGATTCCGGCCCAAGA GACTCAACTCAACTCCAAGCTCTTCAACATCCAGGT CAAGGAGGTCACGCCAGAATGAAGGCACCAA GACCATGCGCCAATAACCTTACCAGCACGATT CAGGTCTTTACCGGACTCGGAATACCAGCTCC CGTACGTCTCGGCTCTCGGCCACCAGGCGCGCGCGCGCGCGCGCGCGCGCGCGCGCTCTTCA TGATTCCTCAGTACGGGTACCTGACTCTGAA CAATGGCAGTCAGGCCGTGGCCGTTCCTC CTTCTACTGCCGGAGTACTTTCCTCTCCAAA TGCTGAGAACGGGGCAACAACTTTGAGTTCAG CTACCAGTTTGAGGACGTGCCTTTTCCAGC AGCTACGCGCCAGCCAAAGCCTGGACCGG CTGATGAACCCCTCATCGACCAGATCCTGT ACTACCTGTCTCGGACTCAGTCCACGGGAG GTACCGCAGGAACTCAGCAGTTGCTATTTTTC TCAGGCCGGGCCAATAACATGTCGGCTCA GGCCAAAAACTGGCTACCCGGGCCCTGCTA CCGGCAGCAACGCGTCTCCACGACACTGTC GCAAATAACAACAGCAACTTGCCTGGACC GGTGCCACCAAGTATCATCTGAATGGCAGAG ACTCTCTGGTAAATCCCGGTGTCGCTATGGC AACCCACAAGGACGACGAAGAGCGATTTTTT CCGTCCAGCGGAGTCTTAATGTTTGGGAAAC AGGGAGCTGGAAAAAACAACGTGGACTATAGCAGCGTTATGCTAACCAGTGAGGAAGAAAT TAAAACCACCAACCCAGTGGCCACAGAACAG TACGGCGTGGTGGCCGATAACCTGCAACAG CAAAACGCCGCTCCTATTGTAGGGGCCGTC AACAGTCAAGGAGCCTTACCTGGCATGGTCT GGCAGAACCGGGACGTGTACCTGCAGGGTC CTATCTGGGCCAAGATTCCTCACACGGACG GAAACTTTCATCCCTCGCCGCTGATGGGAG GCTTTGGACTGAAACACCCGCCTCCTCAGAT CCTGATTAAGAATACACCTGTTCCCGCGGAT CCTCCAACTACCTTCAGTCAAGCTAAGCTGG CGTCGTTCATCACGCAGTACAGCACCGGAC AGGTCAGCGTGGAAATTGAATGGGAGCTGC AGAAAGAAAACAGCAAACGCTGGAACCCAG Petição 870260044145, de 11 / 05 / 2026, pág. 147 / 1140 143 / 530 AGATTCAATACACTTCCAACTACTACAAATCT ACAAATGTGGAC 1 1 1 GCTGTTAACACAGATG GCACTTATTCTGAGCCTCGCCCCATCGGCAC CCGTTACCTCACCCGTAATCTGTAA AAV2 (amino acid) 16 MAADGYLPDWLEDTLSEGIRQWPPWKPPGKPPG PKPAERHKDDSRGLVLPGYKYLGPFNGLDKG EPVNEADAAALEHDKAYDRQLDSGDNPYLKY NHADAEFQERLKEDTSFGGNLGRAVFQAKKR VLEPLGLVEEPVKTAPGKKRPVEHSPVEPDSS SGTGKAGQQQPARKRLDQTGVPQDPQDPQ LGQPPAAPSGLGTNTMATGSGAPMADNNEGA DGVGNSSGNWHCDSTWMGDRVITTSTRTWA LPTYNNHLYKQISSQSGASNDNHYFGYSTPW GYFDFNRFHCHFSPRDWQRLINNNWGFRPKR LNFKLFNIQVKEVTQNDGI 1VQVNTST IVQV TDSEYQLPYVLGSAHQGCLPPFPADVFMVPQ YGYLTLNNGSQAVGRSSFYCLEYFPSQMLRT GNNFTFSYTFEDVPFHSYAHSQSLDRLMNPL IDQYLYYLSRTNTPSGI I IQSRLQFSQAGASDI RDQSRNWLPGPCYRQRQRNVNNSESKY SWIGAIKYHLNGRDSLVNPGPAMASHKDDEE KFFPQSGVLIFGKGSEKINVDIEKVMIIDEEEI RTTNPVATEQYGSVSTNLQRGNRQAATADVN IQGVLPGMVWQDRDVYLQGPIWAKIPHIDGH FHPSPLMGGFGLKHPPPQLIKVPANIPPIIII FSAAKFASFIIQYSIGQVSVEIEWELQKENSKR WNPEIQYISNYNKSVNVDFIVDINGVYSEPRP IGIRYLIRNL AAV2 (DNA) 17 ATGGCTGCCGATGGTTATCTTCCAGATTGGC TCGAGGACACTCTCTCTGAAGGAATAAGACAGIGGIGGAAGCICAAACCIGGCCCACCACC ACCAAAGCCCGCAGAGCGGCAIAAGGACGA CAGCAGGGGTCTTGTGCTTCCTGGGTACAA GTACCTCGGACCCTTCAACGGACTCGACAA GGGAGAGCCGGICAACGAGGCAGACGCCG CGGCCCICGAGCACGACAACGACCAGCCAGCCGACCGACCGACCGA ICAAGIACAACCACGCCGACGCGGAG IIICA GGAGCGCCIIAAAGAAGAIACGIC IIII GGG GGCAACCICGGACGAGCAGICIICCAGGCG AAAAAGAGGGTTCTTGAACCTCTGGGCCTGG TTGAGGAACCTGTTAAGACGGCTCCGGGAA AAAAGAGCCGIAGCAGCCCIGCCIGGGA AGCCAGACICCICCICGGGAACCGGAAAGG CGGGCCAGCAGCCIGCAAGAAAAAGAIIGA Petition 870260044145, of 11 / 05 / 2026, p. 148 / 1140 144 / 530 ATTTTGGTCAGACTGGAGACGCAGACTCAGT ACCTGACCCCCAGCCTCTCGGACAGCCACC AGCAGCCCCCTCTGGTCTGGGAACTAATAC GATGGCTACAGGCAGTGGCGCACCAATGGC AGACAATAACGAGGGCGCCGACGGAGTGGG TAATTCCTCGGGAAATTGGCATTGCGATTCC ACATGGATGGGCGACAGAGTCATCACCACC AGCACCCGAACCTGGGCCCTGCCCACCTAC AACAACCACCTCTACAAACAAA T T T CCAGCC AATCAGGAGCCTCGAACGACAATCACTACTT TGGCTACAGCACCCCTTGGGGGTA TTTT GAC TTCAACAGATTCCACTGCCAC T H CACCAC GTGACTGGCAAAGACTCATCAACAACAACTG GGGATTCCGACCCAAGAGACTCAACTTCAAG CTC T T T AACATTCAAGTCAAAGAGGTCACGC AGAATGACGGTACGACGACGATTGCCAATAA CCTTACCAGCACGGTTCAGGTG T T T ACTGAC TCGGAGTACCAGCTCCCGTACGTCCTCGGC TCGGCGCATCAAGGATGCCTCCCGCCGTTC CCAGCAGACGTCTTCATGGTGCCACAGTATG GATACCTCACCCTGAACAACGGGAGTCAGG CAGTAGGACGCTCTTCA TTTT ACTGCCTGGA GTAC T T T CCTTCTCAGATGCTGCGTACCGGA AACAAC T T T ACC T T CAGC T ACAC TTTT GAGGA CGTTCC T T T CCACAGCAGCTACGCTCACAGC CAGAGTCTGGACCGTCTCATGAATCCTCTCA TCGACCAGTACCTGTATTACTTGAGCAGAAC AAACACTCCAAGTGGAACCACCACGCAGTCA AGGCTTCAG TTTT CTCAGGCCGGAGCGAGT GACATTCGGGACCAGTCTAGGAACTGGCTTCCTGGACCCTGTTACCGCCAGCAGCGAGTAT CAAAGACATCTGCGGATAACAACAACAGTGA ATACTCGTGGACTGGAGCTACCAAGTACCAC CTCAATGGCAGAGACTCTCTGGTGAATCCGG GCCCGGCCATGGCAAGCCAAGGACGATG AAGAAAAG TTAGTTCGTTCGTCTCGTTTTGTT GGGAAGCAAGGCTCAGAGAAAACA AATGTGGACATTGAAAAGGTCATGATTACAG ACGAAGAGGAAATCAGGACAACCAATCCCGT GGCTACGGAGCAGTATGGTTCTGTATCTACC AACCTCCAGAGAGGCAACAGACAAGCAAGCT ACCGCAGATGTCACACACAAGGGTTCCAGTCGAGGTTGAGGGAG ACCTTCAGGGGCCCATCTGGGCAAAGATTC CACACACGGACGGACA TTTT CACCCCTCTCC Petition 870260044145, of 11 / 05 / 2026, p. 149 / 1140 145 / 530 CCTCATGGGTGGATTCGGACTTAAACACCCT CCTCCACAGATTCTCATCAAGAACACCCCGG TACCTGCGAATCCTTCGACCACCTTCAGTGC GGCAAAG 1 1 1 GCTTCCTTCATCACACAGTAC TCCACGGGACAGGTCAGCGTGGAGATCGAG TGGGAGCTGCAGAAGGAAAACAGCAAACGC TGGAATCCCGAAATTCAGTACACTTCCAACT ACAACAAGTCTGTTAATGTGGAC 1 1 1ACTGT GGACACTAATGGCGTGTATTCAGAGCCTCGC CCCATTGGCACCAGATACCTGACTCGTAATC TGTAA AAV1 (aminoácido) 18 MAADGYLPDWLEDNLSEGIREWWDLKPGAPK PKANQQKQDDGRGLVLPGYKYLGPFNGLDKG EPVNAADAAALEHDKAYDQQLKAGDNPYLRY NHADAEFQERLQEDTSFGGNLGRAVFQAKKR VLEPLGLVEEGAKTAPGKKRPVEQSPQEPDSS SGIGKTGQQPAKKRLNFGQTGDSESVPDPQP LGEPPATPAAVGPTTMASGGGAPMADNNEGA DGVGNASGNWHCDSTWLGDRVITTSTRTWAL PTYNNHLYKQISSASTGASNDNHYFGYSTPWG YFDFNRFHCHFSPRDWQRLINNNWGFRPKRL NFKLFNIQVKEVTTNDGVTTIANNLTSTVQVFS DSEYQLPYVLGSAHQGCLPPFPADVFMIPQYG YLTLNNGSQAVGRSSFYCLEYFPSQMLRTGN NFTFSYTFEEVPFHSSYAHSQSLDRLMNPLIDQ YLYYLNRTQNQSGSAQNKDLLFSRGSPAGMS VQPKNWLPGPCYRQQRVSKTKTDNNNSNFT WTGASKYNLNGRESIINPGTAMASHKDDEDKF FPMSGVMIFGKESAGASNTALDNVMITDEEEIK ATNPVATERFGTVAVNFQSSSTDPATGDVHA MGALPGMVWQDRDVYLQGPIWAKIPHTDGHFHPSPLMGGFGLKNPPPQILIKNTPVPANPPAEF SATKFASFITQYSTGQVSVEIEWELQKENSKR WNPEVQYTSNYAKSANVDFTVDNNGLYTEPR PIGTRYLTRPL AAV1 (DNA) 19 atggctgccgatggttatcttccagattggctcgaggacaacctct ctgaggg cattcg cgagtggtgg gacttgaaacctg gagccccg aagcccaaagccaaccagcaaaagcaggacgacg g ccg g g gtctggtgcttcctggctacaagtacctcggacccttcaacggact cgacaagggggag cccgtcaacg cggcggacgcagcgg ccc tcgagcacgacaagg cctacgaccagcagctcaaagcg ggtg acaatccgtacctg cg gtataaccacg ccgacg ccgagtttcag gagcgtctgcaagaagatacgtcttttgggggcaacctcgggcg agcagtcttccaggccaagaagcgggttctcgaacctctcggtct ggttgaggaaggcgctaagacggctcctggaaagaaacgtccg Petição 870260044145, de 11 / 05 / 2026, pág. 150 / 1140 146 / 530 gtagagcagtcg ccacaagagccagactcctcctcg gg catcg gcaagacaggccagcagcccgctaaaaagagactcaattttgg tcagactg g cgactcagagtcagtccccg atccacaacctctcg gagaacctccagcaacccccg ctg ctgtgg gacctactacaatg g cttcagg cggtgg cg caccaatg gcagacaataacgaaggc g ccgacg gagtgggtaatg cctcag gaaattg g cattg cg attcc acatg gctggg cgacagagtcatcaccaccagcacccg cacct ggg ccttg cccacctacaataaccacctctacaagcaaatctcc agtgcttcaacggggggccagcaacgacaaccactacttcggcta cagcaccccctg ggg gtattttg atttcaacagattccactgccact tttcaccacgtgactg g cagcgactcatcaacaacaattgg ggat tccggcccaagagactcaacttcaaactcttcaacatccaagtca aggaggtcacgacgaatg atg g cgtcacaaccatcg ctaataa ccttaccagcacggttcaagtcttctcggactcggagtaccagctt ccgtacgtcctcggctctcgcaccagggctgcctccctccgttcc cg g cg gacgtgttcatgattccg caatacg g ctacctgacg ctca acaatg g cagccaagccgtg g gacgttcatccttttactg cctg g aatatttcccttctcagatgctgagaacgggcaacaactttaccttc agctacacctttgaggaagtgcctttccacagcagctacgcgcac agccagagcctg gaccg g ctg atgaatcctctcatcgaccaata cctgtattacctgaacagaactcaaaatcagtccggaagtg ccc aaaacaaggacttgctgtttagccgtgggtctccagctggcatgtc tgttcagcccaaaaactg g ctacctg g accctgttatcg gcagca gcgcgtttctaaaacaaaaacagacaacaacaacagcaatttta cctg gactggtg cttcaaaatataacctcaatg ggcgtg aatccat catcaaccctg g cactgctatg g cctcacacaaagacg acgaa gacaagttctttcccatgagcggtgtcatgatttttggaaaagaga g cg ccg gagcttcaaacactg cattg gacaatgtcatg attacag acgaagaggaaattaaagccactaaccctgtggccaccgaaa g atttg g gaccgtg g cagtcaatttccagagcagcagcacagac cctg cgaccg gagatgtg catg ctatgg gagcattacctgg catg gtgtgg caagatag agacgtgtacctg cagggtcccatttg ggcc aaaattcctcacacagatggacactttcacccgtctcctcttatggg cggctttggactcaagaacccgcctcctcagatcctcatcaaaaa cacg cctgttcctg cgaatcctccg g cg gagttttcagctacaaag tttg cttcattcatcacccaatactccacaggacaagtgagtgtg g aaattgaatgggagctgcagaaagaaaacagcaagcgctgga atcccgaagtg cagtacacatccaattatg caaaatctg ccaac gttgattttactgtggacaacaatggactttatactgagcctcgccc cattggcacccgttaccttacccgtcccctgtaa AAV5 (aminoácido) 20 MSFVDHPPDWLEEVGEGLREFLGLEAGPPKP KPNQQHQDQARGLVLPGYNYLGPGNGLDRGEPVNRADEVAREHDISYNEQLEAGDNPYLKYN HADAEFQEKLADDTSFGGNLGKAVFQAKKRVL EPFGLVEEGAKTAPTGKRIDDHFPKRKKARTE Petition 870260044145, dated 11 / 05 / 2026, pages 151 / 1140 147 / 530 EDSKPSTSSDAEAGPSGSQQLQIPAQPASSLG ADTMSAGGGGPLGDNNQGADGVGNASGDW HCDSTWMGDRVVTKSTRTWVLPSYNNHQYR EIKSGSVDGSNANAYFGYSTPWGYFDFNRFH SHWSPRDWQRLINNYWGFRPRSLRVKIFNIQV KEVTVQDSI 1 IIANNLTSTVQVFTDDDYQLPYV VGNGTEGCLPAFPPQVFTLPQYGYATLNRDNT ENPTERSSFFCLEYFPSKMLRTGNNFEFTYNF EEVPFHSSFAPSQNLFKLANPLVDQYLYRFVS TNNTGGVQFNKNLAGRYANTYKNWFPGPMG RTQGWNLGSGVNRASVSAFATTNRMELEGAS YQVPPQPNGMTNNLQGSNTYALENTMIFNSQ PANPGTTATYLEGNMLITSESETQPVNRVAYN VGGQMATNNQSSTTAPATGTYNLQEIVPGSV WMERDVYLQGPIWAKIPETGAHFHPSPAMGG FGLKHPPPMMLIKNTPVPGNITSFSDVPVSSFIT QYSTGQVTVEMEWELKKENSKRWNPEIQYTNN YNDPQFVDFAPDSTGEYRTTRPIGTRYLTRPL AAV5 (DNA) 21 atgtcttttgttgatcaccctccagattggttggaagaagttggtgaa ggtcttcgcgagtttttgggccttgaagcgggcccaccgaaacca aaacccaatcagcagcatcaagatcaagcccgtggtcttgtg ct g cctggttataactatctcg gacccg g aaacggtctcg atcgagg agagcctgtcaacagggcagacgaggtcgcgcgagagcacg acatctcgtacaacgagcagcttgag gcgg gagacaaccccta cctcaagtacaaccacgcggacgccgagtttcaggagaagctc g ccgacgacacatccttcg ggg gaaacctcg gaaaggcagtctttcaggccaagaaaagggttctcgaaccttttggcctggttgaaga gggtgctaagacgg cccctaccg gaaagcgg atagacgacca ctttccaaaaagaaagaaggcccggaccgaagaggactccaa g ccttccacctcgtcag acg ccgaagctg gacccagcg g atccc agcagctgcaaatcccagcccaaccagcctcaagtttgggagct g atacaatgtctg cgggaggtggcgg cccattg g g cgacaataa ccaaggtg ccg atggagtggg caatg cctcg ggagattgg catt g cg attccacgtg gatgggg gacagagtcgtcaccaagtccac ccgaacctg ggtg ctg cccagctacaacaaccaccagtaccg a gagatcaaaagcggctccgtcgacggaagcaacgccaacgcc tactttggatacagcaccccctgggggtactttgactttaaccgcttc cacagccactggagcccccgagactggcaaagactcatcaac aactactggggcttcagaccccggtccctcagagtcaaaatcttc aacattcaagtcaaagaggtcacggtgcaggactccaccacca ccatcgccaacaacctcacctccaccgtccaagtgtttacggacg acgactaccagctg ccctacgtcgtcg gcaacgg gaccgagg g atg cctg ccg g ccttccctccg caggtctttacg ctg ccg cagtac ggttacg cgacg ctg aaccg cgacaacacagaaaatcccacc gagaggagcagcttcttctgcctagagtactttcccagcaagatg Petição 870260044145, de 11 / 05 / 2026, pág. 152 / 1140 148 / 530 ctgagaacgggcaacaactttgagtttacctacaactttgaggag gtgcccttccactccagcttcgctcccagtcagaacctcttcaagct ggccaacccgctggtggaccagtacttgtaccgcttcgtgagcac aaataacactggcggagtccagttcaacaagaacctggccggg agatacg ccaacacctacaaaaactggttcccg ggg cccatg g g ccgaacccagg g ctggaacctg g g ctccg g ggtcaaccg cg ccagtgtcagcg ccttcg ccacgaccaatagg atggag ctcgag ggcg cgagttaccag gtg cccccg cagccgaacg g catgacc aacaacctccagggcagcaacacctatgccctggagaacacta tg atcttcaacagccagccg g cgaacccg g g caccaccg ccac gtacctcgagg g caacatg ctcatcaccagcgagagcgagac g cagccggtgaaccg cgtg g cgtacaacgtcg gcgggcagat g g ccaccaacaaccagagctccaccactg cccccg cgaccg g cacgtacaacctccaggaaatcgtgcccggcagcgtgtggatg gagagg gacgtgtacctccaaggacccatctg g g ccaagatcc cagagacgggggcg cactttcacccctctccg g ccatg ggcgg attcg gactcaaacacccaccg cccatgatg ctcatcaagaaca cg cctgtg cccg gaaatatcaccagcttctcg gacgtg cccgtca g cagcttcatcacccagtacagcaccg g g caggtcaccgtg g a gatggagtgggagctcaagaaggaaaactccaagaggtggaa cccagagatccagtacacaaacaactacaacgacccccagttt gtggactttg ccccg g acagcaccg gggaatacag aaccacca gacctatcg gaacccg ataccttacccgacccctttaa TTD-001 Underlined 9mer peptide, beginning at position 587 (immediately subsequent to position 586); 743 aa 3636 MAADGYLPDWLEDNLSEGIREWWALKPGAPQ PKANQQHQDNARGLVLPGYKYLGPGNGLDKG EPVNAADAAAALEHDKAYDQQLKAGDNPYLKY NHADAEFQERLKEDTSFGGKNLGRAVFQKKR LLEPLGLVEEAAKTAPGKKRPVEQSPQEPDSS AGIGKSGAQPAKRLNFGQTGDTESVPDPQPI GEPPAAPSGVGSLTMASGGGAPVADNNEGAD GVGSSSGNWHCDSQWLGDRVITTSTRTWALP TYNNHLYKQISNSTSGGSSNDNAYFGYFGYF GYFDFNRFHCHFSPRDWQRLINNNWGFRPKR LNFKLFNIQVKEVTDNNGVKTIANNLTSTVQVF TDSDYQLPYVLGSAHEGCLPPFPADVFMIPQY GYLTLNDGSQAVGRSSFYCLEYFPSQMLRTG NNFQFSYEFENVPFHSLSLMQSLQML DQYLYYLSKTINGSGQNQQTLKFSVAGPSNMA VQGRNYIPGPSYRQQRVSTTVTQNNNSEFAW PGASSWALNGRNSLMNPGPAMASHKEGEDR FFPLSGSLIFGKQGTGRDNVDADKVMITNEEEI KTTN PVATESYGQVATNHQSPLNGAVHLYA AQTGWVQNQGILPGMVWQDRDVYLQGPIWA KIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTP VPADPPTAFNKDKLNSFITQYSTGQVSVEIEWE Petition 870260044145, of 11 / 05 / 2026, p. 153 / 1140 149 / 530LQKENSKRWNPEIQYTSNYYKSNNVEFAVNTE GVYSEPRPIGTRYLTRNL TTD-001 Underlined 9mer peptide 3623 ATGGCTGCCGATGGTTATCTTCCAGATTGGC TCGAGGACAACCTTAGTGAAGGAATTCGA GTGACGTCAGGGCGGA1 ACCCAAGGCAAATCAACAACATCAAGACAAC GCTCGAGGTCTTGTGCTTCCGGGTTACAAAAT ACCTTGGACCCGGCAACGGACTCGACAAGG GGGAGCCGGTCAACGCAGCAGACGCGGCG GCCCTCGAGCACGACAAGGCCTACGACCAG CAGCTCAAGGCCGGAGACACCAGTACCAGCACCGACCGACCGACCGCCG GAGCGGCTCAAAGAAGATACGTC TTTT GGG GGCAACCTCGGGCGAGCAGTCTTCCAGGCC AAAAAAGAGGCTTCTTGAACCTCTTGGTCTGG TTGAGGAAGCGGCTAAGACGGCTCCTGGAA AGAAGAGGCCTGTAGAGCAGTCTCCTCAGG AACCGGACTCCCGTCCGGATTGATT CGGGTGCACAGCCCGCTAAAAAGAGACTCA AiiiCGGTCAGACTGGCGACACAGAGTCAGT CCCAGACCCTCAACCAATCGGAGAACCTCC CGCAGCCCCCTCAGGTGGGATCTCTTAC AATGGCTTCAGGTGGTGGCGCACCAGTGGC AGACAATAACGAAGGTGCCGATGGAGTGGGGG TAGTTCCTCGGGAAATTGGCATTGCGATTCC CAATGGCTGGGGGACAGAGTCATCACCACC AGCACCCGAACCTGGGCCCTGCCCACCTAC AACAATCACCTCTACAAGCAAATCTCCAACA GCACATCTGGAGGATCTTCAAATGACAACGC CTACTTCGGCTACGCCCTGTTGTTGTTGACTTCAACAGATTCCACTGCCACTTCT CACCACGTGACTGGCAGCGACTCATCAACAA CAACTGGGGATTCCGGCCTAAGCGACTCAA CTTCAAGCTCTTCAACATTCAGGTCAAAGAG GTTACGGACAACAATGGAGTCAAGACCATCG CCAATAACCTTACCAGCACGGTCCAGGTCTT CACGGACTCAGACTATCAGCTCCCGTACGTG CTCGGGTCGGCTCACGAGGGCTGCCTCCCG CCGTTCCCAGCGGACG TTTT CATGATTCCTC AGTACGGGTATCTGACGCTTAATGATGGAAG CCAGGCCGTGGGTCGTTCGTCCT T T TACTGC CTGGAATA T T T CCCGTCGCAAATGCTAAGAA CGGGTAACAACTTCCAGTTCAGCTACGAGTT TGAGAACGTACC T T T CCATAGCAGCTACGCT CACAGCCAAAGCCTGGACCGACTAATGAATC Petição 870260044145, de 11 / 05 / 2026, pág. 154 / 1140 150 / 530 CACTCATCGACCAATACTTGTACTATCTCTCA AAGACTATTAACGGTTCTGGACAGAATCAAC AAACGCTAAAATTCAGTGTGGCCGGACCCAG CAACATGGCTGTCCAGGGAAGAAACTACATA CCTGGACCCAGCTACCGACAACAACGTGTCT CAACCACTGTGACTCAACAACAACAGCAGA Alli GCTTGGCCTGGAGCTTCTTCTTGGGCT CTCAATGGACGTAATAGCTTGATGAATCCTG GACCTGCTATGGCCAGCCACAAAGAAGGAG AGGACCG IIICIIICCI llGICl GGA IClllA Aiiiii ggcaaacaactggaagagaca acgtggatgc cgaagaagaaattaaaactaacccggta gcaacggagtcctatggacaagtggccaca aaccaccagagtccgcttaatggtgccgtc catctttatgctcaggcgcagaccggctgg gttcaaaaccaaggaatacttccgggtatgg II i ggcaggacagagatgtgtacctgca IICCCAICGATCCAAATCGATCGATC CGGCAAC III CACCCTTCTCCGCTGATGGGA GGG III GGAATGAAGCACCCGCCTCCTCAG atcctcatcaaaaacacacctgtacctgccg atcctccaacggccttcaaaggacaagct gaactc II i catcacccagtattctactggc caagtcagc cagaaggaaaaccagcggtggaacccg gagatccagtacacttccaactattacaagt ctaataatgttgaa II i gctgttaatactgaa ggtgtatatagtgaaccccgccccattggca ccagatacctgactcgtaatctgtaa VOY9P39 (amino acid)5147 MAADGYLPDWLEDNLSEGIREWWALKPGAPQ PKANQQHQDNARGLVLPGYKYLGPGNGLDKG EPVNAADAAALEHDKAYDQQLKAGDNPYLKY nhadaefqerlkedtsfggnlgravfqakkr lleplglveeaaktapgkkrpveqspqepdss agigksgaqpakkrlnfgqtgdtesvpdpqpi geppaapsgvgsltmasgggapvadnnegad gvgsssgnwhcdsqwlgdrvittstrtwalp tynnhlykqisnstsggssndnayfgystpw GYFDFNRFHCHFSPRDWQRLINNNWGFRPKR LNFKLFNIQVKEVTDNNGVKTIANNLTSTVQVF TDSDYQLPYVLGSAHEGCLPPFPADVFMIPQY GYLTLNDGSQAVGRSSFYCLEYFPSQMLRTG NNFQFSYEFENVPFHSSYAHSQSLDRLMNPLI DQYLYYLSKTINGSGQNQQTLKFSVAGPSNMA Petição 870260044145, de 11 / 05 / 2026, pág. 155 / 1140 151 / 530 VQGRNYIPGPSYRQQRVSTTVTQNNNSEFAW PGASSWALNGRNSLMNPGPAMASHKEGEDR FFPLSGSLIFGKQGTGRDNVDADKVMITNEEI KTTNPVATESYGQVATNHQSDGTGSTTGWAQ AQTGWVQNQGILLPGMVWQDRDVYGGWAQ KIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTP VPADPPTAFNKDKLNSFITQYSTGQVSVEIEWE LQKENSKRWNPEIQYTSNYKSNNVEFAVNTE GVYSEPRPIGTRYLTRNL VOY9P39 (DNA) 5148 ATGGGCTCGTCGTCGTTGTTGTT TCGAGGACAACCTTAGTGAAGGAATTCGCGA GTGGTGGGC 1 1 1 GAAACCTGGAGCCCCTCA ACCCAAGGCAAATCAACAACATCAAGACAAC GCTCGAGGTCTTGTGCTTCCGGGTTACAAAT ACCTTGGACCCGGCAACGGACTTCGACAAGG GGGAGCCGGATCGCGCGCGCGCGCG GCCCTCGAGCACGACAAGGCCTACGACCAG CAGCTCAAGGCCGGAGACAACCCGTACCTC AAGTACAACCACGCCGACGCCGAGTTCCAG GAGCGGCTCAAAGAAGATACGTC 1 III GGG GGCAACCTCGGGCGAGCAGTCTTCCAGGCC AAAAAGAGGCTTCTTGAACCTGCTGCTGCTGTC TTGAGGAAGCGGCTAAGACGGCTCCTGGAA AGAAGAGGCCTGTAGAGCAGTCTCCTCAGG AACCGGACTCCTCCGCGGGTATTGGCAAAT CGGGTGCACAGCCCTAAAAAGAGACTCA AiiiCGGTCAGACTGGCGACACAGAGTCAGT AATGGCTTCAGGTGGTGGCGCACCAGTGGC AGACAATAACGAAGGTGCCGATGGAGTGGGTAGTTCCTCGGGAAATTGGCATTGCGATTCC CAATGGCTGGGGGACAGAGTCATCACCACC AGCACCCGAACCTGGGCCCTGCCCACCTAC AACAATCACCTCTACAAGCAAATCTCCAACA GCACATCTGGAGGATCTTCAAATGACAACGC CTACTTCGGCTACAGCACCCCCTGGGGGTA MM GACTTCAACAGATTCCACTGCCACTTCT CACCACGTGACTGGCAGCGACTCATCAACAA CAACTGGGGATTCCGGCCTAAGCGACTCAA CTTCAAGCTCTTCAACATTCAGGTCAAAGAG GTTACGGACAACAATGGAGTCAAGACCATCG CCAATAACCTTACCAGCACGGTCCAGGTCTT CACGGACTCAGACTATCAGCTCCCGTACGTG CTCGGGTCGGCTCACGAGGGCTGCCTCCCG Petição 870260044145, de 11 / 05 / 2026, pág. 156 / 1140 152 / 530 CCGTTCCCAGCGGACG IIIICA TGATTCCTC AGTACGGGTATCTGACGCTTAATGGAAG CCAGGCCGTGGGTCGTTCGTCCI II IACTGC CTGGAATAI II CCCGICGCAAAIGCIAAGAA CGGGTAACAACTTCCAGTTCAGCTACGAGTT IGAGAACGIACCI II CCACCIAGCAGTCCI CACAGCCAAAGCCIGGACCGACIAAIGAAIC CACTCATCGACCAATACTTGTACTATCTCTCA AAGACTATTAACGGTTCTGGACAGAATCAAC AAACGCIAAAAIICAGIGGCCGGACCCAG CAACATGGCTGTCCAGGGAAGACACACTACATA AIII GCTTGGCCTGGAGCTTCTTCTTGGGCT CTCAATGGACGTAATAGCTTGATGAATCCTG GACCIGCIAIGGCCAGCCACAAAGAAGGAG AGGACCG IIICIIICCIIIGICI GGAICIIIA AIIIIII GGCAAACAAGGAACIGGAAGAGACA ACGIGGAIGCGGACAACAGGAACAGGAGACA CGAAGAAGAAATTAAAACTACTAACCCGGTA GCAACGGAGICCIAIGGACAAGIGGCCACA AACCCACCAGAGIGACGGAACAGGAAGCACA ACAGGAIGGGCACAGGCGCAGACCGGCIG GGTTCAAAAACCAAGGAATACTTCCGGGTATG GIII GGCAGGACAGAGAIGIGIACCAGGACCAGGACCAGGACCAGGAGAGA ACGGCAAC III CACCCπCTCCGCTGATGGG AGGG III GGAAIGAAGCACCCGCCICCICA GATCCTCATCAAAAACACACCTGTACCTGCC GAICCICCAACGGCCIICAACAAGGACAAGC IGAACIC IIICATCACCCAGTATTCTACTGGC CAAGTCAGCGTGGAGATCGAGTGGGAGCTG CAGAAGGAAAACAGCAAGCGGIGGAACCCG GAGATCCAGTACACTTCCAACTATTACAAGT CIAAIAAIGIIGAAI II GCIGIIAAIACIGAA GGTGTATATAGTGAACCCCGCCCCATTGGCA CCAGATACCTGACTCGTAATCTGTAA

[00236] In some embodiments, the AAV capsid polypeptide, for example, the AAV capsid variant, comprises the amino acid sequence of any of the following SEQ ID NOs: 1, 3, 11, 138, 12, 13, 14, 16, 18, 20, 5147, 3636 or a substantially identical amino acid sequence (for example, having at least 70%, Petition 870260044145, dated 11 / 05 / 2026, pp. 157 / 1140 153 / 530 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98% or 99% sequence identity) to it. In some embodiments, the AAV capsid polypeptide, for example, the AAV capsid variant, comprises an amino acid sequence comprising at least one, two or three modifications, for example, substitutions (e.g., conservative substitutions), insertions or deletions, but not more than 30, 20 or 10 modifications, for example, substitutions (e.g., conservative substitutions), insertions or deletions, with respect to the amino acid sequence of any of the SEQ ID NOs: 1, 3, 11, 138, 12, 13, 14, 16, 18, 20 or 3636.In some embodiments, the AAV capsid polypeptide, for example, the AAV capsid variant, comprises an amino acid sequence encoded by the nucleotide sequence of any of the SEQ ID NOs: 137, 15, 17, 19, 21, 3623, or a substantially identical nucleotide sequence (for example, having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98% or 99% sequence identity) with it.

[00237] In some embodiments, the nucleotide sequence encoding the AAV capsid polypeptide, for example, the AAV capsid variant, comprises the nucleotide sequence of any of the SEQ ID NOs: 137, 15, 17, 19, 21, 5148 or 3623, or a substantially identical nucleotide sequence (for example, having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98% or 99% sequence identity) to it. In some embodiments, the nucleotide sequence encoding the AAV capsid polypeptide, for example, the AAV capsid variant, comprises a nucleotide sequence containing at least one, two, or three modifications, for example, substitutions (e.g., conservative substitutions), insertions, or deletions, but not more than 30, 20, or 10 modifications, for example, substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the sequence. Petition 870260044145, dated 11 / 05 / 2026, pp. 158 / 1140 154 / 530 nucleotides of any of the following SEQ IDs: 137, 15, 17, 19, 21, or 3623.

[00238] In some embodiments, the AAV capsid polypeptide, for example, the AAV capsid variant, comprises the amino acid sequence of SEQ ID NO: 138 or a substantially identical amino acid sequence (for example, having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98% or 99% sequence identity) to it. In some embodiments, the AAV capsid polypeptide, for example, the AAV capsid variant, comprises an amino acid sequence comprising at least one, two or three modifications, for example, substitutions (for example, conservative substitutions), but not more than 30, 20 or 10 modifications, for example, substitutions (for example, conservative substitutions), with respect to the amino acid sequence of SEQ ID NO: 138.In some embodiments, the AAV capsid polypeptide, for example, the AAV capsid variant, comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 137 or a substantially identical nucleotide sequence (for example, having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98% or 99% sequence identity) to it. In some embodiments, the nucleotide sequence encoding the AAV capsid polypeptide, for example, the AAV capsid variant, comprises the nucleotide sequence of SEQ ID NO: 137 or a substantially identical nucleotide sequence (for example, having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to it. In some embodiments, the AAV capsid polypeptide, for example, the AAV capsid variant, comprises a substitution at the K449 position, for example, a K449R substitution, numbered according to SEQ ID NO: 138.

[00239] In some embodiments, the capsid polypeptide of Petition 870260044145, dated 11 / 05 / 2026, pp. 159 / 1140 155 / 530 AAV, for example, the AAV capsid variant, comprises the amino acid sequence of SEQ ID NO: 11 or a substantially identical amino acid sequence (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98% or 99% sequence identity) to it. In some embodiments, the AAV capsid polypeptide, for example, the AAV capsid variant, comprises an amino acid sequence comprising at least one, two or three modifications, e.g., substitutions (e.g., conservative substitutions), but not more than 30, 20 or 10 modifications, e.g., substitutions (conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 11, optionally where position 449 is not R.

[00240] In some embodiments, the capsid polypeptide comprises the amino acid sequence of SEQ ID NO: 1 or a substantially identical amino acid sequence (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98% or 99% sequence identity) to it. In some embodiments, the AAV capsid polypeptide, for example, the AAV capsid variant, comprises an amino acid sequence comprising at least one, two or three modifications, for example, substitutions (e.g., conservative substitutions), but not more than 30, 20 or 10 modifications, for example, substitutions (e.g., conservative substitutions), with respect to the amino acid sequence of SEQ ID NO: 1.

[00241] In some embodiments, the capsid polypeptide comprises the amino acid sequence of SEQ ID NO: 3 or a substantially identical amino acid sequence (for example, having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98% or 99% sequence identity) to it. In some embodiments, the AAV capsid polypeptide, for example, the AAV capsid variant, Petition 870260044145, dated 11 / 05 / 2026, pp. 160 / 1140 156 / 530 comprises an amino acid sequence comprising at least one, two or three modifications, for example, substitutions (e.g., conservative substitutions), but not more than 30, 20 or 10 modifications, for example, substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 3.

[00242] In some embodiments, the capsid polypeptide comprises the amino acid sequence of SEQ ID NO: 5147 or a substantially identical amino acid sequence (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98% or 99% sequence identity) to it. In some embodiments, the AAV capsid polypeptide, for example, the AAV capsid variant, comprises an amino acid sequence comprising at least one, two or three modifications, for example, substitutions (e.g., conservative substitutions), but not more than 30, 20 or 10 modifications, for example, substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 5147.

[00243] In some embodiments, a variant of the AAV capsid disclosed herein comprises a modification in loop VIII of AAV9, for example, at positions 580-599, for example, at positions 587, 588, 589 and / or 590, numbered relative to SEQ ID NO: 5, 8, 138 or 3636-3647. In some embodiments, loop (e.g., loop VIII) is used herein interchangeably with the term variable region (e.g., variable region VIII) or VR (e.g., VR-VIII). In some embodiments, loop VIII comprises positions 580-599 (e.g., amino acids VATNHQSAQAQAQTGWVQNQ (SEQ ID NO: 1195)), numbered according to SEQ ID NO: 138. In some embodiments, loop VIII comprises positions 582-593 (e.g., amino acids TNHQSAQAQAQT (SEQ ID NO: 1196)), numbered from Petition 870260044145, dated 11 / 05 / 2026, pp. 161 / 1140 157 / 530 according to SEQ ID NO: 138. In some embodiments, loop VIII comprises positions 587-593 (e.g., amino acids AQAQAQT (SEQ ID NO: 1197)), numbered according to SEQ ID NO: 138. In some embodiments, loop VIII comprises positions 587-590 (e.g., amino acids AQAQ (SEQ ID NO: 5026)), numbered according to SEQ ID NO: 138. In some embodiments, loop VIII or variable region VIII (VR-VIII) is as described in DiMattia et al. Structural Insights into the Unique Properties of the Adeno-Associated Virus Serotype 9, Journal of Virology, 12(86):6947-6958 (the contents of which are incorporated herein by reference in their entirety), for example, comprising positions 581-593 (e.g., ATNHQSAQAQAQT (SEQ ID NO: 1198)), numbered according to SEQ ID NO: 138.

[00244] In some embodiments, the AAV capsid polypeptide, for example, the AAV capsid variant, comprises a peptide comprising the amino acid sequence TLAVPFK (SEQ ID NO: 1262). In some embodiments, the peptide is present immediately after position 588, relative to a reference sequence numbered according to SEQ ID NO: 138. In some embodiments, the capsid polypeptide comprises the amino acid substitutions A587D and Q588G, numbered according to SEQ ID NO: 138.

[00245] In some embodiments, the AAV capsid polypeptide, for example, the AAV capsid variant, comprises the amino acid substitution of K449R, numbered according to SEQ ID NO: 138; and a peptide comprising the amino acid sequence of TLAVPFK (SEQ ID NO: 1262), wherein the peptide is present immediately after position 588, relative to a reference sequence numbered according to SEQ ID NO: 138.

[00246] In some embodiments, the capsid polypeptide of Petition 870260044145, dated 11 / 05 / 2026, pp. 162 / 1140 158 / 530 AAV, for example, the AAV capsid variant, comprises the amino acid substitution of K449R, numbered according to SEQ ID NO: 138; a peptide comprising the amino acid sequence of TLAVPFK (SEQ ID NO: 1262), where the insertion is present immediately after position 588, relative to a reference sequence numbered according to SEQ ID NO: 138; and the amino acid substitutions of A587D and Q588G, numbered according to SEQ ID NO: 138.

[00247] In some embodiments, the AAV capsid polypeptide, for example, the AAV capsid variant, comprises a peptide comprising the amino acid sequence TLAVPFK (SEQ ID NO: 1262), wherein the insertion is present immediately after position 588, relative to a reference sequence numbered according to SEQ ID NO: 138; and the amino acid substitutions A587D and Q588G, numbered according to SEQ ID NO: 138.

[00248] In some embodiments, the AAV capsid polypeptide, for example, the AAV capsid variant, comprises at least 3, 4, 5, 6, 7, 8 or 9 consecutive amino acids from the PLNGAVHLY amino acid sequence (SEQ ID NO: 3648). In some embodiments, the AAV capsid polypeptide, for example, the AAV capsid variant, comprises the amino acid sequence of PLNGAVHLY (SEQ ID NO: 3648), an amino acid sequence comprising at least one, two or three, but no more than four modifications, for example, substitutions (e.g., conservative substitutions), insertions or deletions, with respect to the amino acid sequence of PLNGAVHLY (SEQ ID NO: 3648), or an amino acid sequence comprising at least one, two or three, but no more than four different amino acids with respect to the amino acid sequence of PLNGAVHLY (SEQ ID NO: 3648), optionally in Petition 870260044145, dated 11 / 05 / 2026, pp. 163 / 1140 159 / 530 where position 7 is H. In some embodiments, the amino acid sequence is present in loop VIII. In some embodiments, the amino acid sequence is present immediately after position 586, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. In some embodiments, the amino acid sequence replaces positions 587 and 588 (e.g., A587 and Q588), numbered according to SEQ ID NO: 138. In some embodiments, the amino acid sequence is present immediately after position 586 and replaces positions 587 and 588 (e.g., A587 and Q588), numbered according to SEQ ID NO: 138.

[00249] In some embodiments, the 3 consecutive amino acids comprise PLN. In some embodiments, the 4 consecutive amino acids comprise PLNG (SEQ ID NO: 3678). In some embodiments, the 5 consecutive amino acids comprise PLNGA (SEQ ID NO: 3679). In some embodiments, the 6 consecutive amino acids comprise PLNGAV (SEQ ID NO: 3680). In some embodiments, the 7 consecutive amino acids comprise PLNGAVH (SEQ ID NO: 3681). In some embodiments, the 8 consecutive amino acids comprise PLNGAVHL (SEQ ID NO: 3682). In some embodiments, the 9 consecutive amino acids comprise PLNGAVHLY (SEQ ID NO: 3648).

[00250] In some embodiments, the four consecutive amino acids comprise NGAV (SEQ ID NO: 3683). In some embodiments, the four consecutive amino acids comprise GAVH (SEQ ID NO: 3684). In some embodiments, the five consecutive amino acids comprise NGAVH (SEQ ID NO: 3685). In some embodiments, the five consecutive amino acids comprise GAVHL (SEQ ID NO: 3686). In some embodiments, the five consecutive amino acids comprise AVHLY (SEQ ID NO: 3687). In some Petition 870260044145, dated 11 / 05 / 2026, pp. 164 / 1140 In some embodiments, the six consecutive amino acids comprise NGAVHL (SEQ ID NO: 3688). In some embodiments, the seven consecutive amino acids comprise NGAVHLY (SEQ ID NO: 3689).

[00251] In some embodiments, the AAV capsid polypeptide, for example, the AAV capsid variant (e.g., an AAV capsid variant described herein), comprises an amino acid sequence encoded by the nucleotide sequence CCGCTTAATGGTGCCGTCCATCTTTAT (SEQ ID NO: 3660) or a substantially identical nucleotide sequence (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to it.In some embodiments, the AAV capsid, for example, an AAV capsid variant described herein, comprises an amino acid sequence encoded by a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, for example, substitutions (e.g., conservative substitutions), insertions, or deletions, but not more than ten modifications, for example, substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the nucleotide sequence of CCGCTTAATGGTGCCGTCCATCTTTAT (SEQ ID NO: 3660).In some embodiments, the AAV capsid polypeptide, for example, the AAV capsid variant (e.g., an AAV capsid variant described herein), comprises an amino acid sequence encoded by a nucleotide sequence comprising at least one, two, three, four, five, six, or seven, but not more than ten nucleotides different from the nucleotide sequence of CCGCTTAATGGTGCCGTCCATCTTTAT (SEQ ID NO: 3660).

[00252] In some embodiments, the AAV capsid polypeptide, for example, the AAV capsid variant, comprises amino acid P at position 587, amino acid L at position 588 and the sequence Petition 870260044145, dated 11 / 05 / 2026, pp. 165 / 1140 161 / 530 of amino acids NGAVHLY (SEQ ID NO: 3689), which is present immediately after position 588, corresponding or numbered according to SEQ ID NO: 3636.

[00253] In some embodiments, the AAV capsid polypeptide, for example, the AAV capsid variant, for example, an AAV capsid variant described herein, comprises the amino acid sequence of SEQ ID NO: 3636, or an amino acid sequence with at least 80% (for example, at least about 85, 90, 95, 96, 97, 98 or 99%) sequence identity with it. In some embodiments, the AAV capsid polypeptide, for example, the AAV capsid variant, for example, an AAV capsid variant described herein, comprises the amino acid sequence of SEQ ID NO: 3636, or an amino acid sequence at least 95% identical to it. In some embodiments, the AAV capsid polypeptide, for example, the AAV capsid variant described herein, comprises the amino acid sequence of SEQ ID NO: 3636, or an amino acid sequence at least 99% identical thereto.

[00254] In some embodiments, the AAV capsid polypeptide, for example, the AAV capsid variant, for example, an AAV capsid variant described herein, comprises an amino acid sequence comprising at least one, two or three modifications, substitutions (e.g., conservative substitutions), insertions or deletions, but not more than 30, 20 or 10 modifications, substitutions (e.g., conservative substitutions), insertions or deletions with respect to the amino acid sequence of SEQ ID NO: 3636. In some embodiments, the AAV capsid polypeptide, for example, the AAV capsid variant, for example, an AAV capsid variant described herein, comprises an amino acid sequence with at least one, two or three, but not more than 30, 20 Petition 870260044145, dated 11 / 05 / 2026, pp. 166 / 1140 162 / 530 or 10 different amino acids compared to the amino acid sequence of SEQ ID NO: 3636.

[00255] In some embodiments, the AAV capsid polypeptide, for example, the AAV capsid variant, comprises the amino acid sequence corresponding to positions 138-743, for example, a VP2, of SEQ ID NO: 3636, or a sequence with at least 80% (for example, at least about 85, 90, 95, 96, 97, 98 or 99%) sequence identity with it. In some embodiments, the AAV capsid variant comprises the amino acid sequence corresponding to positions 203-743, for example, a VP3, of SEQ ID NO: 3636, or a sequence with at least 80% (for example, at least about 85, 90, 95, 96, 97, 98 or 99%) sequence identity with it.In some embodiments, the AAV capsid polypeptide, for example, the AAV capsid variant, comprises the amino acid sequence corresponding to positions 138-736, for example, a VP2, with SEQ ID NO: 138, or a sequence with at least 80% (for example, at least about 85, 90, 95, 96, 97, 98 or 99%) sequence identity with it. In some embodiments, the AAV capsid variant comprises the amino acid sequence corresponding to positions 203-736, for example, a VP3, with SEQ ID NO: 138, or a sequence with at least 80% (for example, at least about 85, 90, 95, 96, 97, 98 or 99%) sequence identity with it. In some embodiments, the amino acid sequence is present immediately after position 586, numbered according to either SEQ ID NO: 138 or 3636, optionally where the amino acid replaces positions 587 and 588 (e.g., A587 and Q588), numbered according to SEQ ID NO: 138.In some forms, the amino acid sequence corresponds to positions 587-595 of SEQ ID NO: 3636.

[00256] In some embodiments, the capsid polypeptide of Petition 870260044145, dated 11 / 05 / 2026, pp. 167 / 1140 163 / 530 AAV, for example, the AAV capsid variant, comprises one or two, but no more than three different amino acids (e.g., substitutions, e.g., conservative substitutions) relative to the amino acid sequence of PLNGAVHLY (SEQ ID NO: 3648), wherein the AAV capsid variant comprises (a) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 138 or 3636; (b) a VP2 protein comprising the amino acid sequence of positions 138-736 of SEQ ID NO: 138 or positions 138-743 of SEQ ID NO: 5, 8 or 3636; (c) a VP3 protein comprising the amino acid sequence of positions 203-736 of SEQ ID NO: 138 or positions 203-743 of SEQ ID NO: 5, 8 or 3636; or (d) an amino acid sequence with at least 90% (for example, at least about 95, 96, 97, 98, or 99%) sequence identity with any of the amino acid sequences in (a)-(c).In some embodiments, the amino acid sequence is present immediately after position 586, numbered according to either SEQ ID NO: 138 or 3636, optionally where the amino acid substitutes for positions 587 and 588 (e.g., A587 and Q588), numbered according to SEQ ID NO: 138. In some embodiments, the amino acid sequence corresponds to positions 587-595 of SEQ ID NO: 3636.

[00257] In some embodiments, the AAV capsid polypeptide, for example, the AAV capsid variant, comprises one or two, but no more than three different amino acids (e.g., substitutions, for example, conservative substitutions) with respect to the PLNGAVHLY amino acid sequence (SEQ ID NO: 3648), wherein the AAV capsid variant comprises the amino acid sequence of any of the SEQ ID NOs: 5, 8, 138 or 3636 or an amino acid sequence with at least 90% (e.g., at least about 95, 96, 97, 98 or 99%) sequence identity with SEQ ID NO: 3636. In some embodiments, the sequence of Petition 870260044145, dated 11 / 05 / 2026, pp. 168 / 1140 The 164 / 530 amino acid sequence is present immediately after position 586, numbered according to either SEQ ID NO: 138 or 3636, optionally where the amino acid replaces positions 587 and 588 (e.g., A587 and Q588), numbered according to SEQ ID NO: 138. In some embodiments, the amino acid sequence corresponds to positions 587-595 of SEQ ID NO: 3636.

[00258] In some embodiments, the AAV capsid polypeptide, for example, the AAV capsid variant, comprises an amino acid sequence comprising at least 5, 6, 7, 8 or 9 consecutive amino acids from the PLNGAVHLY amino acid sequence (SEQ ID NO: 3648), wherein: (i) the 5 consecutive amino acids comprise PLNGA (SEQ ID NO: 3679); (ii) the 6 consecutive amino acids comprise PLNGAV (SEQ ID NO: 3680); (iii) the 7 consecutive amino acids comprise PLNGAVH (SEQ ID NO: 3681); (iv) the 8 consecutive amino acids comprise PLNGAVHL (SEQ ID NO: 3682); or (v) the 9 consecutive amino acids comprise PLNGAVHLY (SEQ ID NO: 3648), wherein the AAV capsid variant comprises: (a) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 3636; (b) a VP2 protein comprising the amino acid sequence of positions 138-736 of SEQ ID NO: 138 or positions 138-743 of SEQ ID NO: 3636;(c) a VP3 protein comprising the amino acid sequence from positions 203-736 of SEQ ID NO: 138 or positions 203-743 of SEQ ID NO: 3636; or (d) an amino acid sequence with at least 90% (e.g., at least about 95, 96, 97, 98, or 99%) sequence identity with any of the amino acid sequences in (a)-(c). In some embodiments, the amino acid sequence is present immediately after position 586, numbered according to either SEQ ID NO: 138 or 3636, optionally wherein the amino acid substitutes for positions 587 and 588 (e.g., A587 and; Petition 870260044145, dated 11 / 05 / 2026, pp. 169 / 1140 165 / 530 Q588), numbered according to SEQ ID NO: 138. In some embodiments, the amino acid sequence corresponds to positions 587595 of SEQ ID NO: 3636.

[00259] In some embodiments, the AAV capsid polypeptide, for example, the AAV capsid variant, comprises an amino acid sequence comprising at least 5, 6, 7, 8 or 9 consecutive amino acids from the PLNGAVHLY amino acid sequence (SEQ ID NO: 3648), wherein: (i) the 5 consecutive amino acids comprise PLNGA (SEQ ID NO: 3679); (ii) the 6 consecutive amino acids comprise PLNGAV (SEQ ID NO: 3680); (iii) the 7 consecutive amino acids comprise PLNGAVH (SEQ ID NO: 3681); (iv) the 8 consecutive amino acids comprise PLNGAVHL (SEQ ID NO: 3682); or (v) the 9 consecutive amino acids comprise PLNGAVHLY (SEQ ID NO: 3648), wherein the AAV capsid variant comprises the amino acid sequence of any of the SEQ ID NOs: 5, 8 or 3636 or an amino acid sequence with at least 90% (e.g., at least about 95, 96, 97, 98 or 99%) sequence identity with any of the SEQ ID NO: 3636.In some embodiments, the amino acid sequence is present immediately after position 586, numbered according to either SEQ ID NO: 138 or 3636, optionally where the amino acid substitutes for positions 587 and 588 (e.g., A587 and Q588), numbered according to SEQ ID NO: 138. In some embodiments, the amino acid sequence corresponds to positions 587-595 of SEQ ID NO: 3636.

[00260] In some embodiments, the nucleotide sequence encoding an AAV capsid polypeptide, for example, an AAV capsid variant described herein, comprises the nucleotide sequence of SEQ ID NO: 3623, or a nucleotide sequence with at least 80% (for example, at least about 85, 90, 95, Petition 870260044145, dated 11 / 05 / 2026, pp. 170 / 1140 166 / 530 96, 97, 98 or 99% sequence identity with it. In some embodiments, the nucleotide sequence encoding the AAV capsid variant comprises a nucleotide sequence comprising at least one, two, or three modifications, for example, substitutions, insertions, or deletions, but not more than 30, 20, or 10 modifications, for example, substitutions, insertions, or deletions, relative to the nucleotide sequence of SEQ ID NO: 3623. In some embodiments, the nucleotide sequence encoding the AAV capsid variant comprises a nucleotide sequence comprising at least one, two, or three, but not more than 30, 20, or 10 different nucleotides, relative to the nucleotide sequence of SEQ ID NO: 3623. In some embodiments, the nucleic acid sequence encoding an AAV capsid polypeptide, for example, an AAV capsid variant, described herein is codon-optimized.

[00261] In some embodiments, an AAV capsid polypeptide, for example, an AAV capsid variant described herein, has an increased tropism for a CNS cell or tissue, for example, a brain cell, brain tissue, spinal cord cell or spinal cord tissue, relative to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 138.

[00262] In some embodiments, an AAV capsid polypeptide, for example, an AAV capsid variant of the present invention, has reduced tropism for the liver. In some embodiments, an AAV capsid variant comprises a modification, for example, substitution (e.g., conservative substitution), insertion, or deletion, which results in reduced tropism (e.g., dedirection) and / or activity in the liver. In some embodiments, the reduced liver tropism is compared to a similar capsid. Petition 870260044145, dated 11 / 05 / 2026, pp. 171 / 1140 167 / 530 that does not comprise the modification, for example, a wild-type capsid polypeptide. In some embodiments, a described AAV capsid variant comprises a modification, for example, substitution (e.g., conservative substitution), insertion, or deletion, that results in one or more of the following properties: (1) reduced liver tropism; (2) diverted liver expression; (3) reduced liver activity; and / or (4) reduced galactose binding. In some embodiments, the reduction in any or all of properties (1)-(3) is compared to a similar AAV capsid variant that does not comprise the modification. Exemplary modifications are provided in WO 2018 / 119330; Pulicherla et al. (2011) Mol. Ther. 19(6): 1070-1078; Adachi et al. (2014) Nature Communications 5(3075), DOI: 10.1038 / ncomms4075; and Bell et al. (2012) J. Virol. 86(13): 7326-33; the content of which is incorporated here by reference in its entirety.In some embodiments, the AAV capsid variant comprises a modification, for example, substitution (e.g., conservative substitution), insertion or deletion, at position N470 (e.g., N470A), D271 (e.g., D271A), N272 (e.g., N272A), Y446 (e.g., Y446A), N498 (e.g., N498Y or N498I), W503 (e.g., W503R or W503A), L620 (e.g., L620F) or a combination thereof, relative to a reference sequence numbered according to SEQ ID NO: 138.In some embodiments, the AAV capsid variant comprises one, two, three, four, five, or all amino acids other than N at position 470 (e.g., A), one amino acid other than D at position 271 (e.g., A), one amino acid other than N at position 272 (e.g., A), one amino acid other than Y at position 446 (e.g., A), one amino acid other than N at position 498 (e.g., Y or I), one amino acid other than W at position 503 (e.g., R or A), and one amino acid other than L at position 620 (e.g., F), relative to a reference sequence. Petition 870260044145, dated 11 / 05 / 2026, pp. 172 / 1140 168 / 530 numbered according to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises a modification, for example, substitution (e.g., conservative substitution), insertion or deletion, at positions N470 (e.g., N470A), D271 (e.g., D271A), N272 (e.g., N272A), Y446 (e.g., Y446A) and W503 (e.g., W503R or W03A), relative to a reference sequence numbered according to SEQ ID NO: 138. In some embodiments, the AAV capsid variant comprises a modification, for example, substitution (e.g., conservative substitution), insertion or deletion, at N498 (e.g., N498Y) and L620 (e.g., L620F).

[00263] In some embodiments, a variant of the AAV capsid included herein comprises a modification as described in Adachi et al. (2014) Nature Communications 5(3075), DOI: 10.1038 / ncomms4075, the contents of which are incorporated herein by reference in their entirety. Exemplary modifications that alter or do not alter tissue transduction in at least the brain, liver, heart, lung and / or kidney can be found in Supplementary Data 2 showing AAV Barcode-Seq data obtained with AAV9-AA-VBCLib from Adachi et al. (supra), the contents of which are incorporated herein by reference in their entirety.

[00264] In some embodiments, an AAV capsid polypeptide, for example, an AAV capsid variant of the present invention, is isolated, for example, recombinant. In some embodiments, a polynucleotide encoding an AAV capsid polypeptide, for example, an AAV capsid variant of the present invention, is isolated, for example, recombinant.

[00265] The present invention relates to structural capsid proteins (including VP1, VP2 and VP3) that are encoded by capsid genes (Cap). These capsid proteins form an envelope. Petition 870260044145, dated 11 / 05 / 2026, pp. 173 / 1140 169 / 530 structural outline of the outer protein (i.e., capsid) of a viral vector, such as AAV. VP capsid proteins synthesized from Cap polynucleotides generally include a methionine as the first amino acid in the peptide sequence (Met1), which is associated with the start codon (AUG or ATG) in the corresponding Cap nucleotide sequence. However, it is common for a first methionine residue (Met1) or generally any first amino acid (AA1) to be cleaved after or during polypeptide synthesis by protein processing enzymes such as Met-aminopeptidases. This Met / AA cleavage process usually correlates with a corresponding acetylation of the second amino acid in the polypeptide sequence (e.g., alanine, valine, serine, threonine, etc.). Met cleavage usually occurs with VP1 and VP3 capsid proteins, but it can also occur with VP2 capsid proteins.

[00266] When Met / AA cleavage is incomplete, a mixture of one or more (one, two, or three) VP capsid proteins comprising the viral capsid may be produced, some of which may include a Met1 / AA1 amino acid (Met+ / AA+) and some of which may not have a Met1 / AA1 amino acid as a result of Met / AA cleavage (Met / AA-). For further discussion of Met / AA cleavage in capsid proteins, see Jin, et al. Direct Liquid Chromatography / Mass Spectrometry Analysis for Complete Characterization of Recombinant Adeno-Associated Virus Capsid Proteins. Hum Gene Ther Methods. 2017 Oct. 28(5):255-267; Hwang, et al. N-Terminal Acetylation of Cellular Proteins Creates Specific Degradation Signals. Science. February 19, 2010. 327(5968): 973-977; whose content is incorporated into this document by reference in its entirety.

[00267] According to the present invention, references to capsid proteins are not limited to (Met- / AA-) cut or (Met+ / AA+) uncut and may, in this context, refer to capsid proteins. Petition 870260044145, dated 11 / 05 / 2026, pp. 174 / 1140 170 / 530 independent, to viral capsids consisting of a mixture of capsid proteins and / or to polynucleotide sequences (or fragments thereof) that encode, describe, produce or result in capsid proteins of the present invention. A direct reference to a capsid protein or capsid polypeptide (such as VP1, VP2 or VP2) may also include VP capsid proteins that include a Met1 / AA1 amino acid (Met+ / AA+), as well as corresponding VP capsid proteins that do not have the Met1 / AA1 amino acid as a result of the cleavage of Met / AA (Met- / AA-).

[00268] According to the present invention, a reference to a specific SEQ ID NO: (whether a protein or nucleic acid) comprising or encoding, respectively, one or more capsid proteins that include an amino acid Met1 / AA1 (Met+ / AA+) should be understood as referring to VP capsid proteins that do not possess the amino acid Met1 / AA1 since, upon review of the sequence, any sequence that simply does not possess the first listed amino acid (Met1 / AA1 or not) becomes readily apparent.

[00269] As a non-limiting example, reference to a VP1 polypeptide sequence that is 736 amino acids long and includes an amino acid Met1 (Met+) encoded by the start codon AUG / ATG can also be understood as referring to a VP1 polypeptide sequence that is 735 amino acids long and does not include the amino acid Met1 (Met-) from the 736 amino acid Met+ sequence. As a second non-limiting example, reference to a VP1 polypeptide sequence that is 736 amino acids long and includes an amino acid AA1 (AA1+) encoded by any NNN start codon can also be understood as referring to a VP1 polypeptide sequence that is 735 amino acids long and does not include the amino acid AA1 (AA1-) from the 736 amino acid AA1+ sequence. Petition 870260044145, dated 11 / 05 / 2026, pp. 175 / 1140 171 / 530

[00270] References to viral capsids formed from VP capsid proteins (as reference to specific AAV capsid serotypes) may incorporate VP capsid proteins that include an amino acid Met1 / AA1 (Met+ / AA1+), corresponding VP capsid proteins that lack the amino acid Met1 / AA1 as a result of the cleavage of Met / AA1 (Met- / AA1-), and combinations thereof (Met+ / AA1+ and Met- / AA1-).

[00271] As a non-limiting example, an AAV capsid serotype may include VP1 (Met+ / AA1+), VP1 (Met- / AA1-), or a combination of VP1 (Met+ / AA1+) and VP1 (Met- / AA1-). An AAV capsid serotype may also include VP3 (Met+ / AA1+), VP3 (Met- / AA1-), or a combination of VP3 (Met+ / AA1+) and VP3 (Met- / AA1-); and may also include similar optional combinations of VP2 (Met+ / AA1) and VP2 (Met- / AA1-).

[00272] Also provided here are polynucleotide sequences encoding any of the AAV capsid variants described above and AAV particles, vectors and cells comprising them. Viral Genome

[00273] In some respects, an AAV particle of the present invention, for example, an AAV particle comprising an AAV capsid polypeptide, for example, an AAV capsid variant described herein, comprises a viral genome encoding an agent to target MAPT, for example, a MAPT-targeting siRNA duplex or a modulator polynucleotide encoding a MAPT-targeting siRNA duplex.

[00274] In some embodiments, an AAV particle, as described herein, comprising an AAV capsid polypeptide, for example, an AAV capsid variant described herein, can be used for the delivery of a viral genome to a tissue (e.g., Petition 870260044145, dated 11 / 05 / 2026, pp. 176 / 1140 172 / 530 CNS, DRG and / or muscle). In some embodiments, an AAV particle comprising an AAV capsid polypeptide, for example, an AAV capsid variant described herein, can be used to deliver a viral genome to a tissue or cell, for example, CNS, DRG, or muscle cell or tissue. In some embodiments, an AAV particle of the present invention is a recombinant AAV particle. In some embodiments, an AAV particle of the present invention is an isolated AAV particle.

[00275] In some embodiments, the AAV particles described herein are used to deliver the agent to the target MAPT (e.g., a MAPT-targeted siRNA duplex or a modulating polynucleotide encoding a CNS cell siRNA duplex) after intravenous administration.

[00276] In some embodiments, a viral genome of an AAV particle comprising an AAV capsid polypeptide, for example, an AAV capsid variant as described herein, comprises a nucleic acid comprising a transgene encoding the MAPT target agent (e.g., a MAPT target siRNA duplex or a modulator polynucleotide encoding an siRNA duplex (e.g., a MAPT target siRNA duplex)). In some embodiments, the viral genome comprises an inverted terminal repeat (ITR) sequence. In some embodiments, the viral genome comprises two ITR sequences, for example, one at the 5' end of the viral genome (e.g., 5' relative to the encoded payload) and one at the 3' end of the viral genome (e.g., 3' relative to the encoded payload).In some embodiments, a viral genome of the AAV particles described herein (e.g., comprising an AAV capsid variant described herein) may comprise a regulatory element (e.g., promoter), untranslated regions (UTRs), a miR binding site, and a polyadenylation sequence. Petition 870260044145, dated 11 / 05 / 2026, p. 177 / 1140 173 / 530 (polyA), a stuffer sequence, an intron and / or a linker sequence, for example, to increase transgene expression.

[00277] In some embodiments, viral genome components are selected and / or engineered for expression of an agent to target MAPT (e.g., a MAPT-targeted siRNA duplex or a modulator polynucleotide encoding an siRNA duplex (e.g., a MAPT-targeted siRNA duplex)) in a target tissue (e.g., a CNS tissue, e.g., brain tissue or spinal cord tissue) or a target cell (e.g., a CNS cell, e.g., a brain cell or a spinal cord cell). Viral Genome Component: Inverted Terminal Repeats (ITRs)

[00278] In some embodiments, the viral genome comprises one ITR and a transgene encoding a payload. In some embodiments, the viral genome has two ITRs. In some embodiments, the two ITRs flank the nucleotide sequence encoding the payload at the 5' and 3' ends. In some embodiments, ITRs function as origins of replication comprising recognition sites for replication. In some embodiments, ITRs comprise sequence regions that may be complementary and symmetrically arranged. In some embodiments, the ITRs incorporated into viral genomes as described in this document may consist of naturally occurring polynucleotide sequences or recombinantly derived polynucleotide sequences.

[00279] In some embodiments, the ITR may be of the same serotype as the capsid polypeptide, for example, a capsid variant selected from any of the known serotypes or a variant thereof. In some embodiments, the ITR may be of a different serotype than the capsid. In one embodiment, the viral genome Petition 870260044145, dated 11 / 05 / 2026, pp. 178 / 1140 174 / 530 comprises two ITR sequence regions, wherein the ITRs are of the same serotype as each other. In another embodiment, the viral genome comprises two ITR sequence regions, wherein the ITRs are of different serotypes. Non-limiting examples include zero, one, or both ITRs having the same serotype as the capsid. In one embodiment, both ITRs of the viral genome of the AAV particle are AAV2 ITRs.

[00280] In some embodiments, the ITR comprises the nucleotide sequence of SEQ ID NO: 5197, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to it. In ...

Claims

1. Short interfering ribonucleic acid (siRNA) to inhibit microtubule-associated tau protein (MAPT) expression, characterized in that it comprises a sense strand sequence and an antisense strand sequence, wherein: (i) the antisense strand sequence comprises at least 20 or 21 contiguous nucleotides of any of the following SEQ ID NOs: 4908, 4920, 4924, 5057, 4916, 4912, 5080, 5104 or 5128; and (ii) the sense strand sequence comprises at least 20 or 21 contiguous nucleotides of any of the following SEQ ID NOs: 4906, 4926, 4946, 4966, 4986, 5006, 4918, 4938, 4958, 4978, 4998, 4922, 4942, 4962, 4982, 5002, 5022, 5054, 5060, 5064, 5066, 5070, 5074, 4914, 4934, 4954, 4974, 4994, 5014, 4910, 4930, 4950, 4970, 4990, 5010, 5077, 5084, 5088, 5092, 5096, 5098, 5101, 5108, 5112, 5116, 5120, 5122, 5125, 5132, 5136, 5140, 5144, or 5146;wherein the sense strand sequence and the antisense strand sequence comprise a region of complementarity of at least 15, 16, 17, 18, 19, or 20 nucleotides.

2. Viral genome of an adeno-associated virus (AAV), characterized in that it comprises a nucleotide sequence positioned between two terminal inverted repeats (ITRs), wherein the nucleotide sequence encodes an siRNA to inhibit MAPT, wherein the siRNA comprises a sense strand sequence and an antisense strand sequence, wherein: (i) the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of any of the SEQ ID NOs: 4908, 4920, 4924, 5057, 4916, 4912, 5080, 5104, or 5128; and (ii) the sense strand sequence comprises at least 19, 20 or 21 contiguous nucleotides of any of the following SEQ ID Nos: 4906, 4926, 4946, 4966, 4986, 5006, 4918, 4938, 4958, 4978, 4998, 4922, Petition 870250070208, dated 06 / 08 / 2025, page.537 / 621 2 / 68 4942, 4962, 4982, 5002, 5022, 5054, 5060, 5064, 5066, 5070, 5074, 4914, 4934, 4954, 4974, 4994, 5014, 4910, 4930, 4950, 4970, 4990, 5010, 5077, 5084, 5088, 5092, 5096, 5098, 5101, 5108, 5112, 5116, 5120, 5122, 5125, 5132, 5136, 5140, 5144, or 5146; wherein the sense strand sequence and the antisense strand sequence comprise a complementarity region of at least 15, 16, 17, 18, 19, or 20 nucleotides.

3. siRNA, according to claim 1, or AAV viral genome, according to claim 2, characterized in that: (i) the antisense strand comprises at least 20 contiguous nucleotides of any of the SEQ ID NOs: 4908, 4920, 4924 or 4912; and / or the sense strand comprises at least 20 contiguous nucleotides of any of the following SEQ ID numbers: 4906, 4926, 4946, 4966, 4986, 5006, 4918, 4938, 4958, 4978, 4998, 4922, 4942, 4962, 4982, 5002, 5022, 4910, 4930, 4950, 4970, 4990, or 5010; (ii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4908 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any of the SEQ ID NOs: 4906, 4926, 4946, 4966, 4986, or 5006;(iii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4920 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any of the SEQ ID NOs: 4918, 4938, 4958, 4978 or 4998; (iv) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4924 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any of the Petition 870250070208, dated 06 / 08 / 2025, page. 538 / 621 3 / 68 of the SEQ ID NOs: 4922, 4942, 4962, 4982, 5002, or 5022; (v) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4912 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any of the SEQ ID NOs: 4910, 4930, 4950, 4970, 4990, or 5010;(vi) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4916 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any of the SEQ ID NOs: 4914, 4934, 4954, 4974, 4994 or 5014; (vii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any of the SEQ ID NOs: 5101, 5108, 5112, 5116, 5120 or 5122; (viii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any of the SEQ ID NOs: 5125, 5132, 5136, 5140, 5144 or 5146;(ix) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of any of the SEQ ID NOs: 5077, 5084, 5088, 5092, 5096 or 5098; ​​or (x) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5057 and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of any of the Petition 870250070208, dated 06 / 08 / 2025, page. 539 / 621 4 / 68 of the SEQ ID Nos: 5054, 5060, 5064, 5066, 5070 or 5074.; 4. siRNA, according to claim 1 or 3, or AAV viral genome, according to claim 2 or 3, characterized in that: (i) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4908 and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4906; (ii) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4920 and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4918; (iii) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4924 and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4922;(iv) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4908 and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4966; (v) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4912 and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4970; (vi) the antisense strand sequence comprises at least Petition 870250070208, dated 06 / 08 / 2025, page. 540 / 621 5 / 68 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4920 and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4978;(vii) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4924 and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4982; (viii) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4910; (ix) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4914; (x) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5057;and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5054; (xi) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4908; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4926; (xii) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4930; (xiii) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4934;(xiv) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4938; (xv) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4924; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4942; (xvi) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5060; (xvii) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4908;and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4946; (xviii) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4950; (xix) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4954; (xx) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4958;(xxi) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4924; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4962; (xxii) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5064; (xxiii) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4974; (xxiv) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5057;and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5066; (xxv) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4908; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4986; (xxvi) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4990; (xxvii) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4994;(xxviii) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4998; (xxix) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4924; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5002; (xxx) the antisense strand sequence comprises at least Petition 870250070208, dated 06 / 08 / 2025, page. 544 / 621 9 / 68 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5070; (xxxi) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4908;and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5006; (xxxii) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5010; (xxxiii) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5014; (xxxiv) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4958;(xxxv) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 4924; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5022; (xxxvi) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5074; (xxxvii) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5077; (xxxviii) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5080;and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5084; (xxxix) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5088; (xl) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5092; (xli) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5096;(xlii) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5098; ​​(xliii) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5101; (xliv) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5108; (xlv) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5104;and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5112; (xlvi) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5116; (xlvii) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5120; (xlviii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5122;(xlix) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5125; (l) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5132; (li) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5136; (lii) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5128;and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5140; (lii i) the antisense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5144; or (liv) the antisense strand sequence comprises at least Petition 870250070208, dated 06 / 08 / 2025, page 548 / 621 13 / 68 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises at least 20 contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 5146.; 5. siRNA, according to any one of claims 1, 3 or 4, or AAV viral genome according to any one of claims 2 to 4, characterized in that: (i) the antisense strand comprises the nucleotide sequence of any one of the SEQ ID NOs: 4908, 4920, 4924 or 4912; and / or the sense strand comprises the nucleotide sequence of any of the following SEQ ID numbers: 4906, 4926, 4946, 4966, 4986, 5006, 4918, 4938, 4958, 4978, 4998, 4922, 4942, 4962, 4982, 5002, 5022, 4910, 4930, 4950, 4970, 4990 or 5010; (ii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908 and the sense strand sequence comprises the nucleotide sequence of any of the SEQ ID NOs: 4906, 4926, 4946, 4966, 4986 or 5006; (iii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920 and the sense strand sequence comprises the nucleotide sequence of any of the SEQ ID NOs: 4918, 4938, 4958, 4978 or 4998;(iv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924 and the sense strand sequence comprises the nucleotide sequence of any of the SEQ ID NOs: 4922, 4942, 4962, 4982, 5002 or 5022; (v) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912 and the sense strand sequence comprises the nucleotide sequence of any of the SEQ ID NOs: 4910, 4930, 4950, 4970, 4990 or 5010; (vi) the antisense strand sequence comprises the sequence Petition 870250070208, dated 06 / 08 / 2025, page. (vii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises the nucleotide sequence of any of the SEQ ID NOs: 5101, 5108, 5112, 5116, 5120 or 5122;(viii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises the nucleotide sequence of any of the SEQ ID NOs: 5125, 5132, 5136, 5140, 5144 or 5146; (ix) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises the nucleotide sequence of any of the SEQ ID NOs: 5077, 5084, 5088, 5092, 5096 or 5098; ​​or (x) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises the nucleotide sequence of any of the following SEQ ID numbers: 5054, 5060, 5064, 5066, 5070, or 5074.

6. siRNA, according to any one of claims 1 or 3 to 5, or AAV viral genome according to any one of claims 2 to 5, characterized in that: (i) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4906; (ii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4918; (iii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924 and the sense strand sequence Petition 870250070208, dated 06 / 08 / 2025, p. 550 / 621 15 / 68 comprises the nucleotide sequence of SEQ ID NO: 4922; (iv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4966;(v) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4970; (vi) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4978; (vii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4982; (viii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4910; (ix) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4914;(x) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5054; (xi) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4926; (xii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4930; (xiii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence Petition 870250070208, dated 06 / 08 / 2025, page 551 / 621 16 / 68 comprises the nucleotide sequence of SEQ ID NO: 4934; (xiv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4938;(xv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4942; (xvi) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5060; (xvii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4946; (xviii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4950; (xix) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4954;(xx) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4958; (xxi) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4962; (xxii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5064; (xxiii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence Petition 870250070208, dated 06 / 08 / 2025, page 552 / 621 17 / 68 comprises the nucleotide sequence of SEQ ID NO: 4974; (xxiv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5066;(xxv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4986; (xxvi) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4990; (xxvii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4994; (xxviii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4998; (xxix) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5002;(xxx) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5070; (xxxi) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5006; (xxxii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5010; (xxxiii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence Petition 870250070208, dated 06 / 08 / 2025, page 553 / 621 18 / 68 comprises the nucleotide sequence of SEQ ID NO: 5014; (xxxiv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4958;(xxxv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5022; (xxxvi) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5074; (xxxvii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5077; (xxxviii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5084; (xxxix) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5088;(xl) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5092; (xli) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5096; (xlii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5098; ​​(xliii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence Petition 870250070208, dated 06 / 08 / 2025, page 554 / 621 19 / 68 comprises the nucleotide sequence of SEQ ID NO: 5101; (xliv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5108;(xlv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5112; (xlvi) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5116; (xlvii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5120; (xlviii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5122; (xlix) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5125;(l) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5132; (li) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5136; (lii) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5140; (lii i) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence Petition 870250070208, dated 06 / 08 / 2025, page 555 / 621 20 / 68 comprises the nucleotide sequence of SEQ ID NO: 5144; or (liv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5146.; 7. siRNA, according to any one of claims 1 or 3 to 6, or AAV viral genome, according to any one of claims 2 to 6, characterized in that: (i) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4907 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4905; (ii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4919 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4917; (iii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4923 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4921;(iv) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4907 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4965; (v) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4911 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4969; (vi) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4919 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4977;or (vii) the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4923 and the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4981.; 8. siRNA, according to any one of claims 1 or 3 to 7, or AAV viral genome, according to any one of claims 2 to 7, characterized in that: (i) the sense strand sequence, the antisense strand sequence, or both the sense strand sequence and the antisense strand sequence comprise at least 15-30, 19-21, or 25-30 nucleotides in length, for example, 17, 18, 20, 21, 22, 25, or 30 nucleotides in length; (ii) the sense strand sequence, the antisense strand sequence, or both the sense strand sequence and the antisense strand sequence comprise an overhang, for example, an overhang at the 5' end of the sense strand sequence and / or at the 3' end of the antisense strand sequence, of 1 or 2 nucleotides; (iii) the sense tape and the antisense tape comprise an incompatibility; and / or (iv) the antisense tape and the target sequence comprise an incompatibility.

9. Modulating polynucleotide, characterized in that Petition 870250070208, dated 06 / 08 / 2025, page 557 / 621 22 / 68 comprises siRNA as defined in any of claims 1 or 3 to 8.

10. AAV viral genome, according to any one of claims 2 to 8, characterized in that the viral genome further encodes a modulator polynucleotide comprising the sense and antisense strands of siRNA.

11. Modulating polynucleotide, according to claim 9, or AAV viral genome, according to claim 10, characterized in that the modulating polynucleotide further comprises one, two, three, or all of: (i) a 5' flanking region; (ii) a loop region; and (iii) a 3' flanking region.

12. Modulating polynucleotide, according to claim 11, or AAV viral genome, according to claim 11, characterized in that: (A) (i) the 5' flanking region comprises the nucleotide sequence of any of the SEQ ID NOs: 4878-4886; a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical thereto; a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of any of the SEQ ID NOs: 4878-4886; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but not more than ten modifications with respect to the nucleotide sequence of any of the SEQ ID NOs: 4878-4886; (ii) the loop region comprises the nucleotide sequence of any of the SEQ ID NOs: 4887-4896;a nucleotide sequence that is at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to it; a nucleotide sequence comprising Petition 870250070208, dated 06 / 08 / 2025, page 558 / 621 23 / 68 one, two, three, or four, but no more than five nucleotides different from the nucleotide sequence of any of the SEQ ID NOs: 4887-4896; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications from the nucleotide sequence of any of the SEQ ID NOs: 4887-4896; and / or (iii) the 3' flanking region comprises the nucleotide sequence of any of the SEQ ID NOs: 4897-4904; a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to it; a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications with respect to the nucleotide sequence of any of the SEQ ID NOs: 4897-4904;or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but not more than ten modifications with respect to the nucleotide sequence of any of the SEQ ID NOs: 4897-4904; and / or (B) (i) the nucleotide sequence encoding the 5' flanking region comprises the nucleotide sequence of any of the SEQ ID NOs: 4353-4361, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to it; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but not more than ten nucleotides different with respect to the nucleotide sequence of any of the SEQ ID NOs: 4353-4361; or a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications with respect to the nucleotide sequence of any of the SEQ ID Nos: 4353-4361;(ii) the nucleotide sequence encoding the loop region comprises the nucleotide sequence of any of the SEQ ID NOs: 4362-4371; a nucleotide sequence at least 85%, Petition 870250070208, dated 06 / 08 / 2025, page 559 / 621 24 / 68 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to it; a nucleotide sequence comprising one, two, three or four, but not more than five nucleotides different from the nucleotide sequence of any of the SEQ ID NOs: 4362-4371; or a nucleotide sequence comprising one, two, three, or four, but not more than five, modifications with respect to the nucleotide sequence of any of the SEQ ID NOs: 4362-4371; and / or (iii) the nucleotide sequence encoding the 3' flanking region comprises the nucleotide sequence of any of the SEQ ID NOs: 4372-4379; a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to it;a nucleotide sequence comprising one, two, three, four, five, six, or seven, but not more than ten nucleotides different from the nucleotide sequence of any of the SEQ ID NOs: 4372-4379; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but not more than ten modifications from the nucleotide sequence of any of the SEQ ID NOs: 4372-4379.

13. Modulating polynucleotide, according to any one of claims 9, 11 or 12, or AAV viral genome, according to any one of claims 10 to 12, characterized in that the modulating polynucleotide comprises: (A) (i) a 5' flanking region comprising the nucleotide sequence of SEQ ID NO: 4879, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4879, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4879; or a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten different nucleotides in relation to the nucleotide sequence of SEQ ID NO: 4879;(ii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4887, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4887, a nucleotide sequence comprising one, two, three or four, but not more than five nucleotides different from the nucleotide sequence of SEQ ID NO: 4887; or a nucleotide sequence comprising one, two, three or four, but not more than five nucleotides different from the nucleotide sequence of SEQ ID NO: 4887;and (iii) a 3' flanking region of SEQ ID NO: 4898, a nucleotide sequence that is at least 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from the nucleotide sequence of SEQ ID NO: 4898; (B) (i) a 5' flanking region comprising the nucleotide sequence of SEQ ID NO: 4879, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4879, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4879;or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but not more than ten modifications with respect to the nucleotide sequence of SEQ ID NO: 4879; Petition 870250070208, dated 06 / 08 / 2025, p. 561 / 621 26 / 68 (ii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4888, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4888, a nucleotide sequence comprising one, two, three, or four, but not more than five nucleotides different from the nucleotide sequence of SEQ ID NO: 4888; or a nucleotide sequence comprising one, two, three or four, but not more than five modifications with respect to the nucleotide sequence of SEQ ID NO: 4888;and (iii) a 3' flanking region of SEQ ID NO: 4898, a nucleotide sequence that is at least 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from the nucleotide sequence of SEQ ID NO: 4898; (C) (i) a 5' flanking region comprising the nucleotide sequence of SEQ ID NO: 4879, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4879, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4879;or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but not more than ten modifications with respect to the nucleotide sequence of SEQ ID NO: 4879; (ii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4887, a nucleotide sequence by Petition 870250070208, dated 06 / 08 / 2025, page 562 / 621 27 / 68 less than 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4887, a nucleotide sequence comprising one, two, three, or four, but not more than five nucleotides different from the nucleotide sequence of SEQ ID NO: 4887; or a nucleotide sequence comprising one, two, three or four, but not more than five modifications with respect to the nucleotide sequence of SEQ ID NO: 4887;and (iii) a 3' flanking region of SEQ ID NO: 4899, a nucleotide sequence that is at least 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4899, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4899, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from the nucleotide sequence of SEQ ID NO: 4899; or (D) (i) a 5' flanking region comprising the nucleotide sequence of SEQ ID NO: 4880, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4880, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4880;or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but not more than ten modifications with respect to the nucleotide sequence of SEQ ID NO: 4880; (ii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4891, a nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4891, a nucleotide sequence comprising one, two, Petition 870250070208, dated 06 / 08 / 2025, page 563 / 621 28 / 68 three or four, but not more than five nucleotides different with respect to the nucleotide sequence of SEQ ID NO: 4891; or a nucleotide sequence comprising one, two, three or four, but not more than five modifications with respect to the nucleotide sequence of SEQ ID NO: 4891;and (iii) a 3' flanking region of SEQ ID NO: 4900, a nucleotide sequence that is at least 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4900, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4900, or a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from SEQ ID NO: 4900.

14. Modulating polynucleotide, according to any one of claims 9 or 11 to 13, or AAV viral genome, according to any one of claims 10 to 13, characterized in that the modulating polynucleotide comprises, in the order 5' to 3': (i) the 5' flanking region, sense strand sequence, loop region, antisense strand sequence and 3' flanking region; or (ii) the 5' flanking region, antisense strand sequence, loop region, sense strand sequence and 3' flanking region.

15. Modulating polynucleotide, according to any one of claims 9 or 11 to 14, or AAV viral genome, according to any one of claims 10 to 14, characterized in that the modulating polynucleotide comprises in the 5' to 3' order: (A) (i) a 5' flanking region comprising the nucleotide sequence of SEQ ID NO: 4880; a sequence of nucleotides at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4880; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4880; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but not more than ten modifications from the nucleotide sequence of SEQ ID NO: 4880; (ii) the sense strand sequence of SEQ ID NO: 4906;(iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4891; a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4891; a nucleotide sequence comprising one, two, three or four, but not more than five nucleotides different from the nucleotide sequence of SEQ ID NO: 4891; or a nucleotide sequence comprising one, two, three or four, but not more than five modifications from the nucleotide sequence of SEQ ID NO: 4891; (iv) the antisense strand sequence of SEQ ID NO: 4908; and (v) a 3' flanking region comprising the nucleotide sequence of SEQ ID NO: 4900; a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4900; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4900;or a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications with respect to SEQ ID NO: 4900; (B) (i) a 5' flanking region comprising the nucleotide sequence of SEQ ID NO: 4880; a sequence of nucleotides at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4880; a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4880; or a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications with respect to the nucleotide sequence of SEQ ID NO: 4880; (ii) the sense strand sequence of SEQ ID NO: 4918; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4891;a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4891; a nucleotide sequence comprising one, two, three, or four, but not more than five nucleotides different from the nucleotide sequence of SEQ ID NO: 4891; or a nucleotide sequence comprising one, two, three, or four, but not more than five modifications from the nucleotide sequence of SEQ ID NO: 4891; (iv) the antisense strand sequence of SEQ ID NO: 4920; and (v) a 3' flanking region comprising the nucleotide sequence of SEQ ID NO: 4900; a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4900; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4900;or a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications with respect to SEQ ID NO: 4900; (C) (i) a 5' flanking region comprising the nucleotide sequence of SEQ ID NO: 4880; a sequence of nucleotides at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4880; a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4880; or a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications with respect to the nucleotide sequence of SEQ ID NO: 4880; (ii) the sense strand sequence of SEQ ID NO: 4922; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4891;a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4891; a nucleotide sequence comprising one, two, three, or four, but not more than five nucleotides different from the nucleotide sequence of SEQ ID NO: 4891; or a nucleotide sequence comprising one, two, three, or four, but not more than five modifications from the nucleotide sequence of SEQ ID NO: 4891; (iv) the antisense strand sequence of SEQ ID NO: 4924; and (v) a 3' flanking region comprising the nucleotide sequence of SEQ ID NO: 4900; a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4900; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4900;or a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications in relation to SEQ ID NO: 4900; (D) (i) a 5' flanking region comprising the nucleotide sequence of SEQ ID NO: 4879, a sequence of nucleotides at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4879, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4879; or a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications with respect to the nucleotide sequence of SEQ ID NO: 4879; (ii) the sense strand sequence of SEQ ID NO: 4966;(iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4888, a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4888, a nucleotide sequence comprising one, two, three or four, but not more than five nucleotides different from the nucleotide sequence of SEQ ID NO: 4888; or a nucleotide sequence comprising one, two, three or four, but not more than five modifications from the nucleotide sequence of SEQ ID NO: 4888; (iv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908;and (v) a 3' flanking region of SEQ ID NO: 4898, a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from the nucleotide sequence of SEQ ID NO: 4898; (E) (i) a 5' flanking region comprising Petition 870250070208, dated 06 / 08 / 2025, page. 568 / 621 33 / 68 the nucleotide sequence of SEQ ID NO: 4879, a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4879, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4879;or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but not more than ten modifications with respect to the nucleotide sequence of SEQ ID NO: 4879; (ii) the sense strand sequence of SEQ ID NO: 4970; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4888, a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4888, a nucleotide sequence comprising one, two, three, or four, but not more than five nucleotides different with respect to the nucleotide sequence of SEQ ID NO: 4888; or a nucleotide sequence comprising one, two, three or four, but not more than five modifications with respect to the nucleotide sequence of SEQ ID NO: 4888; (iv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912;and (v) a 3' flanking region of SEQ ID NO: 4898, a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from the nucleotide sequence of SEQ ID NO: 4898; Petition 870250070208, dated 06 / 08 / 2025, p. 569 / 621 34 / 68 (F) (i) a 5' flanking region comprising the nucleotide sequence of SEQ ID NO: 4879, a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4879, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4879;or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but not more than ten modifications with respect to the nucleotide sequence of SEQ ID NO: 4879; (ii) the sense strand sequence of SEQ ID NO: 4978; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4888, a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4888, a nucleotide sequence comprising one, two, three, or four, but not more than five nucleotides different with respect to the nucleotide sequence of SEQ ID NO: 4888; or a nucleotide sequence comprising one, two, three or four, but not more than five modifications with respect to the nucleotide sequence of SEQ ID NO: 4888; (iv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920;and (v) a 3' flanking region of SEQ ID NO: 4898, a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from the nucleotide sequence of Petition 870250070208, dated 06 / 08 / 2025, page 570 / 621 35 / 68 SEQ ID NO: 4898; or (G) (i) a 5' flanking region comprising the nucleotide sequence of SEQ ID NO: 4879, a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4879, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4879;or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but not more than ten modifications with respect to the nucleotide sequence of SEQ ID NO: 4879; (ii) the sense strand sequence of SEQ ID NO: 4982; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4888, a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4888, a nucleotide sequence comprising one, two, three, or four, but not more than five nucleotides different with respect to the nucleotide sequence of SEQ ID NO: 4888; or a nucleotide sequence comprising one, two, three or four, but not more than five modifications with respect to the nucleotide sequence of SEQ ID NO: 4888; (iv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924;and (v) a 3' flanking region of SEQ ID NO: 4898, a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from the nucleotide sequence of SEQ ID NO: 4898.; 16. Modulating polynucleotide, according to any one of claims 9 or 11 to 15, or AAV viral genome, according to any one of claims 10 to 15, characterized in that the nucleotide sequence encoding the modulating polynucleotide comprises in the order 5' to 3': (A) (i) a 5' flanking region comprising the nucleotide sequence of SEQ ID NO: 4355; a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4355; a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4355; or a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications with respect to the nucleotide sequence of SEQ ID NO: 4355; (ii) the sense strand sequence of SEQ ID NO: 4905;(iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4366; a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4366; a nucleotide sequence comprising one, two, three or four, but not more than five nucleotides different from the nucleotide sequence of SEQ ID NO: 4366; or a nucleotide sequence comprising one, two, three or four, but not more than five modifications from the nucleotide sequence of SEQ ID NO: 4366; (iv) the antisense strand sequence of SEQ ID NO: 4907; and (v) a 3' flanking region comprising the nucleotide sequence of SEQ ID NO: 4375; a sequence of Petition 870250070208, dated 06 / 08 / 2025, page 572 / 621 37 / 68 nucleotides at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4375;a nucleotide sequence comprising one, two, three, four, five, six, or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4375; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but not more than ten modifications from SEQ ID NO: 4375; (B) (i) a 5' flanking region comprising the nucleotide sequence of SEQ ID NO: 4355; a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4355; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4355; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but not more than ten modifications from the nucleotide sequence of SEQ ID NO: 4355; (ii) the sense strand sequence of SEQ ID NO: 4917;(iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4366; a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4366; a nucleotide sequence comprising one, two, three or four, but not more than five nucleotides different from the nucleotide sequence of SEQ ID NO: 4366; or a nucleotide sequence comprising one, two, three or four, but not more than five modifications from the nucleotide sequence of SEQ ID NO: 4366; (iv) the antisense strand sequence of SEQ ID NO: 4919; and (v) a 3' flanking region comprising the nucleotide sequence of SEQ ID NO: 4375; a sequence of Petition 870250070208, dated 06 / 08 / 2025, page 573 / 621 38 / 68 nucleotides at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4375;a nucleotide sequence comprising one, two, three, four, five, six, or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4375; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but not more than ten modifications from SEQ ID NO: 4375; (C) (i) a 5' flanking region comprising the nucleotide sequence of SEQ ID NO: 4355; a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4355; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4355; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but not more than ten modifications from the nucleotide sequence of SEQ ID NO: 4355; (ii) the sense strand sequence of SEQ ID NO: 4921;(iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4366; a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4366; a nucleotide sequence comprising one, two, three or four, but not more than five nucleotides different from the nucleotide sequence of SEQ ID NO: 4366; or a nucleotide sequence comprising one, two, three or four, but not more than five modifications from the nucleotide sequence of SEQ ID NO: 4366; (iv) the antisense strand sequence of SEQ ID NO: 4923; and (v) a 3' flanking region comprising the nucleotide sequence of SEQ ID NO: 4375; a sequence of Petition 870250070208, dated 06 / 08 / 2025, page 574 / 621 39 / 68 nucleotides at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4375;a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4375; or a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from SEQ ID NO: 4375; (D) (i) a 5' flanking region comprising the nucleotide sequence of SEQ ID NO: 4354, a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4354, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4354; or a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from the nucleotide sequence of SEQ ID NO: 4354; (ii) the sense strand sequence of SEQ ID NO: 4965;(iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4363, a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4363, a nucleotide sequence comprising one, two, three or four, but not more than five nucleotides different from the nucleotide sequence of SEQ ID NO: 4363; or a nucleotide sequence comprising one, two, three or four, but not more than five modifications from the nucleotide sequence of SEQ ID NO: 4363; (iv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4907;and (v) a 3' flanking region of SEQ ID NO: 4373, Petition 870250070208, dated 06 / 08 / 2025, page 575 / 621 40 / 68 a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from the nucleotide sequence of SEQ ID NO: 4373; (E) (i) a 5' flanking region comprising the nucleotide sequence of SEQ ID NO: 4354, a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4354, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4354;or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but not more than ten modifications with respect to the nucleotide sequence of SEQ ID NO: 4354; (ii) the sense strand sequence of SEQ ID NO: 4969; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4363, a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4363, a nucleotide sequence comprising one, two, three, or four, but not more than five nucleotides different with respect to the nucleotide sequence of SEQ ID NO: 4363; or a nucleotide sequence comprising one, two, three or four, but not more than five modifications with respect to the nucleotide sequence of SEQ ID NO: 4363; (iv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4911;and Petition 870250070208, dated 06 / 08 / 2025, page 576 / 621 41 / 68 (v) a 3' flanking region of SEQ ID NO: 4373, a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from the nucleotide sequence of SEQ ID NO: 4373; (F) (i) a 5' flanking region comprising the nucleotide sequence of SEQ ID NO: 4354, a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4354, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4354;or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but not more than ten modifications with respect to the nucleotide sequence of SEQ ID NO: 4354; (ii) the sense strand sequence of SEQ ID NO: 4977; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4363, a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4363, a nucleotide sequence comprising one, two, three, or four, but not more than five nucleotides different with respect to the nucleotide sequence of SEQ ID NO: 4363; or a nucleotide sequence comprising one, two, three or four, but not more than five modifications with respect to the nucleotide sequence of SEQ ID NO: 4363; (iv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4919;and (v) a 3' flanking region of SEQ ID NO: 4373, a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from the nucleotide sequence of SEQ ID NO: 4373; or (G) (i) a 5' flanking region comprising the nucleotide sequence of SEQ ID NO: 4354, a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4354, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4354;or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but not more than ten modifications with respect to the nucleotide sequence of SEQ ID NO: 4354; (ii) the sense strand sequence of SEQ ID NO: 4981; (iii) a loop region comprising the nucleotide sequence of SEQ ID NO: 4363, a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4363, a nucleotide sequence comprising one, two, three, or four, but not more than five nucleotides different with respect to the nucleotide sequence of SEQ ID NO: 4363; or a nucleotide sequence comprising one, two, three or four, but not more than five modifications with respect to the nucleotide sequence of SEQ ID NO: 4363; Petition 870250070208, dated 06 / 08 / 2025, p. 578 / 621 43 / 68 (iv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4923;and (v) a 3' flanking region of SEQ ID NO: 4373, a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten nucleotides different from the nucleotide sequence of SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six or seven, but not more than ten modifications from the nucleotide sequence of SEQ ID NO: 4373.; 17. Modulating polynucleotide, according to any one of claims 9 or 11 to 16, or AAV viral genome, according to any one of claims 10 to 16, characterized in that the nucleotide sequence encoding the modulating polynucleotide comprises the nucleotide sequence of any one of the SEQ ID NOs: 4405, 4408, 4409, 4390, 4391, 4393, 4394, 4380-4389, 4392, 4395-4404, 4406 or 4407, or nucleotide sequence at least 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical thereto.

18. AAV viral genome, characterized in that it comprises a promoter operatively linked to a nucleic acid encoding the modulating polynucleotide as defined in any one of claims 9 or 11 to 17 or the siRNA as defined in any one of claims 1 or 3 to 8.

19. AAV viral genome, according to any one of claims 3 to 8 or 10 to 17, characterized in that the AAV viral genome further comprises a promoter operably linked to the nucleotide sequence encoding the sense strand sequence and the antisense strand sequence or the nucleotide sequence encoding the modulating polynucleotide. Petition 870250070208, dated 06 / 08 / 2025, p. 579 / 621 44 / 68 20. AAV viral genome according to claim 18 or 19, characterized in that the promoter: (i) is a ubiquitous promoter; (ii) is a cell- or tissue-specific promoter; (iii) is selected from human elongation factor 1α subunit (EF1a), immediate-early enhancer and / or promoter of cytomegalovirus (CMV), chicken β-actin (CBA) and its derivative CAG, β-glucuronidase (GUSB) or ubiquitin C (UBC), neuron-specific enolase (NSE), platelet-derived growth factor (PDGF), platelet-derived growth factor B chain (PDGF-β), intercellular adhesion molecule 2 (ICAM-2), synapsin (Syn), methyl-CpG binding protein 2 (MeCP2), Ca2+ / calmodulin-dependent protein kinase II (CaMKII), metabotropic glutamate receptor 2 (mGluR2), neurofilament light chain (NFL) or neurofilament heavy chain (NFH), β-globin nβ2 minigene, preproenkephalin (PPE), Enkephalin (Enk) and excitatory amino acid transporter 2 (EAAT2).glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), a cardiovascular promoter (e.g., αMHC, cTnT, and CMV-MLC2k), a hepatic promoter (e.g., hAAT, TBG), a skeletal muscle promoter (e.g., desmin, MCK, C512), or a functional fragment, e.g., a truncation or a functional variant thereof; (iii) is a CBA promoter or a variant thereof; (iv) comprises the nucleotide sequence of any of the nucleotide sequences provided in Table 2; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven, but not more than ten modifications, e.g., substitutions, insertions, or deletions, with respect to any of the nucleotide sequences provided in Table 2; or a nucleotide sequence with at least 85%, 90%, 92%, 95%, 96%, Petition 870250070208, dated 06 / 08 / 2025, page 580 / 621 45 / 68 97%,98% or 99% sequence identity with any of the nucleotide sequences provided in Table 2; or (v) comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 5199; or a nucleotide sequence with at least 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% sequence identity with SEQ ID NO: 5199.

21. AAV viral genome, according to any one of claims 2 to 8 or 10 to 20, characterized in that the AAV viral genome further comprises: (i) at least one or two inverted terminal repeat (ITR) sequences, optionally wherein the AAV viral genome comprises an ITR sequence positioned 5' relative to the nucleic acid encoding the modulating polynucleotide or siRNA and / or an ITR sequence positioned 3' relative to the nucleic acid encoding the modulating polynucleotide or siRNA; (ii) a polyadenylation signal sequence (polyA); (iii) an enhancer, a Kozak sequence, an intron region and / or an exon region; and / or (iv) a nucleotide sequence that encodes a microRNA (miR) binding site, for example, an miR binding site that modulates, for example, reduces the expression of the payload encoded by the viral genome in a cell or tissue where the corresponding miRNA is expressed;optionally where the encoded miR binding site modulates, for example, reduces the expression of the encoded payload in a DRG cell or tissue, liver, heart, hematopoietic lineage or a combination thereof; 22. AAV viral genome according to claim 21, Petition 870250070208, dated 06 / 08 / 2025, pp. 581 / 621 46 / 68 characterized in that: (i) the ITR positioned 5' relative to the nucleic acid encoding the modulating polynucleotide or siRNA comprises the nucleotide sequence of SEQ ID NO: 5197 or 4469; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, relative to SEQ ID NO: 5197 or 4469; or a nucleotide sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 5197 or 4469; (ii) the ITR positioned 3' relative to the nucleic acid encoding the modulating polynucleotide or siRNA comprises the nucleotide sequence of SEQ ID NO: 5200 or 4470;a nucleotide sequence comprising at least one, two, three, four, five, six, or seven, but not more than ten modifications, for example, substitutions, insertions, or deletions, with respect to SEQ ID NO: 5200 or 4470; or a nucleotide sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 5200 or 4470; (iii) the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven, but not more than ten modifications, for example, substitutions, insertions, or deletions, with respect to SEQ ID NO: 4476; or a nucleotide sequence with at least 80% (e.g., 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with SEQ ID NO: 4476; (iv) the enhancer comprises a CMVie enhancer or a variant thereof;(v) the enhancer comprises the nucleotide sequence Petition 870250070208, dated 06 / 08 / 2025, p. 582 / 621 47 / 68 of SEQ ID NO: 4471 or 4472; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 4471 or 4472; or a nucleotide sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity with SEQ ID NO: 4471 or 4472; and / or (vi) the intron comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 4475; or a nucleotide sequence with at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity with SEQ ID NO: 4475.; 23. AAV viral genome, according to any one of claims 2 to 8 or 10 to 22, characterized in that the AAV viral genome is self-complementary or single-stranded.

24. AAV viral genome, according to any one of claims 2 to 8 or 10 to 23, characterized in that the AAV viral genome further comprises a nucleotide sequence encoding a Rep protein, for example, a non-structural protein, wherein the Rep protein comprises a Rep78 protein, a Rep68 protein, a Rep52 protein and / or a Rep40 protein (for example, a Rep78 protein and a Rep52 protein).

25. AAV viral genome, according to any one of claims 2 to 8 or 10 to 24, characterized in that it comprises in the order of 5' to 3': (A) (i) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 5197; (ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 4471;or a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4471; (iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 5199; or a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5199; (iv) an intron, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4475;(v) a nucleotide sequence encoding a modulating polynucleotide, wherein the nucleotide sequence comprises any of the SEQ ID NOs: 4380-4409 or 5027-5050, or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical thereto; Petition 870250070208, dated 06 / 08 / 2025, p. 584 / 621 49 / 68 (vi) a polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4476; and (vii) an ITR, where the ITR comprises the nucleotide sequence of SEQ ID NO: 5200;a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 5200; or (B) (i) an ITR, where the ITR comprises the nucleotide sequence of SEQ ID NO: 4469; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4469; or a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 4469; (ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4472;a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 4472; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4472; (iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5199; (iv) an intron, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 4475;a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4475; (v) a nucleotide sequence encoding a modulating polynucleotide, wherein the nucleotide sequence comprises any of the SEQ ID NOs: 4380-4409 or 5027-5050, or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical thereto; (vi) a polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 4476;or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4476; and (vii) an ITR, where the ITR comprises the nucleotide sequence of SEQ ID NO: 4470; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4770; or a nucleotide sequence comprising Petition 870250070208, dated 06 / 08 / 2025, p. 586 / 621 51 / 68 at least one, two, three, four, five, six or seven, but no more than ten modifications, for example, replacements, insertions or deletions, in relation to SEQ ID NO: 4470.; 26. AAV viral genome, according to any one of claims 2 to 8 or 10 to 25, characterized in that it comprises in the order of 5' to 3': (A) (i) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 5197; (ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 4471;or a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4471; (iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 5199; or a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5199; (iv) an intron, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, Petition 870250070208, dated 06 / 08 / 2025, p. 587 / 621 52 / 68 but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 4475;or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4475; (v) a nucleotide sequence encoding a modulating polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4405, or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical thereto; (vi) a polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4476; and (vii) an ITR, where the ITR comprises the nucleotide sequence of SEQ ID NO: 5200;a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 5200; (B) (i) an ITR, where the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 5197; Petition 870250070208, dated 06 / 08 / 2025, p. 588 / 621 53 / 68 (ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471;a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4471; (iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5199; (iv) an intron, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 4475;a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4475; (v) a nucleotide sequence encoding a modulating polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4408, or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to it; (vi) a polyA signal sequence, where the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 4476;or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4476; and (vii) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 5200; (C) (i) an ITR, where the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 5197;(ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4471; (iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5199;(iv) an intron, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4475; (v) a nucleotide sequence encoding a modulating polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4409, or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical thereto; (vi) a polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476;a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4476; and (vii) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 5200; (D) (i) an ITR, where the ITR comprises the nucleotide sequence of SEQ ID NO: 5197;a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 5197; (ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4471; (iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199;a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5199; (iv) an intron, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 4475; or a nucleotide sequence that is at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4475;(v) a nucleotide sequence encoding a modulating polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4390, or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical thereto; (vi) a polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4476; and (vii) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5200;or a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 5200; (E) (i) an ITR, where the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 5197; (ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 4471;or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4471; (iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a sequence of nucleotides comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5199; (iv) an intron, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 4475;or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4475; (v) a nucleotide sequence encoding a modulating polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4391, or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical thereto; (vi) a polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4476; and (vii) an ITR, where the ITR comprises the nucleotide sequence of SEQ ID NO: 5200;a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 5200; (F) (i) an ITR, where the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 5197; (ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471;a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4471; (iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5199; (iv) an intron, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 4475;a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4475; (v) a nucleotide sequence that encodes a Petition 870250070208, dated 06 / 08 / 2025, p. 595 / 621 60 / 68 modulating polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4393, or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical thereto; (vi) a polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 4476;or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4476; and (vii) an ITR, wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 5200; or (G) (i) an ITR, where the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 5197;(ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, Petition 870250070208, dated 06 / 08 / 2025, p. 596 / 621 61 / 68 substitutions, insertions or deletions, in relation to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4471; (iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5199;(iv) an intron, wherein the intron comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, with respect to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4475; (v) a nucleotide sequence encoding a modulating polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4394, or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical thereto; (vi) a polyA signal sequence, wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476;a nucleotide sequence comprising at least one, two, three, four, five, six or seven, but not more than ten modifications, for example, substitutions, insertions or deletions, in relation to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4476; and (vii) an ITR, wherein the ITR comprises the nucleotide sequence of Petition 870250070208, dated 06 / 08 / 2025, page 597 / 621 62 / 68 5200; a nucleotide sequence that is at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven, but not more than ten modifications, for example, substitutions, insertions, or deletions, in relation to SEQ ID NO: 5200.

27. AAV viral genome, according to any one of claims 2 to 8 or 10 to 26, characterized in that it comprises the nucleotide sequence of any one of the SEQ ID NOs: 5173, 5195, 5196, 5182, 5183, 5184, 5185, 5149-5172, 5174-5181, 5186-5194 or 4439-4468, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical to any one of the SEQ ID NOs: 5173, 5195, 5196, 5182, 5183, 5184, 5185, 51495172, 5174-5181, 5186-5194 or 4439-4468.

28. AAV particle, characterized in that it comprises the AAV viral genome as defined in any one of claims 2 to 8 or 10 to 27, an AAV viral genome encoding the modulating polynucleotide as defined in any one of claims 9 or 11 to 17, or a viral genome encoding the siRNA as defined in any one of claims 1 or 3 to 8, and an AAV capsid protein.

29. AAV particle, according to claim 28, characterized in that the capsid protein comprises: (i) an AAV5 capsid protein or a variant thereof, an AAV9 capsid protein or a variant thereof, a VOY101 capsid protein or a variant thereof, a PHPeB capsid protein or a variant thereof, a PHP.B capsid protein or a variant thereof, a PHP.N capsid protein or a variant thereof, an AAV1 capsid protein or a variant thereof, a capsid protein of Petition 870250070208, dated 06 / 08 / 2025, page 1.598 / 621 63 / 68 AAV2 or a variant thereof, a capsid protein of AAVrh10 or a variant thereof, or a capsid protein of VOY9P39 or a variant thereof; (ii) a capsid protein of AAV9 or a variant thereof; (iii) a capsid protein of AAV5 or a variant thereof; (iv) an amino acid sequence provided in Table 1 or an amino acid sequence at least 85%, 90%, 92%, 95%, 97%, 98% or 99% identical to it; or (v) the nucleotide sequence encoding the AAV capsid protein comprises any of the nucleotide sequences in Table 1, or a nucleotide sequence at least 85%, 90%, 92%, 95%, 97%, 98% or 99% identical to it.

30. Vector, characterized in that it comprises the AAV viral genome as defined in any one of claims 2 to 8 or 10 to 27, a nucleotide sequence encoding the modulating polynucleotide as defined in any one of claims 9 or 11 to 17, or a nucleotide sequence encoding the siRNA as defined in any one of claims 1 or 3 to 8.

31. Cell, characterized in that it comprises the AAV particle as defined in claim 28 or 29, the AAV viral genome as defined in any one of claims 2 to 8 or 10 to 27, the modulating polynucleotide as defined in any one of claims 9 or 11 to 17, or the siRNA as defined in any one of claims 1 or 3 to 8, optionally wherein the cell is: (a) a mammalian cell or an insect cell; (b) a cell of a brain region or a spinal cord region (e.g., a CNS cell); (c) a cell of the cortex, hippocampus, thalamus or brainstem; or (d) a neuron, a glial cell or an oligodendrocyte.

32. Method for making an AAV particle, characterized in that it comprises: (i) providing a host cell comprising the AAV viral genome as defined in any one of claims 2 to 8 or 10 to 27, an AAV viral genome encoding the modulating polynucleotide as defined in any one of claims 9 or 11 to 17, or a viral genome encoding the siRNA as defined in any one of claims 1 or 3 to 8; (ii) incubating the host cell under suitable conditions to wrap the viral genome in an AAV capsid protein; thereby making the AAV particle.

33. Pharmaceutical composition, characterized in that it comprises the AAV particle as defined in claim 28 or 29, the AAV viral genome as defined in any one of claims 2 to 8 or 10 to 27, the modulating polynucleotide as defined in any one of claims 9 or 11 to 17, or the siRNA as defined in any one of claims 1 or 3 to 8, and a pharmaceutically acceptable excipient.

34. Method for delivering an siRNA to inhibit MAPT expression to a cell, characterized in that it comprises administering to the cell an effective amount of the pharmaceutical composition as defined in claim 33, of the AAV particle as defined in claim 28 or 29, of the AAV viral genome as defined in any one of claims 2 to 8 or 10 to 27, of the modulating polynucleotide as defined in any one of claims 9 or 11 to 17, or of the siRNA as defined in any one of claims 1 or 3 to 8, thereby delivering the siRNA to inhibit MAPT expression to the cell. Petition 870250070208, dated 06 / 08 / 2025, pp. 600 / 621 65 / 68 35. Method according to claim 34, characterized in that the cell is: (a) a mammalian cell or an insect cell; (b) a cell from a region of the brain or a region of the spinal cord (e.g., a CNS cell); (c) a cell from the cortex, hippocampus, thalamus or brainstem; (d) a neuron, a glial cell or an oligodendrocyte; and / or (e) in an individual.

36. A method according to claim 35, characterized in that the individual has or has been diagnosed as having a genetic disorder (for example, a monogenic disorder or a polygenic disorder); a neurological disorder (for example, a neurodegenerative disorder); a disorder associated with tau expression, for example, aberrant tau expression; and / or a tauopathy.

37. Method for treating an individual having or diagnosed as having a genetic disorder (e.g., a monogenic disorder or a polygenic disorder); a neurological disorder (e.g., a neurodegenerative disorder); a disorder associated with tau expression, e.g., aberrant tau expression; and / or a tauopathy, the method characterized in that it comprises administering to the individual an effective amount of the pharmaceutical composition as defined in claim 33, of the AAV particle as defined in claim 28 or 29, the AAV viral genome as defined in any one of claims 2 to 8 or 10 to 27, of the modulating polynucleotide as defined in any one of claims 9 or 11 to 17, or of the siRNA as defined in any one of claims 1 or 3 to 8.

38. Method, according to claim 36 or 37, characterized in that the genetic disorder, neurological disorder (e.g., neurodegenerative disorder), disorder associated with the expression Petition 870250070208, dated 06 / 08 / 2025, p. 601 / 621 66 / 68 of tau (e.g., aberrant tau expression) and / or tauopathy is Alzheimer's disease (AD), frontotemporal dementia (FTD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration (FTLD), Dravet syndrome (DS), neurodegenerative disease, traumatic brain injury (TBI), chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), Down syndrome, Pick's disease, corticobasal degeneration (CBD), corticobasal syndrome, amyotrophic lateral sclerosis (ALS), prion diseases, CJD, multisystem atrophy, mild cognitive impairment, entangled dementia only, or progressive subcortical gliosis.

39. Method according to claim 37 or 38, characterized in that the treatment comprises prevention of progression of the genetic disorder, neurological disorder (e.g., neurodegenerative disorder), disorder associated with tau expression (e.g., aberrant tau expression) and / or tauopathy in the individual.

40. A method according to any one of claims 37 to 39, characterized in that it further comprises performing a blood test, an imaging examination (e.g., a PET scan or a PET scan in combination with a biomarker, e.g., serum biomarker staining), a CNS biopsy sample or an aqueous cerebrospinal fluid biopsy, optionally wherein the blood test, imaging examination, biopsy sample or aqueous cerebrospinal fluid biopsy are performed before, during or after treatment with the AAV particle, modulating polynucleotide, siRNA or pharmaceutical composition.

41. Method, according to any one of claims 37 to 40, characterized in that the pharmaceutical composition, AAV particle, modulating polynucleotide and siRNA are administered to the individual: Petition 870250070208, dated 06 / 08 / 2025, pp. 602 / 621 67 / 68 (i) intravenously, by intracystinal magna injection (ICM), intracerebral, intrathecal, intracerebroventricular, intraparenchymal or intramuscular administration; (ii) by means of focused ultrasound (FUS), for example, coupled with intravenous microbubble administration (FUS-MB), or MRI-guided FUS coupled with intravenous administration; (iii) intravenously.

42. Pharmaceutical composition according to claim 33, AAV particle according to claim 28 or 29, AAV viral genome according to any one of claims 2 to 8 or 10 to 27, modulating polynucleotide according to any one of claims 9 or 11 to 17, or siRNA according to any one of claims 1 or 3 to 8, characterized in that it is for use in a method of delivering an siRNA to inhibit MAPT expression to a cell.

43. Pharmaceutical composition according to claim 33, AAV particle according to claim 28 or 29, AAV viral genome according to any one of claims 2 to 8 or 10 to 27, modulating polynucleotide according to any one of claims 9 or 11 to 17, or siRNA according to any one of claims 1 or 3 to 8, characterized in that it is for use in the manufacture of a medicament.

44. Pharmaceutical composition according to claim 33, AAV particle according to claim 28 or 29, AAV viral genome according to any one of claims 2 to 8 or 10 to 27, modulating polynucleotide according to any one of claims 9 or 11 to 17, or siRNA according to any one of claims 1 or 3 to 8, characterized in that it is for use in the treatment of a genetic disorder, neurological disorder (e.g., neurodegenerative disorder), disorder associated with tau expression Petition 870250070208, dated 06 / 08 / 2025, p. 603 / 621 68 / 68 (e.g., aberrant tau expression) and / or tauopathy.

45. Use of the pharmaceutical composition as defined in claim 33, AAV particle as defined in claim 28 or 29, AAV viral genome as defined in any one of claims 2 to 8 or 10 to 27, modulating polynucleotide as defined in any one of claims 9 or 11 to 17, or siRNA as defined in any one of claims 1 or 3 to 8, characterized in that it is used in the manufacture of a medicament to deliver an siRNA to inhibit MAPT expression to a cell.

46. ​​Use of the pharmaceutical composition as defined in claim 33, AAV particle as defined in claim 28 or 29, AAV viral genome as defined in any one of claims 2 to 8 or 10 to 27, modulating polynucleotide as defined in any one of claims 9 or 11 to 17, or siRNA as defined in any one of claims 1 or 3 to 8, characterized in that it is used in the manufacture of a medicament.

47. Use of the pharmaceutical composition as defined in claim 33, AAV particle as defined in claim 28 or 29, AAV viral genome as defined in any one of claims 2 to 8 or 10 to 27, modulating polynucleotide as defined in any one of claims 9 or 11 to 17, or siRNA as defined in any one of claims 1 or 3 to 8, characterized in that it is used in the manufacture of a medicament to treat a genetic disorder, neurological disorder (e.g., neurodegenerative disorder), disorder associated with tau expression (e.g., aberrant tau expression) and / or tauopathy.

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