Oligonucleotides for modulating synaptogyrin-3 expression

Abstract

The present invention relates to regions within the synaptogyrin-3 RNA sequence that are targetable by oligonucleotide inhibitors, such as antisense oligonucleotides. Specifically, these synaptogyrin-3 inhibitors are provided for general pharmaceutical use and for treating or inhibiting the progression of tauopathy or the symptoms of tauopathy.

Description

[Technical Field]

[0001] The present invention relates to regions within the synaptogyrin-3 RNA sequence that are targetable by oligonucleotide inhibitors, such as antisense oligonucleotides. Specifically, these synaptogyrin-3 inhibitors are provided for general pharmaceutical use and for treating or inhibiting the progression of tauopathy or the symptoms of tauopathy. [Background technology]

[0002] Tau pathology is associated with more than 20 neurodegenerative diseases, including Alzheimer's disease (Wang & Mandelkow 2016 Nat Rev Neurosci 17:5-21). Hyperphosphorylation or mutation of the microtubule-associated protein tau is common to all of these diseases, collectively referred to as tauopathies, and filamentous inclusions of hyperphosphorylated tau are the hallmark pathology of Alzheimer's disease and other tauopathies (Ballatore et al 2007 Nature Reviews Neuroscience 8:663-672). Tau pathology is not simply a by-product of other pathological pathways, but is itself a key mediator of neurotoxicity (Roberson et al. 2007 Science 316:750-754; Hutton et al. 1998 Nature 393:702-705; Caffrey & Wade-Martins 2007 Neurobiol Dis 27:1-10; Le Guennec et al. 2016 Molecular Psychiatry 1-7). Under physiological conditions, tau is expressed in neurons and bound to axonal microtubules. However, under pathological conditions, tau mutations (in FTDP-17) or abnormal tau phosphorylation (including sporadic Alzheimer's disease) reduce its microtubule-binding affinity (Hong et al., 1998, Science 282:1914-1917; Wang & Mandelkow, 2016, Nat Rev Neurosci, 17:5-21), leading to its dissociation from axonal microtubules and subsequent mislocalization to synapses (Spires-Jones & Hyman, 2014, Neuron, 82:756-771; Tai et al., 2012, Am J Pathol, 181:1426-1435; Tai et al., 2014, Acta Neuropathol Commun, 2:146). This mislocalization of soluble tau plays a key role in disrupting synaptic function in early disease stages, which may contribute to subsequent synapse loss and neurodegeneration.

[0003] Previous research by the inventors of this application indicated that when tau is present at presynaptic terminals, it binds to synaptic vesicles and clusters them. Synaptogyrin-3 (Syngr3) was identified as a physical interactor of tau (WO2019 / 016123). Furthermore, partial loss of Syngr3 in both mice and flies expressing pathogenic P301S tau ("PS19"), a well-accepted model of tauopathy that recapitulates features seen in patients, including synapse loss, neuroinflammation, and cognitive decline, was demonstrated in vivo to restore working memory and rescue synaptic degeneration. Interestingly, partial (and complete) loss of Syngr3 is benign in mice and Drosophila. Given the potential of Syngr3 as a clinical target for tauopathy, it would be advantageous to develop inhibitors that specifically downregulate Syngr3 transcript levels. Summary of the Invention

[0004] The present inventors have found that several subsequences within the synaptogyrin-3 gene are significantly more accessible to oligonucleotides, such as antisense oligonucleotide (ASO) molecules, and are therefore preferred target regions for designing oligonucleotides suitable for or capable of reducing the expression and / or activity of synaptogyrin-3. The boundaries of these identified target regions were determined by transcript walking.

[0005] In one aspect, the present invention relates to oligonucleotides that specifically bind to synaptogyrin-3 transcripts and reduce the expression of synaptogyrin-3 through antisense or RNAi technology. More specifically, oligonucleotides 10 to 50 nucleotides in length are provided, comprising a contiguous nucleotide sequence of at least 10 contiguous nucleotides in length, where the contiguous nucleotide sequence is at least 90% complementary to an equal length portion of a target region within the synaptogyrin-3 transcript set forth in SEQ ID NO: 1, wherein the target region is between nucleobase positions 449 and 531, 549 and 653, 640 and 733, 720 and 875, 915 and 1108, 1197 and 1271, 1258 and 1308 of SEQ ID NO: 1. and 1344, 1332 and 1450, 1450 and 1527, 1515 and 1600, 1580 and 1700, 1680 and 1837, 1824 and 1885, 1850 and 2100, 2100 and 2250, 2308 and 2428, 2416 and 2441, 2428 and 2625, 2649 and 2796, 2962 and 3086, 3153 and 3460, 3450 and 3530, 3508 and 3551, 3538 and 3636, or between nucleobase positions 3626 and 4599, wherein the endpoints are inclusive. In one embodiment, the oligonucleotide is capable of binding to a synaptogyrin-3 mRNA transcript set forth in SEQ ID NO:1. In another embodiment, said binding of the oligonucleotide to said synaptogyrin-3 mRNA transcript may reduce the expression and / or activity of synaptogyrin-3.

[0006] In one embodiment, the oligonucleotide is a single-stranded nucleic acid molecule, more specifically, an antisense portion of an ASO molecule or an RNAi molecule. In another embodiment, the oligonucleotide is at least 16 nucleotides in length.

[0007] In specific embodiments, the oligonucleotides of the present application are selected from the group consisting of SEQ ID NOs: 10, 12, 20, 25, 29-31, 33, 50, 53, 58-59, 62, 69, 79, 84, 87, 91, 94, 110-111, 135, 140-141, 170, 172, 179, 181, 184, 188, 193-194, 210, 216, 220-221, 224, 227, 228, 230, 232, 234, 236, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 300, 301, 302, 303, 304, 305, 306, 29, 231, 235, 241, 246, 248, 250, 259, 268, or 269. More specifically, the target region is at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 99%, or completely complementary (100% complementary) to an equal length portion of a target region selected from SEQ ID NOs: 2-9, 11, 13-19, 21-24, 26-28, 32, 34-49, 51-52, 54-57, 60-61, 63-68, 70-78, 80-83, 85-86, 88-90, 92-93, 95-109, 112-134, 136-139, 142-169, 171 , 173-178, 180, 182-183, 185-187, 189-192, 195-209, 211-215, 217-219, 222-223, 225-226, 228, 230, 232-234, 236-240, 242-245, 247, 249, 251-258, or 260-267. In more specific embodiments, the oligonucleotide comprises a contiguous nucleotide sequence of at least 10 contiguous nucleotides in length having at least 90% sequence identity to any of SEQ ID NOs: 270-489. In another embodiment, a contiguous nucleotide sequence from the oligonucleotide of the present application is 100% complementary to one of the target regions disclosed herein.

[0008] In another embodiment, the oligonucleotides of the present application comprise one or more internucleoside linkages and / or one or more 2' sugar-modified nucleosides, more particularly, the internucleoside linkages are phosphorothioate internucleoside linkages and / or the 2' sugar-modified nucleosides are selected from the group consisting of 2'-O-methyl-, 2'-O-methoxyethyl-, 2'-O-alkyl-, 2'-alkoxy, 2'-amino-, 2'-fluoro-, and LNA nucleosides. In specific embodiments, the oligonucleotides of the present application comprise gapmers of the formula 5'-FG-F'-3', wherein regions F and F' independently comprise between 1 and 8 nucleosides, 1 to 5 of which are independently 2' sugar-modified nucleosides, defining the 5' and 3' ends of the F and F' regions, and G is a region of between 5 and 18 nucleosides for recruiting RNase H, and more specifically, the internucleoside linkages between one or more nucleosides of regions F and / or F' and / or between F and G and / or between F' and G are phosphorothioate internucleoside linkages.

[0009] Pharmaceutical compositions comprising the oligonucleotides of the present application are also provided.

[0010] Synaptogyrin-3 in cells by at least 45% compared to the control situation in the absence of antisense or RNAi molecules Also provided are antisense oligonucleotides or RNAi molecules capable of reducing the level of mRNA, synaptogyrin-3 protein, synaptogyrin-3 activity, or a combination thereof, wherein the antisense oligonucleotide or RNAi molecule nucleic acid sequence targets a subsequence of mRNA encoding synaptogyrin-3 selected from the group consisting of SEQ ID NOs: 10, 12, 20, 25, 29-31, 33, 50, 53, 58-59, 62, 69, 79, 84, 87, 91, 94, 110-111, 135, 140-141, 170, 172, 179, 181, 184, 188, 193-194, 210, 216, 220-221, 224, 227, 229, 231, 235, 241, 246, 248, 250, 259, 268, or 269.

[0011] The oligonucleotides of the present application, including the antisense oligonucleotides and RNAi molecules disclosed herein, are provided as therapeutic agents for treating or reducing the symptoms of tauopathy.Therefore, pharmaceutical compositions comprising the oligonucleotides of the present application and methods for treating tauopathy in subjects in need thereof are provided, wherein the method comprises administering any of the antisense oligonucleotides and RNAi molecules provided herein.Also provided are the oligonucleotides of the present application for use as medicines, more particularly for treating or inhibiting the progression of tauopathy disorders, or for treating or inhibiting the symptoms of tauopathy disorders. [Brief explanation of the drawings]

[0012] [Figure 1] Figures 1 and 2 illustrate exemplary, non-limiting architectures of the oligonucleotides of the present application. In Figure 1, the oligonucleotides are siRNA molecules that follow a 21 / 19 bp structure, in which the sense strand is 19 nucleotides and the antisense strand is 21 nucleotides, with a 2-nucleotide overhang at the 3' end. The strands are 2'OMe (green) / 2"F (blue) modified. The red bars indicate phosphorothioate modifications, and "N" is complementary to the target mRNA. [Figure 2-1] 2A-B show other non-limiting alternative architectures of oligonucleotides of the present disclosure. [Figure 2-2] 2A-B show other non-limiting alternative architectures of oligonucleotides of the present disclosure. [Figure 3-1] Figure 3 shows the different target regions on the synaptogyrin-3 mRNA transcript identified herein, their start (5') and end (3') positions according to SEQ ID NO: 1, their sequences, and the sequences of the oligonucleotides disclosed herein. [Figure 3-2]Figure 3 shows the different target regions on the synaptogyrin-3 mRNA transcript identified herein, their start (5') and end (3') positions according to SEQ ID NO: 1, their sequences, and the sequences of the oligonucleotides disclosed herein. [Figure 3-3] Figure 3 shows the different target regions on the synaptogyrin-3 mRNA transcript identified herein, their start (5') and end (3') positions according to SEQ ID NO: 1, their sequences, and the sequences of the oligonucleotides disclosed herein. [Figure 3-4] Figure 3 shows the different target regions on the synaptogyrin-3 mRNA transcript identified herein, their start (5') and end (3') positions according to SEQ ID NO: 1, their sequences, and the sequences of the oligonucleotides disclosed herein. [Figure 3-5] Figure 3 shows the different target regions on the synaptogyrin-3 mRNA transcript identified herein, their start (5') and end (3') positions according to SEQ ID NO: 1, their sequences, and the sequences of the oligonucleotides disclosed herein. [Figure 4-1] FIG. 4 shows the extended target region within the synaptogyrin-3 mRNA transcript. [Figure 4-2] FIG. 4 shows the extended target region within the synaptogyrin-3 mRNA transcript. [Figure 4-3] FIG. 4 shows the extended target region within the synaptogyrin-3 mRNA transcript. [Figure 5] Figure 5 shows the off-target analysis of three independent ASO molecules, consisting of the sequences of SEQ ID NO: 346, SEQ ID NO: 373, and SEQ ID NO: 384. Expression of Syngr3 and several predicted off-target genes was quantified in human iPSC-derived neurons after 4 days of incubation with the ASO molecules. DETAILED DESCRIPTION OF THE INVENTION

[0013] In one aspect, the present invention relates to oligonucleotides ("oligonucleotides of the present disclosure") that specifically bind to synaptogyrin-3 mRNA or pre-mRNA and reduce synaptogyrin-3 expression, e.g., through antisense or RNAi technology. In some aspects, the oligonucleotides of the present disclosure reduce synaptogyrin-3 expression levels, synaptogyrin-3 activity (e.g., dopamine transporter activity), synaptogyrin-3-mediated exocytosis, or a combination thereof. In some aspects, the oligonucleotides of the present disclosure are 10-50, 10-40, or 10-30 nucleotides in length and comprise a contiguous nucleotide sequence of at least 10 contiguous nucleotides in length that is at least 90% complementary to an equal portion of the target region within the synaptogyrin-3 transcript set forth in SEQ ID NO:1. In some aspects, the target region within SEQ ID NO:1 is selected from the group consisting of nucleobase positions 449 and 531, 549 and 653, 640 and 733, 720 and 875, 915 and 1108, 1197 and 1271, 1258 and 1344, 1332 and 1450, 1450 and 1527, 1515 and 1600, 1580 and 1700, 1680 and 1837, 1824 and 1885, 1890 and 1900, 1915 and 2000, 2015 and 2020, 2020 and 2100, 2115 and 2120, 2135 and 2140, 2155 and 2160, 2175 and 2185, 2195 and 2200, 2215 and 2220, 2235 and 2240, 2255 and 2300, 2315 and 2320, 2332 and 2450, 2345 and 2460, 2355 and 2480, 2365 and 2380, 2395 and 2490, 2495 and 2500, 2515 and 2520, 2535 and 2540, 2555 and 2600, 2615 and 2620, 2635 and 2640, 2655 and 2700, 2715 and 2720, 2735 and 2740, 2755 and 2800, located between 850 and 2100, 2100 and 2250, 2308 and 2428, 2416 and 2441, 2428 and 2625, 2649 and 2796, 2962 and 3086, 3153 and 3460, 3450 and 3530, 3508 and 3551, 3538 and 3636, or between nucleobase positions 3626 and 4599, where the endpoints are inclusive.

[0014] In some aspects, oligonucleotides of the present disclosure are 10-50, 10-40, or 10-30 nucleotides in length and comprise a contiguous nucleotide sequence of at least 10 contiguous nucleotides in length that is at least 90% complementary to a portion of equal length of a target region within human synaptogyrin-3, wherein the target region is set forth in SEQ ID NOs: 10, 12, 20, 25, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, Selected from the list consisting of: 31, 33, 50, 53, 58-59, 62, 69, 79, 84, 87, 91, 94, 110-111, 135, 140-141, 170, 172, 179, 181, 184, 188, 193-194, 210, 216, 220-221, 224, 227, 229, 231, 235, 241, 246, 248, 250, 259, 268, or 269.

[0015] In some aspects, the oligonucleotides of the present disclosure are selected from the group consisting of SEQ ID NOs: 2-9, 11, 13-19, 21-24, 26-28, 32, 34-49, 51-52, 54-57, 60-61, 63-68, 70-78, 80-83, 85-86, 88-90, 92-93, 95-109, 112-134, 136-139, 142-169, 171, 173-178, 180, 182 -183, 185-187, 189-192, 195-209, 211-215, 217-219, 222-223, 225-226, 228, 230, 232-234, 236-240, 242-245, 247, 249, 251-258, or 260-267.

[0016] In some aspects, the oligonucleotides of the present application comprise or consist of 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 nucleotides in length. In other aspects, the oligonucleotides of the present application comprise or consist of 14, 15, 16, or more nucleotides in length and comprise or consist of a sequence selected from the list consisting of SEQ ID NOs: 270-489, or overlap with one of SEQ ID NOs: 270-489 by at least 12, 13, 14, 15, or 16 nucleotides.

[0017] The present disclosure also provides a method of treatment comprising administering the oligonucleotides of the present disclosure or combinations thereof to a subject in need thereof. Pharmaceutical compositions, pharmaceutical formulations, and kits and articles comprising the oligonucleotides of the present disclosure are also provided. Methods of manufacturing the oligonucleotides of the present disclosure are also provided. definition

[0018] In order that this specification may be more readily understood, certain terms are first defined. Additional definitions are provided in the Detailed Description. The present invention will be described with respect to specific embodiments and with reference to certain drawings; however, the present invention is not limited thereto but only by the claims. Any reference signs in the claims should not be construed as limiting the scope. The drawings described are schematic only and are not limiting. In the drawings, the size of some of the elements may be exaggerated and not drawn to scale for illustrative purposes.

[0019] It should be noted that the term "a" or "an" entity refers to one or more of that entity; for example, a "nucleotide sequence" is understood to refer to one or more nucleotide sequences. As such, the terms "a" (or "an"), "one or more," and "at least one" can be used interchangeably herein.

[0020] Furthermore, "and / or," as used herein, should be taken as a specific disclosure of each of the two specified features or components with or without the other. Thus, the term "and / or" used herein in phrases such as "A and / or B" is intended to encompass "A and B," "A or B," "A" (alone), and "B" (alone). Similarly, the term "and / or" used in phrases such as "A, B, and / or C" is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0021] Where an indefinite or definite article is used when referring to a singular noun, e.g., "a," "an," or "the," this includes the plural of that noun unless something specifically stated otherwise. Furthermore, the terms first, second, third, and the like in this specification and claims are used to distinguish between similar elements and not necessarily to describe an organizational or chronological order. It is to be understood that terms so used are interchangeable under appropriate circumstances and that the embodiments of the invention described herein are capable of operation in arrangements other than those described or illustrated herein.

[0022] Wherever an aspect is described herein by the phrase "comprising," it is understood that otherwise similar aspects described with the terms "consisting of" and / or "consisting essentially of" are also provided. Where the term "comprising" is used in the specification and claims, it does not exclude other elements or steps. Unless specifically defined herein, all terms used herein have the same meaning as they would have to one skilled in the art of the invention.

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this disclosure pertains.For example, Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and Oxford Dictionary of Biochemistry and Molecular Biology, Revised, 2000, Oxford University Press provide those skilled in the art with a general dictionary of many of the terms used in this disclosure. For definitions and terms of the art, practitioners are specifically directed to Sambrook et al., Molecular Cloning: A Laboratory Manual, 4th ed., Cold Spring Harbor Press, Plainsview, New York (2012); and Ausubel et al., Current Protocols in Molecular Biology (Supplement 100), John Wiley & Sons, New York (2012). The definitions provided herein should not be construed to have a scope less than that understood by a person skilled in the art.

[0024] Units, prefixes, and symbols are denoted in their International System of Units (SI) accepted form. Numerical ranges are inclusive of the numbers defining the range. Unless otherwise indicated, nucleotide sequences are written left to right in 5' to 3' orientation. Amino acid sequences are written left to right in amino to carboxy orientation. The headings provided herein are not limitations of the various aspects of this disclosure that may be had by reference to the specification in its entirety. Accordingly, the terms defined immediately below are more fully defined by reference to the specification in its entirety.

[0025] The term "about" is used herein to mean approximately, roughly, around, or within a range of. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the stated numerical values. Generally, the term "about" can modify a numerical value above and below the stated value, for example, by a variance of 10 percent upward or downward (higher or lower). For example, if it is stated that an oligonucleotide of the present disclosure reduces Syngr-3 transcript expression in cells by at least about 60% after administration of the oligonucleotide of the present disclosure, it implies that Syngr-3 expression levels are reduced by a range of 50% to 70%.

[0026] As used herein, the terms "reverse complement," "reverse complementary," and "reverse complementarity" are interchangeable with the terms "complement," "complementary," and "complementarity."

[0027] The term "identical" or percent "identity" in the context of two or more nucleic acids refers to two or more sequences that, when compared and aligned (introducing gaps, if necessary) for maximum correspondence, are the same or have a specified percentage of nucleotide or amino acid residues that are the same. Any conservative amino acid substitutions are not considered part of the sequence identity. Percent identity can be measured using sequence comparison software or algorithms or by visual inspection. Various algorithms and software that can be used to align amino acid or nucleotide sequences are known in the art.

[0028] The term "percent sequence identity" or "percent identity" between two polynucleotide or polypeptide sequences refers to the number of identical matched positions shared by the sequences in the comparison window. It takes into account the addition or deletion (i.e., gap) that must be introduced for optimal alignment of the two sequences. A matched position is any position where the same nucleotide or amino acid is present in both the target sequence and the reference sequence. Since gaps are not nucleotides or amino acids, gaps present in the target sequence are not counted. Similarly, gaps present in the reference sequence are not counted, since target sequence nucleotides or amino acids are counted, not nucleotides or amino acids from the reference sequence.

[0029] One such non-limiting example of a sequence alignment algorithm is the algorithm described in Karlin et al., 1990, Proc. Natl. Acad. Sci., 87:2264-2268, modified in Karlin et al., 1993, Proc. Natl. Acad. Sci., 90:5873-5877, and incorporated into the NBLAST and XBLAST programs (Altschul et al., 1991, Nucleic Acids Res., 25:3389-3402). In certain aspects, Gapped BLAST can be used as described in Altschul et al., 1997, Nucleic Acids Res. 25:3389-3402. BLAST-2, WU-BLAST-2 (Altschul et al., 1996, Methods in Enzymology, 266:460-480), ALIGN, ALIGN-2 (Genentech, South San Francisco, California), or Megalign (DNASTAR) are additional publicly available software programs that can be used to align sequences. In certain aspects, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package (e.g., using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 90 and a length weight of 1, 2, 3, 4, 5, or 6). In certain alternative aspects, the GAP program in the GCG software package, which incorporates the algorithm of Needleman and Wunsch (J. Mol. Biol. (48):444-453 (1970)), can be used to determine percent identity between two amino acid sequences (e.g., using either a BLOSUM 62 matrix or a PAM250 matrix and gap weights of 16, 14, 12, 10, 8, 6, or 4 and length weights of 1, 2, 3, 4, 5).Alternatively, in certain aspects, percent identity between nucleotide or amino acid sequences is determined using the algorithm of Myers and Miller (CABIOS, 4:11-17 (1989)). For example, percent identity can be determined using the ALIGN program (version 2.0) using PAM120 as the residue table, a gap length penalty of 12, and a gap penalty of 4. One of skill in the art can determine appropriate parameters for maximal alignment with particular alignment software. In certain aspects, the default parameters of the alignment software are used.

[0030] Those skilled in the art will understand that the generation of sequence alignments for calculating percent sequence identity is not limited to binary sequence-sequence comparisons driven solely by primary sequence data. Sequence alignments can also be derived from multiple sequence alignments. One suitable program for generating multiple sequence alignments is ClustalW2, available from www.clustal.org. Another suitable program is MUSCLE, available from www.drive5.com / muscle / . ClustalW2 and MUSCLE are alternatively available, for example, from EBI (European Bioinformatics Institute).

[0031] In certain aspects, the percentage identity "X" of a first nucleotide sequence to a second nucleotide sequence is calculated as 100 x (Y / Z), where Y is the number of amino acid residues scored as identical matches on an alignment of the first and second sequences (aligned by visual inspection or by a specific sequence alignment program) and Z is the total number of residues on the second sequence. If the length of the first sequence is longer than the second sequence, the percent identity of the first sequence to the second sequence will be higher than the percent identity of the second sequence to the first sequence.

[0032] Different regions in a single polynucleotide target sequence that aligns with a polynucleotide reference sequence can each have their own percent sequence identity.It should be noted that percent sequence identity values ​​are rounded to one decimal place.For example, 80.11, 80.12, 80.13, and 80.14 are rounded down to 80.1, and 80.15, 80.16, 80.17, 80.18, and 80.19 are rounded up to 80.2.It should also be noted that length values ​​will always be integers.

[0033] As used in this disclosure, the terms "nucleic acid molecule of the invention" and "oligonucleotide of the disclosure" and grammatical variations thereof are used interchangeably.

[0034] As used herein, the term "defined by SEQ ID NO: X" refers to a biological sequence consisting of the sequence of nucleotides given in SEQ ID NO: X. SEQ ID NO: X is interchangeable with SEQ ID NO: X. When the present application refers to "the group consisting of SEQ ID NOs: 2 to 4," this is the same as the group consisting of SEQ ID NOs: 2, 3, and 4.

[0035] The target nucleic acid of the present invention is synaptogyrin-3, more specifically a nucleic acid encoding human synaptogyrin-3, such as mRNA, primary mRNA transcript, or pre-mRNA. "Synaptogyrin-3", "Synaptogyrin-3", "Synaptogyrin-3", "Syngr-3", "Syngr-3", "SYNGR-3", or "SYNGR-3" are used interchangeably and, unless otherwise specified, refer to synaptogyrin-3 transcripts herein.

[0036] As used herein, "primary mRNA transcript" refers to the single-stranded ribonucleic acid (RNA) product synthesized by transcription of DNA, which is subsequently processed (including, for example, 5' capping, 3' polyadenylation, and alternative splicing) to produce various mature RNA products, such as mRNA, tRNA, and rRNA. Primary transcripts designated as mRNAs are modified in preparation for translation. For example, precursor mRNAs or pre-mRNAs are the forms of primary transcripts that are processed into messenger RNAs (mRNAs).

[0037] "Pre-mRNA" is synthesized from a DNA template in the cell nucleus by transcription. Pre-mRNA comprises the majority of heterogeneous nuclear RNA (hnRNA). Once pre-mRNA is fully processed, it is called "mature messenger RNA" or simply "messenger RNA" or "mRNA." Although the term hnRNA is often used synonymously with pre-mRNA, in the strict sense, hnRNA can encompass nuclear RNA transcripts that do not ultimately become cytoplasmic mRNA.

[0038] The human nucleic acid sequence of synaptogyrin-3 (hSyngr-3) is set forth in SEQ ID NO: 1; however, nucleic acid sequence variants of synaptogyrin-3 that may exist due to allelic variation, such as mRNAs encoding synaptogyrin-3 allelic variants, are also within the scope of the present invention. Such variations are defined herein as "allelic variants of SEQ ID NO: 1." The term "allelic variant" refers to one of several alternative forms of a gene occupying a given locus on a chromosome of an organism (Genes II, Lewin, B., ed., John Wiley & Sons, New York (1985)). These allelic variants may differ at either the polynucleotide and / or polypeptide level and are encompassed by the present disclosure. Alternatively, non-naturally occurring variants may be produced by mutagenesis techniques or by direct synthesis. In some aspects, synaptogyrin-3 variants are splice variants. In some aspects, synaptogyrin-3 variants are post-translationally modified variants. In some aspects, the synaptogyrin-3 variant is a mutant synaptogyrin-3, for example, a mutant comprising at least one nucleotide point mutation, deletion, or insertion. In some aspects, the mutation is a silent mutation. In some aspects, the synaptogyrin-3 variant is a mutant protein comprising at least one amino acid substitution, deletion, or insertion. In some aspects, the synaptogyrin-3 variant is a loss-of-function variant. In some aspects, the synaptogyrin-3 variant is a gain-of-function variant.

[0039] As used herein, "specific for synaptogyrin-3" refers to the fact that the nucleic acid molecule or oligonucleotide of the present invention acts at the level of synaptogyrin-3, but not at the level of another transcript. Specificity can be confirmed, for example, by determining the expression level of a closely related RNA sequence.

[0040] The term "statistically significantly" different is well known to those skilled in the art. Statistical significance plays a central role in statistical hypothesis testing. It is used to determine whether the null hypothesis should be rejected or retained. The null hypothesis is the default assumption that nothing has happened or changed, and therefore, for example, there is no difference in the synaptogyrin-3 transcript level in the presence of antisense or RNAi molecules compared to the synaptogyrin-3 transcript level in the absence of antisense or RNAi molecules. To reject the null hypothesis, the observed result must be statistically significant. That is, the observed p-value is less than the pre-specified significance level α. The resulting p-value, p, is the probability of obtaining a result that is at least as extreme if the null hypothesis is true. In one embodiment, α is 0.05. In a more specific embodiment, α is 0.01. In an even more specific embodiment, α is 0.001. Nucleic acid molecules that inhibit the expression of synaptogyrin-3

[0041] The present disclosure provides nucleic acid molecules, more specifically oligonucleotides, comprising a sequence complementary (fully or partially) to a region of the mRNA or pre-mRNA encoding the human synaptogyrin-3 protein or the mRNA or pre-mRNA of an allelic variant or isoform thereof (e.g., any of the variants and isoforms disclosed in UniProtKB / Swiss-Prot entry O43761). SEQ ID NO: 1 represents the nucleic acid sequence of the human synaptogyrin-3 gene (Ensembl GRCh38:16;1989660:1994275). SEQ ID NO: 1: Gene sequence human Syngr3, Ensembl GRCh38:16 (1989660:1994275)

[0042] In some aspects, the nucleic acid molecules or oligonucleotides (e.g., ASO, siRNA, shRNA) of the present disclosure include oligonucleotides between 10 and 50 nucleotides in length.

[0043] In some aspects, the nucleic acid molecule or oligonucleotide of the present disclosure comprises or consists of one oligonucleotide (for example, ASO oligomer or shRNA).In some aspects, the nucleic acid molecule or oligonucleotide of the present disclosure comprises or consists of two oligonucleotides (for example, siRNA).In some aspects, the two oligonucleotides are a sense oligonucleotide and an antisense oligonucleotide.In some aspects, the sense oligonucleotide and the antisense oligonucleotide are connected by a loop.

[0044] In some aspects, a nucleic acid molecule of the present disclosure comprises or consists of a sequence of about 8 to about 70 contiguous nucleotides in length as disclosed herein, a sequence of about 10 to about 60 contiguous nucleotides in length as disclosed herein, a sequence of about 12 to about 50 contiguous nucleotides in length as disclosed herein, a sequence of about 8 to about 40 nucleotides in length, a sequence of about 10 to about 35 contiguous nucleotides in length as disclosed herein, a sequence of about 12 to about 30 contiguous nucleotides in length as disclosed herein, a sequence of about 14 to about 28 contiguous nucleotides in length as disclosed herein, a sequence of about 16 to about 25 nucleotides in length as disclosed herein, a sequence of about 17 to about 24 nucleotides in length as disclosed herein, or a sequence of about 18 to about 23 contiguous nucleotides in length as disclosed herein. In some aspects, nucleic acid molecules of the invention are 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 nucleotides in length. In one embodiment, "a length of nucleotides" refers to "a length of consecutive nucleotides."

[0045] As used herein, "nucleotide" refers to the building block of oligonucleotides and polynucleotides, and for the purposes of the present invention, includes both naturally occurring and non-naturally occurring nucleotides. In nature, nucleotides, such as DNA and RNA nucleotides, contain a ribose sugar moiety, a nucleobase moiety, and one or more phosphate groups (which are absent in nucleosides). A nucleotide without a phosphate group is called a "nucleoside," and is therefore a compound containing a nucleobase moiety and a sugar moiety. As used herein, "nucleobase" refers to a group of atoms that can be linked to a sugar moiety to create a nucleoside that can be incorporated into an oligonucleotide, where the group of atoms can bind to a complementary naturally occurring nucleobase of another oligonucleotide or nucleic acid. Naturally occurring nucleobases in RNA or DNA include the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C), and uracil (U).

[0046] The term "contiguous nucleotides" or "contiguous nucleotide sequence" refers to a region of an oligonucleotide that is complementary to a target nucleic acid. As used herein, "contiguous" means adjacent or together in sequence. Thus, contiguous nucleotides are linked nucleotides (i.e., there are no additional nucleosides between the linked ones). The target nucleic acid of the present invention is synaptogyrin-3. Unless otherwise specified, "synaptogyrin-3," "synaptogyrin-3," "Syngr3," "Syngr-3," "SYNGR3," or "SYNGR-3" are used interchangeably herein to refer to the synaptogyrin-3 transcript. The human nucleic acid sequence of synaptogyrin-3 is set forth in SEQ ID NO: 1. However, nucleic acid sequence variants of synaptogyrin-3 that may exist due to allelic variation are also within the scope of the present invention. Such variations are defined herein as "allelic variants of SEQ ID NO: 1." The term "allelic variant" refers to one of several alternative forms of a gene occupying a given locus on a chromosome of an organism (Genes II, Lewin, B., ed., John Wiley & Sons, New York (1985)). These allelic variants can differ at either the polynucleotide and / or polypeptide level and are encompassed by the present disclosure. Alternatively, non-naturally occurring variants can be produced by mutagenesis techniques or by direct synthesis.

[0047] In the context of this disclosure, the terms "oligomer" or "oligonucleotide" are used interchangeably and refer to a molecule formed by the covalent linkage of two or more nucleotides. Herein, a single nucleotide (unit) may also be referred to as a monomer or unit.

[0048] In some aspects, the present disclosure provides the derivative of the oligonucleotide of the present disclosure, which is conjugate, for example, GalNAc conjugate.The term " derivative " used herein refers to the chemical compound that is structurally related to the compound disclosed herein (for example, the oligonucleotide of the present disclosure).For example, it has the same carbon skeleton, but is chemically modified at one or more positions, for example, by introducing side chain or group, and wherein the biological activity of the entity or molecule that it is derivative of is substantially similar (for example, the ability to reduce Syngr3 expression).

[0049] The term "complementary" means that two sequences are complementary, such that one sequence can bind to the other in an antiparallel sense, with the 3' end of each sequence binding to the 5' end of the other, and each A, T(U), G, and C of one sequence aligning with the T(U), A, C, and G, respectively, of the other sequence. Normally, complementary sequences of oligonucleotides have at least 90%, preferably 95%, and most preferably 100% complementarity to a given sequence.

[0050] In determining the degree of "complementarity" between an oligonucleotide (or region thereof) of the present disclosure and a target region, such as those disclosed herein, the degree of "complementarity" (also, "homology" or "identity") is expressed as the percentage identity (or percentage homology) between the sequence of the oligonucleotide (or region thereof) and the sequence of the target region (or reverse complement of the target region) with which it best aligns. The percentage is calculated by counting the number of aligned bases that are identical between the two sequences, dividing by the total number of contiguous monomers (e.g., nucleotides) on the oligomer (e.g., oligonucleotide), and multiplying by 100. In such a comparison, if gaps exist, it is preferred that such gaps are simply mismatches rather than areas where the number of monomers within the gap differs between the oligomer of the present disclosure and the target region.

[0051] In some embodiments, the above-described nucleic acid molecule or contiguous nucleotide sequence thereof is less than 60 nucleotides, less than 59 nucleotides, less than 58 nucleotides, less than 57 nucleotides, less than 56 nucleotides, less than 55 nucleotides, less than 54 nucleotides, less than 53 nucleotides, less than 52 nucleotides, less than 51 nucleotides, less than 50 nucleotides, less than 49 nucleotides, less than 48 nucleotides, less than 47 nucleotides, less than 46 nucleotides, less than 45 nucleotides, less than 44 nucleotides, less than 43 nucleotides, less than 42 nucleotides, less than 41 nucleotides, less than 40 nucleotides, less than 39 nucleotides, less than 38 nucleotides, less than 37 nucleotides. less than 36 nucleotides, less than 35 nucleotides, less than 34 nucleotides, less than 33 nucleotides, less than 32 nucleotides, less than 31 nucleotides, less than 30 nucleotides, less than 29 nucleotides, less than 28 nucleotides, less than 27 nucleotides, less than 26 nucleotides, less than 25 nucleotides, less than 24 nucleotides, less than 23 nucleotides, less than 22 nucleotides, less than 21 nucleotides, less than 20 nucleotides, less than 19 nucleotides, less than 18 nucleotides, less than 17 nucleotides, less than 16 nucleotides, less than 15 nucleotides, less than 14 nucleotides, less than 13 nucleotides, or less than 12 nucleotides.

[0052] Any range given herein should be understood to include the endpoints of the range, thus, when a nucleic acid molecule is said to include 10 to 30 nucleotides, both 10 and 30 nucleotides are included.

[0053] In some embodiments, the contiguous nucleotide sequence comprises or consists of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 contiguous nucleotides in length. In some aspects, nucleic acid molecules of the invention are 14 nucleotides in length. In some aspects, nucleic acid molecules of the invention are 15 nucleotides in length. In some aspects, nucleic acid molecules of the invention are 16 nucleotides in length. In some aspects, nucleic acid molecules of the invention are 17 nucleotides in length. In some aspects, nucleic acid molecules of the invention are 18 nucleotides in length. In some aspects, nucleic acid molecules of the invention are 19 nucleotides in length. In some aspects, nucleic acid molecules of the invention are 20 nucleotides in length. In some aspects, nucleic acid molecules of the invention are 21 nucleotides in length. In some aspects, nucleic acid molecules of the invention are 22 nucleotides in length. In some aspects, nucleic acid molecules of the invention are 24 nucleotides in length.

[0054] The nucleic acid molecule(s) or oligonucleotide(s) of the present application are typically for regulating the expression of synaptogyrin-3 as a target nucleic acid in mammals. In some embodiments, the nucleic acid molecule(s) such as siRNA, shRNA, or antisense oligonucleotide are typically for inhibiting the expression of a target nucleic acid. More specifically, the oligonucleotide of the present application is provided as being able to reduce the level of synaptogyrin-3 (pre)mRNA transcript (and therefore indirectly SYNGR3 protein) in cells, wherein the reduction is determined by comparison with the level of synaptogyrin-3 mRNA transcript in the same cells or the same cell type grown under the same conditions but in the absence of the oligonucleotide of the present application.

[0055] The oligonucleotides described herein are partially or completely complementary to equal-length portions of target regions within synaptogyrin-3 as set forth in SEQ ID NO: 1 or its allelic variants. Specific target regions are described in detail below. In another embodiment, the oligonucleotides of the present invention comprise a contiguous nucleotide sequence complementary to one of the specific target regions, and in some embodiments, may further comprise one or more additional nucleotides, e.g., 1 to 30, e.g., 1 to 20, e.g., 1 to 10, e.g., 1, 2, 3, 4, or 5, in addition to the contiguous nucleotide sequence. In some embodiments, the additional nucleotides are complementary to the contiguous nucleotide sequence and can form a stem-loop (hairpin) structure by hybridizing to the contiguous nucleotide sequence. In some embodiments, the additional nucleotides are 1 to 5 phosphodiester-linked nucleotides. In some embodiments, all nucleotides of the oligonucleotide form a contiguous nucleotide sequence.

[0056] In one embodiment, the nucleic acid molecule(s) or oligonucleotide(s) of the present application are man-made and / or chemically synthesized and / or are typically purified or isolated.

[0057] In yet another embodiment, the oligonucleotide of the present invention can be or comprise an antisense oligonucleotide (ASO), or can be another oligomeric nucleic acid molecule, such as CRISPR(g)RNA, siRNA, shRNA, aptamer, or ribozyme. In a specific embodiment, the oligonucleotide of the present invention is an antisense oligonucleotide (ASO), such as a single-stranded antisense oligonucleotide, for example, a high-affinity modified antisense oligonucleotide that interacts with RNase H, such as a gapmer (see below for more details). As used herein, the term "antisense oligonucleotide" or "ASO" is defined as an oligonucleotide that can regulate the expression of a target gene by hybridizing to a target nucleic acid, specifically to a continuous sequence on the target nucleic acid. Antisense oligonucleotides are not essentially double-stranded, and therefore are not siRNA or shRNA. Preferably, the antisense oligonucleotide of the present invention is single-stranded. It is understood that the single-stranded oligonucleotide of the present invention can form a hairpin or intermolecular duplex structure (a duplex between two molecules of the same oligonucleotide), as long as the degree of complementarity within or between them is less than 50% over the entire length of the oligonucleotide.

[0058] In another specific embodiment, the single-stranded antisense oligonucleotide of the present invention does not contain RNA nucleoside, because this would reduce nuclease resistance.More specifically, the antisense oligonucleotide of the present invention comprises one or more modified nucleosides or nucleotides, such as 2' sugar-modified nucleosides.Moreover, it is advantageous that unmodified nucleosides are DNA nucleosides.

[0059] In another specific embodiment, the oligonucleotide of the invention is an RNAi molecule or RNAi agent, more specifically an siRNA, di-siRNA, shRNA, or miRNA.

[0060] The term "RNAi agent" or "RNA interference (RNAi) molecule" refers to any molecule that inhibits RNA expression or translation through the RNA reduction silencing complex (RISC) in the cytoplasm of a cell, where the RNAi molecule interacts with the catalytic RISC component Argonaute. Small interfering RNA (siRNA) is typically a double-stranded RNA complex containing a passenger (sense) and a guide (antisense) oligonucleotide (strand), which, when administered to a cell, results in the incorporation of the guide (antisense) strand into the RISC complex (siRISC), leading to the RISC-associated inhibition of translation or degradation of the complementary RNA target nucleic acid in the cell. The sense strand is also referred to as the passenger strand, and the antisense strand is also referred to as the guide strand. Short hairpin RNA (shRNA) is a single nucleic acid molecule that forms a stem-loop (hairpin) structure that can degrade mRNA through RISC. RNAi nucleic acid molecules can be synthesized chemically (typically in siRNA complexes) or by in vitro transcription, or can be expressed from a vector.

[0061] shRNA molecules are generally between 40 and 70 nucleotides in length, e.g., between 45 and 65 nucleotides in length, e.g., between 50 and 60 nucleotides in length, and interact with an endonuclease known as Dicer. This appears to process dsRNA into 19-23 base pair short interfering RNAs with characteristic 2-nucleotide 3' overhangs. These are then incorporated into the RNA-induced silencing complex (RISC). Typically, the guide (antisense) strand of an siRNA (or the antisense region of an shRNA) is 17-25 nucleotides in length, e.g., 19-23 nucleotides in length, and is complementary to the target nucleic acid or target sequence. In the siRNA complex, the guide (antisense) strand and passenger (sense) strand form a double-stranded duplex, which may contain, for example, a 1-3 nucleotide 3' overhang (similar to the product produced by Dicer) or may be blunt-ended (no overhangs on one or both ends of the duplex). It will be appreciated that RNAi can be mediated by longer dsRNA substrates, such as miRNAs, that are processed into siRNAs within the cell, a process thought to involve the dsRNA endonuclease DICER.

[0062] In one embodiment, the oligonucleotide of the present invention, such as a therapeutic antisense oligonucleotide, shRNA, or siRNA, comprises one or more internucleoside linkages modified from natural phosphodiester, for example, one or more modified internucleoside linkages that are more resistant to nuclease attack.The term "modified internucleoside linkage" is defined as a linkage other than a phosphodiester (PO) linkage that covalently couples two nucleosides together, as generally understood by those skilled in the art.The increased resistance of oligonucleotides to nuclease compared to phosphodiester linkages is particularly advantageous for therapeutic oligonucleotides.Nuclease resistance can be determined by incubating oligonucleotides in serum or by using nuclease resistance assays (e.g., snake venom phosphodiesterase (SVPD)).Both are well known in the art.An internucleoside linkage that can enhance the nuclease resistance of oligonucleotides is called a nuclease-resistant internucleoside linkage. In some embodiments, at least 50% of the internucleoside linkages in the oligonucleotide or its consecutive nucleotide sequence are modified.For example, at least 60%, for example at least 70%, for example at least 80%, or for example at least 90% of the internucleoside linkages in the oligonucleotide or its consecutive nucleotide sequence are nuclease-resistant internucleoside linkages.In some embodiments, all of the internucleoside linkages in the oligonucleotide or its consecutive nucleotide sequence are nuclease-resistant internucleoside linkages.It will be appreciated that in some embodiments, the nucleoside that connects the oligonucleotide of the present invention to a non-nucleotide functional group such as a conjugate can be phosphodiester.In a specific embodiment, the modified internucleoside linkage is phosphorothioate.

[0063] Phosphorothioate internucleoside linkages are particularly useful due to their nuclease resistance, favorable pharmacokinetics, and ease of manufacture.In some embodiments, at least 50% of the internucleoside linkages in oligonucleotide or its consecutive nucleotide sequence are phosphorothioate.For example, at least 60%, for example at least 70%, for example at least 80%, or for example at least 90% of the internucleoside linkages in oligonucleotide or its consecutive nucleotide sequence are phosphorothioate.In some embodiments, all of the internucleoside linkages in oligonucleotide or its consecutive nucleotide sequence are phosphorothioate.The use of fully phosphorothioate modified oligonucleotide or consecutive nucleotide sequence is often used in antisense oligonucleotide, but in siRNA, partial phosphorothioate modification may be preferred.This is because it has been reported that fully phosphorothioate modification limits RNAi activity, especially when used in guide (antisense) strand. Phosphorothioate modifications can be incorporated into the 5' and 3' ends of the antisense strand of the siRNA without unduly limiting RNAi activity.

[0064] Nuclease-resistant linkages, such as phosphorothioate linkages, are particularly useful in regions of an oligonucleotide that can recruit nucleases when forming a duplex with a target nucleic acid, such as region G of a gapmer. However, phosphorothioate linkages can also be useful in regions that do not recruit nucleases and / or affinity-enhancing regions, such as regions F and F' of a gapmer. In some embodiments, a gapmer oligonucleotide can contain one or more phosphodiester linkages in regions F or F', or in both regions F and F', and the internucleoside linkages in region G can be entirely phosphorothioate. In specific embodiments, all internucleoside linkages along the contiguous nucleotide sequence of an antisense oligonucleotide are phosphorothioate linkages.

[0065] In other embodiments, the antisense oligonucleotides may contain other internucleoside linkages (other than phosphodiester and phosphorothioate), for example, alkylphosphonate / methylphosphonate internucleoside linkages.

[0066] In some embodiments, the RNAi molecule of the present disclosure comprises one or more phosphorothioate internucleoside linkages. In RNAi molecules, phosphorothioate internucleoside linkages can reduce nuclease cleavage in RISC. Therefore, it is advantageous that not all internucleoside linkages are modified. Phosphorothioate internucleoside linkages can be advantageously located on the 3' and / or 5' end of the RNAi molecule, particularly on the part of the molecule that is not complementary to the target nucleic acid (e.g., the sense strand or passenger strand on an siRNA molecule). However, the region of the RNAi molecule that is complementary to the target nucleic acid (e.g., the antisense or guide strand on an siRNA molecule) can also have the first two to three internucleoside linkages at the 3' and / or 5' end modified.

[0067] In other embodiments, the oligonucleotide of the present disclosure can be chemically modified by incorporating high affinity nucleosides, such as 2' sugar-modified nucleosides, for example, 2'-4' bicyclic ribose-modified nucleosides, including LNA and cET, or 2'-substituted modifications such as 2'-O-alkyl-RNA, 2'-O-methyl-RNA, 2'-alkoxy-RNA, 2'-O-methoxyethyl-RNA (MOE), 2'-amino-DNA, 2'-fluoro-DNA, arabinonucleic acid (ANA), 2'-fluoro-ANA.For example, see WO 2002 / 044321, which discloses 2'-O-methyl-modified siRNA; WO2004083430, which discloses the use of LNA nucleosides in siRNA complexes known as siLNA; and WO2007107162, which discloses the use of discontinuous passenger strands in siRNA, such as siLNA complexes.

[0068] In specific embodiments, the oligonucleotides of the present disclosure comprise a 2' sugar modified nucleoside selected from the list consisting of 2'-O-methyl (2'-OMe), 2'-O-methoxyethyl (2'-MOE), and 2'-fluoro (2'-F).

[0069] In other embodiments, oligonucleotides of the present disclosure may include one or more of the chemically modified sugar nucleosides described above and may include one or more of the phosphorothioate internucleoside linkages described above.

[0070] Those skilled in the art know how to design the oligonucleotides disclosed herein. siRNA and shRNA design programs are publicly and / or commercially available. Non-limiting examples include the open-source siRNA and ASO design tool PFRED from Pfizer (Sciabola et al., 2020, PLoS One); Antisense LNA Gapmer Custom Builder Help from Qiagen; siDESIGN from ThermoScientific; siDirect (Naito et al.); BLOCK-IT RNAi Designer from Invitrogen; siRNA Wizard from InvivoGen; shRNA design tool from Gene Link; and shRNA design tool from transomic. Manufacturers of ASO and / or RNAi products also provide guidelines for designing ASO, siRNA, and shRNA molecules. siRNA sequences between 19 and 29 nucleotides (nt) are generally most effective. Sequences longer than 30 nt may result in nonspecific silencing. The ideal targeting site encompasses the AA dinucleotide and its 3' 19 nt on the target mRNA sequence. Typically, siRNAs with 3' dUdU or dTdT dinucleotide overhangs are more effective. While other dinucleotide overhangs may maintain activity, GG overhangs should be avoided. siRNA designs with 4-6 poly(T) tracts (which act as termination signals for RNA pol III) should also be avoided, and a G / C content between 35-55% is recommended. shRNAs should contain sense and antisense sequences separated by a loop structure (recommended lengths of 19-21 nt each) and a 3' AAAA overhang. An effective loop structure is suggested to be 3-9 nt in length. It is suggested to follow the sense-loop-antisense order when designing shRNA cassettes and to avoid 5' overhangs on shRNA constructs. Finally, several companies offer pre-made ASOs, siRNAs, and shRNAs commercially.

[0071] In some aspects, any of the oligonucleotides of the present disclosure is provided, wherein the oligonucleotide is an ASO or RNAi molecule comprising at least one nucleotide variant (e.g., an LNA unit). In some aspects, the oligonucleotide of the present disclosure further comprises at least one non-nucleotide or non-polynucleotide moiety (e.g., a GalNac moiety) covalently attached to the oligonucleotide, either directly or via a linker located between the contiguous nucleotide sequence and the non-nucleotide or non-polynucleotide moiety.

[0072] In some aspects, the present disclosure provides an oligonucleotide of the present disclosure comprising a 16-22 contiguous oligonucleotide in length comprising a 16-nucleotide contiguous sequence that is 100% complementary to a human synaptogyrin-3 target sequence selected from the group consisting of SEQ ID NOs: 2-269, wherein the oligonucleotide is an ASO or RNAi molecule such as an siRNA, shRNA, or di-siRNA that comprises at least one nucleotide variant (e.g., an LNA unit), and the ASO or RNAi molecule targets the synaptogyrin-3 transcript set forth in SEQ ID NO: 1.

[0073] In some aspects, the oligonucleotides of the present disclosure comprise, consist of, or consist essentially of an ASO or RNAi molecule that binds to the human synaptogyrin-3 transcript defined in SEQ ID NO: 1, and the ASO or RNAi molecule comprises a sequence selected from the group consisting of SEQ ID NOs: 270-489.

[0074] In some aspects, oligonucleotides of the disclosure include ASOs or RNAi molecules comprising a sequence selected from the group consisting of SEQ ID NOs: 270-489, except for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleobase substitutions. In some aspects, oligonucleotides of the disclosure include ASOs or RNAi molecules comprising a sequence that is at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to a sequence selected from the group consisting of SEQ ID NOs: 270-489. In some aspects, oligonucleotides of the present disclosure include ASOs or RNAi molecules comprising a sequence that is about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to a sequence selected from the group consisting of SEQ ID NOs: 270-489. In some aspects, oligonucleotides of the present disclosure comprise a sequence that overlaps with a 9, 10, 11, 12, 13, 14, 15, or 16 nucleobase subsequence from a sequence selected from the group consisting of SEQ ID NOs: 270-489.

[0075] In some aspects, the oligonucleotides of the present disclosure contain at least one non-cleavable internucleoside linkage, e.g., a phosphorothioate linkage. In some aspects, all internucleoside linkages on the oligonucleotides of the present disclosure are non-cleavable, e.g., phosphorothioate linkages. In some aspects, non-cleavable internucleoside linkages, e.g., phosphorothioate linkages, are present only in the wing portions of a gapmer, e.g., the 5'-end or the last 1, 2, or 3 linkages in the oligonucleotide and the 5'-end or the last 1, 2, or 3 linkages in the oligonucleotide. In some aspects, the oligonucleotides of the present disclosure contain nucleotide analogs. In some aspects, the oligonucleotides of the present disclosure contain affinity-enhancing nucleotide analogs. In some aspects, the nucleotide analogs are sugar-modified nucleotides, e.g., sugar-modified nucleotides independently or dependently selected from the group consisting of 2'-O-alkyl-RNA units, 2'-OMe-RNA units, 2'-amino-DNA units, and 2'-fluoro-DNA units.

[0076] In some aspects, the oligonucleotides of the present disclosure are ASOs or antisense strands from RNA duplexes. In some aspects, the oligonucleotides of the present disclosure comprise one or more locked nucleic acids (LNAs). In some aspects, the LNA oligonucleotides comprise wings of two to four nucleotide analogs, preferably LNA analogs, on each side (5' and 3'). In some aspects, the oligonucleotides of the present disclosure can optionally comprise an additional 1 to 6 nucleotides (e.g., 1, 2, 3, 4, 5, or 6 nucleotides), which can form or comprise a biologically cleavable nucleotide region, such as a phosphate nucleotide linker. In some aspects, the biologically cleavable nucleotide region is formed from a short stretch (e.g., 1, 2, 3, 4, 5, or 6 nucleotides) of physiologically unstable nucleotides. This can be achieved by using phosphodiester linkages in DNA / RNA nucleosides, or other nucleosides can be used if physiological stability can be maintained.

[0077] In some aspects, the LNA is oxy-LNA, thio-LNA, amino-5 LNA, 5'-methyl-LNA, ENA, cET, cMOE, or a combination thereof. In some aspects, the LNA is a stereoisomer of the beta-D or alpha-L configuration. In some aspects, the oligonucleotide of the present application comprises at least one cET unit. In some aspects, the oligonucleotide comprises 2, 3, 4, 5, 6, or 7 LNA units. In some aspects, every LNA unit on the oligonucleotide is a stereoisomer of the same configuration. In some aspects, every LNA unit on the oligonucleotide is a beta-D-oxyLNA unit, or every LNA unit on the oligonucleotide is an alpha-L-oxy-LNA unit. In some aspects, the sequence of the oligonucleotide comprises at least one phosphorothioate, phosphorodithioate, or boranophosphate internucleoside linkage. In some aspects, one or more of the internucleoside linkages contain a chiral center in the R and / or S conformation. In some aspects, oligonucleotides containing LNAs can form duplexes with human synaptogyrin-3 target sequences selected from the group consisting of SEQ ID NOs: 2-269 that have increased thermal stability relative to corresponding duplexes containing the corresponding oligonucleotides without LNAs.

[0078] In some aspects, the oligonucleotides of the present disclosure are ASO or RNAi molecule conjugates comprising an ASO or RNAi molecule covalently attached to a non-nucleotide or non-polynucleotide moiety, which may be attached to the 5' end, the 3' end, or both. In some aspects, the non-nucleotide or non-polynucleotide moiety is a targeting moiety attached to the 5' end or the 3' end of the ASO or RNAi molecule. In some aspects, the targeting moiety is linked to the ASO or RNAi molecule via a linker. In some aspects, the targeting moiety comprises a carbohydrate conjugate moiety comprising a carbohydrate selected from the group consisting of galactose, lactose, N-acetylgalactosamine (GalNAc), mannose, mannose-6-phosphate, and combinations thereof. In some aspects, the carbohydrate conjugate moiety is not a linear carbohydrate polymer. In some aspects, the carbohydrate conjugate moiety is a carbohydrate group comprising one, two, three, or four carbohydrate moieties. In some aspects, the carbohydrate moieties are identical or non-identical. In some aspects, the carbohydrate conjugate moiety comprises at least one asialoglycoprotein receptor targeting conjugate moiety. In some aspects, the asialoglycoprotein receptor-targeting conjugate moiety comprises a monovalent, divalent, trivalent, or tetravalent GalNAc cluster. In some aspects, each GalNAc in the GalNAc cluster is attached to a branch point group via a spacer. In some aspects, the branch point group comprises a dilysine. In some aspects, the spacer comprises a PEG spacer. In some aspects, the linker comprises a C6-C12 aminoalkyl group or a biologically cleavable phosphate nucleotide linker comprising between 1 and 6 nucleotides. In some aspects, the targeting moiety targets the oligonucleotides of the present disclosure to the central nervous system (CNS). In some aspects, the targeting moiety allows the oligonucleotides of the present disclosure to penetrate the blood-brain barrier (BBB).

[0079] In some aspects, the oligonucleotides of the present disclosure, more particularly the RNAi molecules of the present disclosure, are double-stranded nucleic acids. In some aspects, the RNAi molecules are siRNAs. In some aspects, the RNAi molecules of the present disclosure are di-siRNAs. In some aspects, the RNAi molecules of the present disclosure are shRNAs. In some aspects, the antisense oligomer portion of the oligonucleotides of the present disclosure is an antisense oligonucleotide (ASO). In some aspects, the antisense oligomer portion of the oligonucleotides of the present disclosure is a multimer. In some aspects, the antisense oligomer portion of the oligonucleotides of the present disclosure is a multimeric ASO. For example, it may comprise several concatenated antisense oligomers of the present disclosure. In some aspects, the antisense oligomer portion of the oligonucleotides of the present disclosure comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 concatenated antisense oligomers. In some aspects, the concatenated oligomers are connected via cleavable linkers inserted between each ASO unit on the ASO multimer.

[0080] In some aspects, the antisense oligomer portion of the oligonucleotides of the present disclosure may target a target region on synaptogyrin-3 mRNA selected from the group consisting of SEQ ID NOs: 2-269.

[0081] In some aspects, the antisense oligomer portion of the oligonucleotide of the present disclosure comprises a complementary region that is complementary to at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 nucleotides of a target region on synaptogyrin-3 mRNA selected from the group consisting of SEQ ID NOs: 2-269.

[0082] The oligonucleotides of the present disclosure can regulate the expression of the synaptogyrin-3 gene by specifically targeting a target region on synaptogyrin-3 RNA, e.g., mRNA or pre-mRNA. In some aspects, the oligonucleotides of the present disclosure can down-regulate the expression of the synaptogyrin-3 gene by binding to such a target region. Therefore, in some aspects, the oligonucleotides of the present disclosure can affect (reduce or inhibit) the expression of synaptogyrin-3 in a mammalian subject, e.g., a human, by binding to a specific target region on synaptogyrin-3 RNA, e.g., mRNA or pre-mRNA. In some aspects, the oligonucleotides of the present disclosure can affect the expression of synaptogyrin-3 in human cells by binding to a specific target region on synaptogyrin-3 RNA, e.g., mRNA. In some aspects, the RNA is mRNA, e.g., pre-mRNA. In some aspects, the RNA is mature mRNA. The oligonucleotides according to the present disclosure are preferably capable of hybridizing to a target nucleic acid.

[0083] In some aspects, the target sequence may extend 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides beyond the 5' end of the synaptorgyrin-3 target region comprising or consisting of a sequence set forth in SEQ ID NOs: 2-269. In some aspects, the target sequence may extend 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides beyond the 3' end of the synaptorgyrin-3 target region comprising or consisting of a sequence set forth in SEQ ID NOs: 2-269. In some aspects, the target sequence may extend 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides beyond the 5' end and / or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides beyond the 3' end of the synaptorgyrin-3 target region comprising or consisting of a sequence set forth in SEQ ID NOs: 2-269. In some aspects, the extended target region overlaps 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 nucleotides of a synaptogyrin-3 target region comprising or consisting of a sequence set forth in SEQ ID NOs: 2-269.

[0084] In some aspects, nucleotides extending beyond the 5' and / or 3' ends of the sequences set forth in SEQ ID NOs: 2-269 are complementary (partially or fully complementary) to corresponding sequences in the nucleotide sequence of SEQ ID NO: 1. The present disclosure also provides antisense oligonucleotides that are complementary, e.g., fully complementary, to these target sequences.

[0085] In some aspects, the present disclosure provides target sequences comprising a 21mer sequence selected from SEQ ID NOs: 10, 12, 20, 25, 29-31, 33, 50, 53, 58-59, 62, 69, 79, 84, 87, 91, 94, 110-111, 135, 140-141, 170, 172, 179, 181, 184, 188, 193-194, 210, 216, 220-221, 224, 227, 229, 231, 235, 241, 246, 248, 250, 259, 268, or 269, or a 12, 13, 14, 15, 16, 17, 18, 19, or 20-mer subsequence thereof. Furthermore, the present disclosure provides a method for the preparation of a nucleotide sequence comprising: (i) SEQ ID NOs: 10, 12, 20, 25, 29-31, 33, 50, 53, 58-59, 62, 69, 79, 84, 87, 91, 94, 110-111, 135, 140-141, 170, 172, 179, 181, 184, 188, 193-194, 210, 216, 220-221, 224, 227, 229, 231, 235, 241, 246, 248, 250, 259, 268, or or 269, and a 12-mer, 13-mer, 14-mer, 15-mer, 16-mer, 17-mer, 18-mer, 19-mer, or 20-mer subsequence thereof, plus (ii) 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 additional 5' nucleotides and / or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 additional 3' nucleotides. In some aspects, the additional 5' and / or 3' nucleotides are complementary (partially or fully complementary) to the corresponding sequence on the mRNA transcript of SEQ ID NO: 1. The present disclosure also provides antisense oligonucleotides that are complementary, e.g., fully complementary, to these target sequences.

[0086] In some aspects, the present disclosure provides SEQ ID NOs: 2-9, 11, 13-19, 21-24, 26-28, 32, 34-49, 51-52, 54-57, 60-61, 63-68, 70-78, 80-83, 85-86, 88-90, 92-93, 95-109, 112-134, 136-139, 142-169, 171, 173-178, 180, 182-183, 184-185, 186-187, 188-189, 190-191, 191-192, 192-193, 193-194, 194-195, 195-196, 196-197, 197-198, 198-199, 199-200, 200-201, 201-202, 202-203, 203-204, 204-205, 205-206, 206-207, 207-208, 208-209, 210-211, 211-212, 212-213, 213-214, 214-215, 215-216, 216-217, 217-218, 218-219, 220-221, 222-223, 224-225, 226-227, 228-229, 230-2 A target sequence is provided that includes a 16-mer sequence selected from 85-187, 189-192, 195-209, 211-215, 217-219, 222-223, 225-226, 228, 230, 232-234, 236-240, 242-245, 247, 249, 251-258, or 260-267, or a 12-, 13-, 14-, or 15-mer subsequence thereof. Furthermore, the present disclosure provides the nucleic acid sequences of SEQ ID NOs: 2-9, 11, 13-19, 21-24, 26-28, 32, 34-49, 51-52, 54-57, 60-61, 63-68, 70-78, 80-83, 85-86, 88-90, 92-93, 95-109, 112-134, 136-139, 142-169, 171, 173-178, 180, 182-183, 185-187, 189-192, 195-209, 211-215, 217-219, 222-223, 225-226, 228, 230, 232 The present disclosure provides a target sequence comprising a sequence selected from the group consisting of 234, 236-240, 242-245, 247, 249, 251-258, or 260-267, and a 12-mer, 13-mer, 14-mer, 15-mer, 16-mer, 17-mer, 18-mer, 19-mer, or 20-mer subsequence thereof, plus (ii) 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 additional 5' nucleotides and / or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 additional 3' nucleotides. In some aspects, the additional 5' and / or 3' nucleotides are complementary (partially or fully complementary) to the corresponding sequence on an mRNA transcript of SEQ ID NO: 1. The present disclosure also provides antisense oligonucleotides that are complementary, e.g., fully complementary, to these target sequences.

[0087] In some aspects, the target region comprises or consists of a corresponding target sequence region derived from the sequence of a mutant or allelic variant of the human synaptogyrin-3 gene encoding the mRNA transcript of SEQ ID NO: 1. In other aspects, the target region may be a subsequence present on another synaptogyrin-3 mRNA transcript variant encoding human synaptogyrin-3. In some aspects, the target region comprises or consists of a corresponding target sequence region derived from the sequence of a paralog or ortholog of the human synaptogyrin-3 gene encoding the pre-mRNA of SEQ ID NO: 1. In some aspects, the target region is within an exon. In some aspects, the target region comprises a junction between an intron and an exon.

[0088] In some aspects, the oligonucleotides of the present disclosure bind to a subsequence of a target nucleic acid (e.g., an mRNA or pre-mRNA transcript, wherein the subsequence is selected from the group consisting of SEQ ID NOs: 2-269), and the effect on synaptogyrin-3 expression and / or activity levels is at least about a 10% to about a 20% reduction in synaptogyrin-3 expression and / or activity levels compared to normal or control synaptogyrin-3 expression levels (e.g., synaptogyrin-3 expression levels in saline-treated cells, animals, or humans) and / or normal or control synaptogyrin-3 activity levels (e.g., expression levels in saline-treated cells, animals, or humans). In some aspects, the reduction in synaptogyrin-3 expression and / or activity is at least about 10%, at least about 15%, at least about 20%, or at least about a 10% to about a 20% reduction in synaptogyrin-3 expression and / or activity levels compared to normal or control expression and / or activity levels. about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 10 In some aspects, the reduction in synaptogyrin-3 expression and / or activity is about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% compared to normal or control synaptogyrin-3 expression and / or activity levels.

[0089] In some aspects, the synaptogyrin-3 expression level and / or protein level and / or activity level after administration of an oligonucleotide of the present disclosure is less than about 2%, less than about 5%, less than about 10%, less than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about 35%, less than about 40%, less than about 45%, less than about 50%, less than about 55%, less than about 60%, less than about 65%, less than about 70%, less than about 75%, or less than about 80% of the synaptogyrin-3 expression level and / or protein level and / or activity level prior to administration of the oligonucleotide of the present disclosure.

[0090] In some aspects, the synaptogyrin-3 expression level and / or protein level and / or activity level after administration of an oligonucleotide of the present disclosure is about 2% to about 5%, about 5% to about 10%, about 10% to about 15%, about 15% to about 20%, about 20% to about 25%, about 25% to about 30%, about 30% to about 35%, about 35% to about 40%, about 40% to about 45%, about 45% to about 50%, about 50% to about 55%, about 55% to about 60%, about 60% to about 65%, about 65% to about 70%, about 70% to about 75%, or about 75% to about 80% of the synaptogyrin-3 expression level and / or protein level and / or activity level prior to administration of the oligonucleotide of the present disclosure.

[0091] Thus, the present disclosure provides an in vitro or in vivo method for downregulating or inhibiting expression of synaptogyrin-3 protein and / or mRNA transcripts in a cell expressing synaptogyrin-3 protein and / or mRNA, the method comprising administering to the cell an oligonucleotide of the present disclosure, e.g., as a pharmaceutical composition of the present disclosure, to downregulate or inhibit expression of synaptogyrin-3 protein and / or mRNA in the cell. Preferably, the cell is a mammalian cell, such as a human cell.

[0092] It should be understood that in some aspects, the oligonucleotides of the present disclosure may be multimers comprising, for example, 2, 3, 4, 5, 6, or more chains of the oligonucleotides disclosed herein, which may optionally be connected by spacers or linkers comprising nucleotide or non-nucleotide units interposed between each oligonucleotide on the multimer. Thus, in some aspects, oligonucleotides of the present disclosure can comprise or consist of a contiguous nucleotide sequence totaling at least about 20, at least about 25, at least about 30, at least about 35, at least about 40, at least about 45, at least about 50, at least about 55, at least about 60, at least about 65, at least about 70, at least about 75, at least about 80, at least about 85, at least about 90, at least about 95, at least about 100, at least about 110, at least about 120, at least about 130, at least about 140, at least about 150, at least about 160, at least about 170, at least about 180, at least about 190, or at least about 200 contiguous nucleotides in length.

[0093] In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 270 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 271 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 272 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 273 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 274 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 275 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 276 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 277 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 278 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 279 or a 12-16 contiguous nucleotide subsequence thereof.In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 280 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 281 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 282 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 283 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 284 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 285 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 286 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 287 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 288 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 289 or a 12-16 contiguous nucleotide subsequence thereof.In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 290 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 291 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 292 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 293 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 294 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 295 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 296 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 297 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 298 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 299 or a 12-16 contiguous nucleotide subsequence thereof.In some aspects, oligonucleotides of the present disclosure comprise single-stranded oligomers, eg, 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 300 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 301 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 302 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 303 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 304 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 305 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 306 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 307 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 308 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 309 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 310 or a 12-16 contiguous nucleotide subsequence thereof.In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 311 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 312 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 313 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 314 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 315 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 316 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 317 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 318 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 319 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 320 or a 12-16 contiguous nucleotide subsequence thereof.In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 321 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 322 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 323 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 324 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 325 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 326 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 327 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 328 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 329 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 330 or a 12-16 contiguous nucleotide subsequence thereof.In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 331 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 332 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 333 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 334 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 335 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 336 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 337 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 338 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 339 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 340 or a 12-16 contiguous nucleotide subsequence thereof.In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 341 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 342 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 343 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 344 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 345 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 346 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 347 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 348 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 349 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 350 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 351 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 352 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 353 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 354 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 355 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 356 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 357 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 358 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 359 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 360 or a 12-16 contiguous nucleotide subsequence thereof.In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 361 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 362 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 363 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 364 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 365 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 366 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 367 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 368 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 369 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 370 or a 12-16 contiguous nucleotide subsequence thereof.In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 371 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 372 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 373 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 374 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 375 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 376 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 377 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 378 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 379 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 380 or a 12-16 contiguous nucleotide subsequence thereof.In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 381 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 382 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 383 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 384 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 385 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 386 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 387 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 388 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 389 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 390 or a 12-16 contiguous nucleotide subsequence thereof.In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 391 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 392 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 393 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 394 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 395 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 396 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 397 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 398 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 399 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 400 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 401 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 402 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 403 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 404 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 405 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 406 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 407 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 408 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 409 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 410 or a 12-16 contiguous nucleotide subsequence thereof.In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 411 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 412 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 413 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 414 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 415 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 416 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 417 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 418 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 419 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 420 or a 12-16 contiguous nucleotide subsequence thereof.In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 421 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 422 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 423 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 424 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 425 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 426 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 427 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 428 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 429 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 430 or a 12-16 contiguous nucleotide subsequence thereof.In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 431 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 432 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 433 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 434 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 435 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 436 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 437 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 438 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 439 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 440 or a 12-16 contiguous nucleotide subsequence thereof.In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 441 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 442 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 443 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 444 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 445 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 446 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 447 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 448 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 449 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 450 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 451 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 452 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 453 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 454 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 455 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 456 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 457 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 458 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 459 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 460 or a 12-16 contiguous nucleotide subsequence thereof.In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 461 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 462 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 463 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 464 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 465 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 466 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 467 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 468 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 469 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 470 or a 12-16 contiguous nucleotide subsequence thereof.In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 471 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 472 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 473 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 474 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 475 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 476 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 477 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 478 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 479 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 480 or a 12-16 contiguous nucleotide subsequence thereof.In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 481 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 482 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 483 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 484 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 485 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 486 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 487 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 488 or a 12-16 contiguous nucleotide subsequence thereof. In some aspects, oligonucleotides of the present disclosure include single-stranded oligomers, e.g., 16-mers, comprising the antisense sequence set forth in SEQ ID NO: 489 or a 12-16 contiguous nucleotide subsequence thereof.

[0094] In some aspects of the above-disclosed antisense sequences, all odd-numbered positions on the antisense sequence comprise 2' O-methyl modifications and all even-numbered positions on the antisense sequence comprise 2' fluoro modifications. In some aspects of the above-disclosed antisense sequences, the first two 5' and last two 3' internucleoside linkages are phosphorothioate.

[0095] In some aspects, the nucleic acid of the present disclosure is a duplex (e.g., siRNA or shRNA) comprising the antisense sequence disclosed above and a sense strand that is partially or completely complementary to the antisense sequence. In some aspects of the nucleic acid duplex sequence, the 3' end of the sense strand and the 5' end of the antisense strand are connected by a loop. In some aspects of the nucleic acid duplex sequence, all odd-numbered positions on the antisense strand sequence contain 2'-O-methyl modifications, and all even-numbered positions on the antisense sequence contain 2'-fluoro modifications. In some aspects of the nucleic acid duplex sequence, all even-numbered positions on the sense strand sequence contain 2'-O-methyl modifications, and all off-positions on the sense strand sequence contain 2'-fluoro modifications, except for the first 5'-terminal nucleotide (position 1), which contains a 2'-O-methyl modification. In some aspects of the nucleic acid duplex sequence, the first two 5' and last two 3' internucleoside linkages of the sense strand are phosphorothioate. In some aspects of the nucleic acid duplex sequence, the first two 5' and the last two 3' internucleoside linkages of the antisense strand are phosphorothioate. The target region within synaptogyrin-3 of the present application

[0096] Surprisingly, it was found that some regions within the synaptogyrin-3 pre-mRNA transcript are significantly more accessible to oligonucleotides, such as ASO molecules, and are therefore preferred regions for designing oligonucleotides suitable for or capable of reducing synaptogyrin-3 expression and / or activity. The boundaries of the identified regions were determined by transcript walking (Table 1). Syngr-3 mRNA levels were determined in SH-SY5Y cells using 30 nM and 3 nM doses of ASOs containing 16-mer oligonucleotide sequences. Dose-response curves (DRCs) were determined for ASOs that could significantly reduce Syngr-3 mRNA transcript levels (Table 2).

[0097] Table 1. Summary of ASO molecules developed and tested by the inventors of this application, listed 5' to 3' based on their binding position on the synaptogyrin-3 transcript as defined in SEQ ID NO:1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7]

[0098] The threshold for suitable regions for oligonucleotide design was set at the level of the tested ASO that would reduce human Syngr-3 transcripts by at least 45% relative to a reference system (e.g., baseline levels in an individual or population of individuals, or below a predetermined threshold value) in at least one experiment (at a dose of 3 nM or 30 nM). Nevertheless, because the DRC results ultimately showed a stronger reduction in Syngr-3 transcript levels (Tables 1-2), therapeutic efficacy may be achieved at levels of inhibition of human Syngr-3 expression below 45%. ASO molecules selected from the primary screen were retested in two different cell lines (i.e., SH-SY5Y and iPSC-derived neurons) (Table 2).

[0099] Table 2. Confirmation of IC50 and maximal inhibition of selected ASO molecules from Table 1 in SH-SY5Y cells and iPSC-derived neurons. [Table 2-1] [Table 2-2]

[0100] As used herein, the term "reducing," e.g., reducing hSYNGR3 mRNA transcript expression and / or hSYNGR3 protein level and / or hSYNGR3 activity, refers to the ability of an oligonucleotide (e.g., ASO or siRNA) of the present disclosure to statistically significantly reduce (or decrease, inhibit, or lower) hSYNGR3 gene transcript expression and / or hSYNGR3 protein level and / or activity in a cell, tissue, or subject. In some aspects, the term "reducing" refers to complete inhibition (100% inhibition or undetectable levels) of hSyngr3 gene transcript and / or hSyngr3 protein level and / or activity. In other aspects, the term "reducing" refers to, for example, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least 90%, at least 95%, or at least 99% reduction or inhibition of hSyngr3 mRNA transcript and / or hSYNGR3 protein expression and / or activity in a cell, tissue, or subject.

[0101] The terms "individual," "subject," "host," and "patient" are used interchangeably herein and refer to any mammalian subject, particularly a human, for whom diagnosis, treatment, or therapy is desired. The compositions and methods described herein are applicable to both human therapy and veterinary applications. In some aspects, the subject is a mammal, and in other aspects, the subject is a human. As used herein, "mammalian subject" encompasses all mammals, including, without limitation, humans, domestic animals (e.g., dogs, cats, and the like), agricultural animals (e.g., cows, sheep, pigs, horses, and the like), and laboratory animals (e.g., monkeys, rats, mice, rabbits, guinea pigs, and the like).

[0102] Therefore, the present application provides target regions within the human Syngr-3 gene or Syngr3 (pre)mRNA transcript for designing oligonucleotides (e.g., ASOs, siRNAs, shRNAs) that reduce hSyngr3 expression by at least 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least 90%, at least 95%, or at least 99%, compared to a control situation in which, for example, no oligonucleotide (e.g., ASO, siRNA, shRNA) is administered or a scrambled control molecule is added as a negative control. The target regions and corresponding sequences are shown in Figures 3 and 4.

[0103] In one embodiment, the synaptogyrin-3 polypeptide is selected from SEQ ID NOs: 10, 12, 20, 25, 29-31, 33, 50, 53, 58-59, 62, 69, 79, 84, 87, 91, 94, 110-111, 135, 140-141, 170, 172, 179, 181, 184, 188, 193-194, 210, 216, 220-221, 224, 227, 229, 231, 235, 241, 246, 248, 250, 259, 268, or 269. The mRNA transcript target sequence is provided for designing antisense oligonucleotides or RNAi molecules that can reduce the level of synaptogyrin-3 transcripts, the level of expressed synaptogyrin-3, the level of synaptogyrin-3 activity, or a combination thereof in cells by at least 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least 90%, at least 95%, or at least 99%, for example, compared to a control situation in which no oligonucleotide (e.g., ASO, siRNA, or shRNA) is administered or a scrambled control molecule is used as a negative control. In a specific embodiment, the synaptogyrin-3 The mRNA transcript target sequences are SEQ ID NOs: 2-9, 11, 13-19, 21-24, 26-28, 32, 34-49, 51-52, 54-57, 60-61, 63-68, 70-78, 80-83, 85-86, 88-90, 92-93, 95-109, 112-134, 136-139, 142-169, 171, 173-178, 180 , 182-183, 185-187, 189-192, 195-209, 211-215, 217-219, 222-223, 225-226, 228, 230, 232-234, 236-240, 242-245, 247, 249, 251-258, or 260-267.

[0104] In another embodiment, the oligonucleotides of the present application (described in detail above) comprise a contiguous nucleotide sequence at least 10 contiguous nucleotides in length that is partially or fully complementary to a target region of synaptogyrin-3, or an allelic variant thereof, as set forth in SEQ ID NO: 1. In specific embodiments, the contiguous nucleotide sequence at least 10 contiguous nucleotides in length is at least 80%, at least 81%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% complementary to a target region on a Syngr-3 mRNA transcript. In a specific embodiment, the contiguous nucleotide sequence at least 10 contiguous nucleotides in length is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% complementary to the target region on the Syngr-3 mRNA transcript. In another specific embodiment, the contiguous nucleotide sequence at least 10 contiguous nucleotides in length is complementary to an equal length portion of the target region on the synaptogin-3 mRNA transcript set forth in SEQ ID NO: 1 or a variant thereof, such as an allelic variant thereof.

[0105] The target regions of the present disclosure are defined below as subsequences of SEQ ID NO: 1, where the subsequences are delineated by their 5' and 3' ends. For example, a target region between nucleobases 2 and 10 of SEQ ID NO: 1 consists of nucleobases 2, 3, 4, 5, 6, 7, 8, 9, and 10, or CTACCCCTT, of SEQ ID NO: 1. Therefore, any range given herein should be understood to encompass the endpoints of the range. Thus, if the target region is between nucleotides 2 and 10 of SEQ ID NO: 1, both nucleotides 2 and 10 of SEQ ID NO: 1 are encompassed.

[0106] As used in this disclosure, the terms "target region of SEQ ID NO: 1" or "target region on a synaptogyrin-3 mRNA transcript" or generally "target region," and grammatical variations thereof, refer to a region or subsequence on a synaptogyrin-3 mRNA transcript targeted by an oligonucleotide of the present disclosure. In some aspects, the synaptogyrin-3 mRNA transcript containing the target region is the synaptogyrin-3 mRNA transcript set forth in SEQ ID NO: 1. However, in other aspects, the synaptogyrin-3 mRNA transcript containing the target region may be a synaptogyrin-3 mRNA transcript variant, such as an allelic variant of the synaptogyrin-3 mRNA transcript set forth in SEQ ID NO: 1, an isoform thereof, or an ortholog thereof.

[0107] In one specific embodiment, the target region is a subsequence located between nucleobase positions 449 and 531 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1, or is contained within the nucleotide subsequence defined by nucleobases 449 and 531 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Specifically, the target region is a subsequence located between nucleobase positions 449 and 531 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Nucleobase positions 450 and 531, 451 and 531, 452 and 531, 453 and 531, 454 and 531, 455 and 531, 456 and 531, 457 and 531, 458 and 531, 459 and 531, 460 and 531, 461 and 531, 462 and 531, 463 and 531, 464 and 531, 465 and 531, 466 and 531, 467 and 531, 468 and 531, 469 and 531, 470 and 531, 471 and 531, 472 and 531, 473 and 531, 474 and 531, 475 and 531, 476 and 531, 477 and 531, 478 and 531, 479 and 531, 480 and 531, 481 and 531, 482 and 531, 483 and 531, 484 and 531, 485 and 531, 486 and 531, 487 and 531, 488 and 531, 489 and 531, 490 and 531, 491 and 531, 492 and 531, 493 and 531, 494 and 531, 495 and 531, 496 and 531, 497 and 531, 498 and 531, 499 and 531, 500 and Between 73 and 531, 474 and 531, 475 and 531, 476 and 531, 477 and 531, 478 and 531, 479 and 531, 480 and 531, 481 and 531, 482 and 531, 483 and 531, 484 and 531, 485 and 531, 486 and 531, 487 and 531, 449 and 522, 449 and 523, 449 and 524, 449 and 525, 449 and 526, 449 and 527, 449 and 528, 449 and 529, or 449 and 530. More specifically, the target region is located between nucleobase positions 487 and 522 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1, more specifically between nucleobase positions 488 and 521, 489 and 520, 490 and 519, and 491 and 518, and even more specifically between nucleobase positions 492 and 517 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1.

[0108] In more specific embodiments, the target region is defined by SEQ ID NO: 10. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NOs: 2, 4, 5, 6, 7, 8, and / or 9. In most specific embodiments, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NOs: 270, 271, 272, 273, 274, 275, 276, and / or 277.

[0109] In another specific embodiment, the target region is a subsequence located between nucleobase positions 549 and 653 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1, or is contained within the nucleotide subsequence defined by nucleobases 549 and 653 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Specifically, the target region is a subsequence located between nucleobase positions 549 and 653 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Nucleobase positions 550 and 653, 551 and 653, 552 and 653, 553 and 653, 554 and 653, 555 and 653, 556 and 653, 557 and 653, 558 and 653, 559 and 653, 560 and 653, 561 and 653, 562 and 653, 563 and 653, 564 and 653, 565 and 653, 566 and 653, 567 and 653, 568 and 653, 569 and 653, 570 and 653, 571 and 653, 572 and 653, 573 and 653, 574 and 653, 575 and 653, 576 and 653, 577 and 653, 578 and 653, 579 and 653, 580 and 653, 581 and 653, 582 and 653, 549 and 607, 549 and 608, 549 and 609, 549 and 610, 549 and 611, 549 and 612, 549 and 613 , 549 and 614, 549 and 615, 549 and 616, 549 and 617, 549 and 618, 549 and 619, 549 and 620, 549 and 621, 549 and 622, 549 and 623, 549 and 624, 549 and 625, 549 and 626, 549 and 627, 549 and 628, 549 and 629, 549 and 630, 549 and 631, 549 and 632, 549 and 633, 549 and 63 4, 549 and 635, 549 and 636, 549 and 637, 549 and 638, 549 and 639, 549 and 640, 549 and 641, 549 and 642, 549 and 643, 549 and 644, 549 and 645, 549 and 646, 549 and 647, 549 and 648, 549 and 649, 549 and 650, 549 and 651, or 549 and 652.More specifically, the target region is located between nucleobase positions 582 and 607 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1, more specifically between nucleobase positions 583 and 606, 584 and 605, 585 and 604, 586 and 603, and even more specifically between nucleobase positions 587 and 602 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1.

[0110] In more specific embodiments, the target region is defined by SEQ ID NO: 12. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NO: 11. In a most specific embodiment, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NO: 278.

[0111] In another specific embodiment, the target region is located between nucleobase positions 640 and 733 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1 or is contained within the nucleotide subsequence defined by nucleobases 640 and 733. Specifically, the target region is located between nucleobase positions 640 and 733 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Nucleobase positions 641 and 733, 642 and 733, 643 and 733, 644 and 733, 645 and 733, 646 and 733, 647 and 733, 648 and 733, 649 and 733, 650 and 733, 651 and 733, 652 and 733, 653 and 733, 654 and 733, 655 and 733, 656 and 733, 657 and 733, 658 and 733, 659 and 733, 660 and 733, 661 and 733, 662 and 733, 663 and 733, 664 and 733, 665 and 733, 666 and 733 It is positioned between 667 and 733, 668 and 733, 669 and 733, 670 and 733, 671 and 733, 672 and 733, 673 and 733, 674 and 733, 675 and 733, 676 and 733, 677 and 733, 678 and 733, 679 and 733, 640 and 720, 640 and 721, 640 and 722, 640 and 723, 640 and 724, 640 and 725, 640 and 726, 640 and 727, 640 and 728, 640 and 729, 640 and 730, 640 and 731, or 640 and 732. More specifically, between nucleobase positions 679 and 720 of SEQ ID NO:1, more specifically between nucleobase positions 680 and 719, 681 and 718, 682 and 717, 683 and 716, and even more specifically between nucleobase positions 684 and 715 of the Syngr-3 mRNA transcript defined by SEQ ID NO:1.

[0112] In more specific embodiments, the target region is defined by SEQ ID NO: 20. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NOs: 13, 14, 15, 16, 17, 18, and / or 19. In most specific embodiments, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NOs: 279, 280, 281, 282, 283, 284, and / or 285.

[0113] In another specific embodiment, the target region is located between nucleobase positions 720 and 875 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1 or is contained within the nucleotide subsequence defined by nucleobases 720 and 875. Specifically, the target region is located between nucleobase positions 720 and 875 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Nucleobase positions 721 and 875, 722 and 875, 723 and 875, 724 and 875, 725 and 875, 726 and 875, 727 and 875, 728 and 875, 729 and 875, 730 and 875, 731 and 875, 732 and 875, 733 and 875, 734 and 875, 735 and 875, 736 and 875, 737 and 875, 738 and 875, 739 and 875, 740 and 875, 741 and 875, 742 and 875, 743 and 875, 744 and 875, 745 and 875 , 746 and 875, 747 and 875, 748 and 875, 749 and 875, 750 and 875, 751 and 875, 752 and 875, 753 and 875, 754 and 875, 755 and 875, 756 and 875, 757 and 875, 758 and 875, 759 and 875, 760 and 875, 761 and 875, 762 and 875, 763 and 875, 764 and 875, 765 and 875, 720 and 795, 720 and 796, 720 and 797, 720 and 798, 720 and 799, 720 and 800, 720 and 8 01, 720 and 802, 720 and 803, 720 and 804, 720 and 805, 720 and 806, 720 and 807, 720 and 808, 720 and 809, 720 and 810, 720 and 811, 720 and 812, 720 and 813, 720 and 814, 720 and 815, 720 and 816, 720 and 817, 720 and 818, 720 and 819, 720 and 820, 720 and 821, 720 and 822, 720 and 823, 720 and 824, 720 and 825, 720 and 826, 720 and 827, 72 0 and 828, 720 and 829, 720 and 830, 720 and 831, 720 and 832, 720 and 833, 720 and 834, 720 and 835, 720 and 836, 720 and 837, 720 and 838, 720 and 839, 720 and 840, 720 and 841, 720 and 842, 720 and 843, 720 and 844, 720 and 845, 720 and 846, 720 and 847, 720 and 848, 720 and 849, 720 and 850, 720 and 851, 720 and 852, 720 and 853, 720 and 854,It is positioned between 720 and 855, 720 and 856, 720 and 857, 720 and 858, 720 and 859, 720 and 860, 720 and 861, 720 and 862, 720 and 863, 720 and 864, 720 and 865, 720 and 866, 720 and 867, 720 and 868, 720 and 869, 720 and 870, 720 and 871, 720 and 872, 720 and 873, or 720 and 874. More specifically, between nucleobase positions 765 and 795 of SEQ ID NO:1, more specifically between nucleobase positions 766 and 794, 767 and 793, 768 and 792, and 769 and 791, and even more specifically between nucleobase positions 770 and 790 of the Syngr-3 mRNA transcript defined by SEQ ID NO:1.

[0114] In more specific embodiments, the target region is defined by SEQ ID NO: 25. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NOs: 21, 22, 23, and / or 24. In most specific embodiments, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NOs: 286, 287, 288, and / or 289.

[0115] In another specific embodiment, the target region is located between or contained within the nucleotide subsequence defined by nucleobase positions 915 and 1108 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Specifically, the target region is located between nucleobase positions 916 and 1108, 917 and 1108, 918 and 1108, 919 and 1108, 920 and 1108, 921 and 1108, 922 and 1108, 923 and 1108, 924 and 1108, 925 and 1108, 926 and 1108, 927 and 1108, 928 and 1108, 929 and 1108, 930 and 1108, 931 and 1108, 932 and 1108, 933 and 1108, 934 and 1108, 935 and 1108, 936 and 1108, 937 and 1108, 938 and 1108, 939 and 1108, 940 and 1108, 941 and 1108, 942 and 1108, 943 and 1108, 944 and 1108, 945 and 1108, 946 and 1108, 947 and 1108, 948 and 1108, 949 and 1108, 950 and 1108, 951 and 1108, 952 and 1108, 953 and 1108, 954 and 1108, 955 and 1108 3 and 1108, 934 and 1108, 935 and 1108, 936 and 1108, 937 and 1108, 938 and 1108, 939 and 1108, 940 and 1108, 941 and 1108, 942 and 1108, 943 and 1108, 944 and 1108, 945 and 1108, 946 and 1108, 947 and 1108, 948 and 1108, 949 and 1108, 950 and 1108, 951 and 1108, 915 and 1072, 915 and 1073, 915 and 1074, 915 and 1075, 915 and 1076, 915 and 1077, 915 and 1078, 915 and 1079, 915 and 1080, 915 and 1081, 915 and 1082, 915 and 1083, 915 and 1084, 915 and 1085, 915 and 1086, 915 and 1087, 915 and 1088, 915 and 1089, 915 and 109 0, 915 and 1091, 915 and 1092, 915 and 1093, 915 and 1094, 915 and 1095, 915 and 1096, 915 and 1097, 915 and 1098, 915 and 1099, 915 and 1100, 915 and 1101, 915 and 1102, 915 and 1103, 915 and 1104, 915 and 1105, 915 and 1106, or 915 and 1107. More specifically, between nucleobase positions 951 and 1072 of SEQ ID NO:1, more specifically between nucleobase positions 952 and 1071, 953 and 1070, 954 and 1069, 955 and 1068, and even more specifically between nucleobase positions 956 and 1067 of the Syngr-3 mRNA transcript defined by SEQ ID NO:1.

[0116] In more specific embodiments, the target region is defined by SEQ ID NO: 29. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NOs: 26, 27, and / or 28. In most specific embodiments, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NOs: 290, 291, and / or 292.

[0117] In another specific embodiment, the target region is located between nucleobase positions 915 and 1000 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1, or is contained within a nucleotide subsequence defined by nucleobase positions 915 and 1000. Specifically, the target region is located between nucleobase positions 915 and 1000 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Nucleobase positions 916 and 986, 917 and 1000, 918 and 1000, 919 and 1000, 920 and 1000, 921 and 1000, 922 and 1000, 923 and 1000, 924 and 1000, 925 and 1000, 926 and 1000, 927 and 1000, 928 and 1000, 929 and 1000, 930 and 1000, 931 and 1000, 932 and 1000, 933 and 1000, 934 and 1000, 935 and 1000, 936 and 1000, 937 and 1000, 938 and 1000, 939 and 1000, 94 It can be positioned between 0 and 1000, 941 and 1000, 942 and 1000, 943 and 1000, 944 and 1000, 945 and 1000, 946 and 1000, 947 and 1000, 948 and 1000, 949 and 1000, 950 and 1000, 951 and 1000, 915 and 986, 915 and 987, 915 and 988, 915 and 989, 915 and 990, 915 and 991, 915 and 992, 915 and 993, 915 and 994, 915 and 995, 915 and 996, 915 and 997, 915 and 998, or 915 and 999. More specifically, the target region is located between nucleobase positions 951 and 986 of SEQ ID NO:1, more specifically between nucleobase positions 952 and 985, 953 and 984, 954 and 983, and 955 and 982, and even more specifically between nucleobase positions 956 and 981 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1.

[0118] In a more specific embodiment, the target region is defined by SEQ ID NO:30.

[0119] In another specific embodiment, the target region is located between nucleobase positions 1000 and 1108 of SEQ ID NO: 1 or is contained within a nucleotide subsequence defined by nucleobase positions 1000 and 1108. Specifically, the target region is located between nucleobase positions 1000 and 1108 of Syngr-3 as defined in SEQ ID NO: 1. Nucleobase positions of mRNA transcripts 1001 and 1108, 1002 and 1108, 1003 and 1108, 1004 and 1108, 1005 and 1108, 1006 and 1108, 1007 and 1108, 1008 and 1108, 1009 and 1108, 1010 and 1108, 1011 and 1108, 1012 and 1108, 1013 and 1108, 1014 and 1108, 1015 and 1108, 1016 and 1108, 1017 and 1108, 1018 and 1108, 1019 and 1108, 1020 and 1108, 1021 and 1108 1 and 1108, 1021 and 1108, 1022 and 1108, 1023 and 1108, 1024 and 1108, 1025 and 1108, 1026 and 1108, 1027 and 1108, 1028 and 1108, 1029 and 1108, 1030 and 1108, 1031 and 1108, 1032 and 1108, 1033 and 1108, 1034 and 1108, 1035 and 1108, 1036 and 1108, 1037 and 1108, 1038 and 1108, 1039 and 1108, 1040 and 1108, 1041 and 1108, 1042 and 1108, 1043 and 1108, 1044 and 1108, 1045 and 1108, 1046 and 1108, 1047 and 1108, 1000 and 1072, 1000 and 1073, 1000 and 1074, 1000 and 1075, 1000 and 1076, 1000 and 1077, 1000 and 1078, 1000 and 1079, 1000 and 1080, 1000 and 1082, 1000 and 1083, 1000 and 1084, 1000 and 1085, 1000 and 1086, 1000 and 10 87, 1000 and 1088, 1000 and 1089, 1000 and 1090, 1000 and 1091, 1000 and 1092, 1000 and 1093, 1000 and 1094, 1000 and 1095, 1000 and 1096, 1000 and 1097, 1000 and 1098, 1000 and 1099, 1000 and 1100, 1000 and 1101, 1000 and 1102, 1000 and 1103, 1000 and 1104, 1000 and 1105, 1000 and 1106, or 1000 and 1107.More specifically, the target region is located between nucleobase positions 1047 and 1072 of SEQ ID NO:1, more specifically between nucleobase positions 1048 and 1071, 1049 and 1070, 1050 and 1069, 1051 and 1068, and even more specifically between nucleobase positions 1052 and 1067 of SEQ ID NO:1.

[0120] In a more specific embodiment, the target region is defined by SEQ ID NO:31.

[0121] In another specific embodiment, the target region is located between nucleobase positions 1197 and 1271 of SEQ ID NO: 1 or is contained within the nucleotide subsequence defined by nucleobase positions 1197 and 1271. Specifically, the target region is located between nucleobase positions 1198 and 1271, 1199 and 1271, 1200 and 1271, 1201 and 1271, 1202 and 1271, 1203 and 1271, 1197 and 1228, 1197 and 1229, 1197 and 1230, 1197 and 1231, 1197 and 1232, 1197 and 1233, 1197 and 1234, 1197 and 1235, 1197 and 1236, 1197 and 1237, 1197 and 1238, 1197 and 1239, 1197 and 1240, 1197 and 1241, 1197 and 1242, 1197 and 1243, 1197 and 1244, 1197 and 1245, 1197 and 1246, 1197 and 1247, 1197 and 1248, 1197 and 1249, 1197 and 1250, 1197 and 1251, 1197 and 1252, 1197 and 1253, 1197 and 1254, 1197 and 1255, 1197 and 1256, 1197 and 125 1233, 1197 and 1234, 1197 and 1235, 1197 and 1236, 1197 and 1237, 1197 and 1238, 1197 and 1239, 1197 and 1240, 1197 and 1241, 1197 and 1242, 1197 and 1243, 1197 and 1244, 1197 and 1245, 1197 and 1246, 1197 and 1247, 1197 and 1248, 1197 and 1249, 1197 and 1250, 1197 and 1251, 1197 and 1252, 1197 and 1253, 1197 and 1254, 1197 and 1255, 1197 and 1256, 1197 and 1257, 1197 and 1258, 1197 and 1259, 1197 and 1260, 1197 and 1261, 1197 and 1262, 1197 and 1263, 1197 and 1264, 1197 and 1265, 1197 and 1266, 1197 and 1267, 1197 and 1268, 1197 and 1269, or 1197 and 1270 of SEQ ID NO: 1. More specifically, the target region is located between nucleobase positions 1203 and 1228 of SEQ ID NO: 1, more specifically between nucleobase positions 1204 and 1227, 1205 and 1226, 1206 and 1225, 1207 and 1224, and even more specifically between nucleobase positions 1208 and 1223 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1.

[0122] In more specific embodiments, the target region is defined by SEQ ID NO: 33. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NO: 32. In most specific embodiments, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NO: 293.

[0123] In another specific embodiment, the target region is located between nucleobase positions 1258 and 1344 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1 or is contained within the nucleotide subsequence defined by nucleobase positions 1258 and 1344. Specifically, the target region is located between nucleobase positions 1258 and 1344 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. and located between nucleobase positions 1259 and 1344, 1260 and 1344, 1261 and 1344, 1262 and 1344, 1263 and 1344, 1264 and 1344, 1265 and 1344, 1258 and 1329, 1258 and 1330, 1258 and 1331, 1258 and 1332, 1258 and 1333, 1258 and 1334, 1258 and 1335, 1258 and 1336, 1258 and 1337, 1258 and 1338, 1258 and 1339, 1258 and 1340, 1258 and 1341, 1258 and 1342, or 1258 and 1343 of the mRNA transcript. More specifically, the target region is located between nucleobase positions 1265 and 1329 of SEQ ID NO:1, more specifically between nucleobase positions 1266 and 1328, 1267 and 1327, 1268 and 1326, 1269 and 1325, and even more specifically between nucleobase positions 1270 and 1324 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1.

[0124] In a more specific embodiment, the target region is defined by and mapped to SEQ ID NO: 50. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NOs: 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, and / or 49. In a most specific embodiment, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NOs: 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, and / or 309.

[0125] In another specific embodiment, the target region is located between nucleobase positions 1332 and 1450 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1, or is contained within the nucleotide subsequence defined by nucleobase positions 1332 and 1450. Specifically, the target region is located between nucleobase positions 1332 and 1450 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Nucleobase positions 1333 and 1450, 1334 and 1450, 1335 and 1450, 1336 and 1450, 1337 and 1450, 1338 and 1450, 1339 and 1450, 1340 and 1450, 1341 and 1450, 1342 and 1450, 1343 and 1450, 1344 and 1450, 1345 and 1450, 1346 and 1450, 1347 and 1450, 1348 and 1450, 1349 and 1450, 1350 and 1450 It is positioned between 1351 and 1450, 1332 and 1432, 1332 and 1433, 1332 and 1434, 1332 and 1435, 1332 and 1436, 1332 and 1437, 1332 and 1438, 1332 and 1439, 1332 and 1440, 1332 and 1441, 1332 and 1442, 1332 and 1443, 1332 and 1444, 1332 and 1446, 1332 and 1447, 1332 and 1448, or 1332 and 1449. More specifically, the target region is located between nucleobase positions 1351 and 1432 of SEQ ID NO:1, more specifically between nucleobase positions 1352 and 1431, 1353 and 1430, 1354 and 1429, 1355 and 1428, and even more specifically between nucleobase positions 1356 and 1427 of SEQ ID NO:1.

[0126] In a more specific embodiment, the target region is defined by SEQ ID NO:59.

[0127] In another specific embodiment, the target region is located between nucleobase positions 1332 and 1400 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1, or is contained within the nucleotide subsequence defined by nucleobase positions 1332 and 1400. Specifically, the target region is located between nucleobase positions 1332 and 1400 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Nucleobase positions of mRNA transcripts 1333 and 1400, 1334 and 1400, 1335 and 1400, 1336 and 1400, 1337 and 1400, 1338 and 1400, 1339 and 1400, 1340 and 1400, 1341 and 1400, 1342 and 1400, 1343 and 1400, 1344 and 1400, 1345 and 1400, 1346 and 1400, 1347 and 1400, 1348 and 1400, 1349 and 1400, 1350 and 1400, 1351 and 1400, 1332 and 1378, 1332 and 1379, 1332 and 1380, 1332 and 1381, 1332 and 1382, 1332 and 1383, 1332 and 1384, 1332 and 1385, 1332 and 1386, 1332 and 1387, 1332 and 1388, 1332 and 1389, 1332 and 1390, 1332 and 1391, 1332 and 1392, 1332 and 1393, 1332 and 1394, 1332 and 1395, 1332 and 1396, 1332 and 1397, 1332 and 1398, or 1332 and 1399. More specifically, the target region is located between nucleobase positions 1351 and 1377 of SEQ ID NO:1, more specifically between nucleobase positions 1352 and 1376, 1353 and 1375, 1354 and 1374, 1355 and 1373, and even more specifically between nucleobase positions 1356 and 1372 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1.

[0128] In more specific embodiments, the target region is defined by SEQ ID NO: 53. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NOs: 51 and / or 52. In most specific embodiments, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NOs: 310 and / or 311.

[0129] In another specific embodiment, the target region is located between or contained within the nucleotide subsequence defined by nucleobase positions 1380 and 1450 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Specifically, the target region is located between nucleobases 1381 and 1450, 1382 and 1450, 1383 and 1450, 1384 and 1450, 1385 and 1450, 1386 and 1450, 1387 and 1450, 1388 and 1450, 1389 and 1450, 1390 and 1450, 1391 and 1450, 1392 and 1450, 1393 and 1450, 1394 and 1450, 1380 and 1433, 1380 and 1450 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. 434, 1380 and 1435, 1380 and 1436, 1380 and 1437, 1380 and 1438, 1380 and 1439, 1380 and 1440, 1380 and 1441, 1380 and 1442, 1380 and 1443, 1380 and 1444, 1380 and 1445, 1380 and 1446, 1380 and 1447, 1380 and 1448, or 1380 and 1449. More specifically, the target region is located between nucleobases 1394 and 1432 of SEQ ID NO:1, more specifically between nucleobase positions 1395 and 1431, 1396 and 1430, 1397 and 1429, 1398 and 1428, and even more specifically between nucleobase positions 1399 and 1427 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1.

[0130] In more specific embodiments, the target region is defined by SEQ ID NO: 58. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NOs: 54, 55, 56, and / or 57. In most specific embodiments, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NOs: 312, 313, 314, and / or 315.

[0131] In another specific embodiment, the target region is located between nucleobase positions 1450 and 1527 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1 or is contained within the nucleotide subsequence defined by nucleobases 1450 and 1527. Specifically, the target region is located between nucleobase positions 1451 and 1527, 1452 and 1527, 1453 and 1527, 1454 and 1527, 1455 and 1527, 1456 and 1527, 1457 and 1527, 1458 and 1527, 1459 and 1527, 1460 and 1527, 1461 and 1527 of SEQ ID NO: 1. 1527, 1462 and 1527, 1463 and 1527, 1464 and 1527, 1465 and 1527, 1466 and 1527, 1467 and 1527, 1468 and 1527, 1469 and 1527, 1470 and 1527, 1471 and 1527, 1472 and 1527, 1473 and 1527, 1474 and 1527, 1475 and 1527, 1476 and 1527, 1477 and 1527, 1478 and 1527, 1479 and 1527, 1480 and 1527, 1481 and 1527, 1482 and 1527, 1483 and 1527, 1484 and 1527, 1485 and 1527, 1486 and 1527, 1487 and 1527, 1488 and 1527, 1489 and 1527, 1490 and 1527, 1491 and 1527, 1492 and 1527, 1493 and 1527, 1494 and 1527, 1495 and 1527, 1496 and 1527, 1497 and 1527, or 1450 and 1526. More specifically, the target region is located between nucleobase positions 1497 and 1526 of SEQ ID NO: 1, more specifically between nucleobase positions 1498 and 1525, 1499 and 1524, 1500 and 1523, 1501 and 1522, and even more specifically between nucleobase positions 1502 and 1521 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1.

[0132] In more specific embodiments, the target region is defined by SEQ ID NO: 62. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NOs: 60 and / or 61. In most specific embodiments, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NOs: 316 and / or 317.

[0133] In another specific embodiment, the target region is located between or contained within the nucleotide subsequence defined by nucleobase positions 1515 and 1600 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Specifically, the target region is located between nucleobase positions 1516 and 1600, 1517 and 1600, 1518 and 1600, 1519 and 1600, 1520 and 1600, 1521 and 1600, 1522 and 1600, 1523 and 1600, 1524 and 1600, 1525 and 1600, 1526 and 1600, 1527 and 1600, 1528 and 1600 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. 1600, 1529 and 1600, 1530 and 1600, 1531 and 1600, 1532 and 1600, 1533 and 1600, 1534 and 1600, 1535 and 1600, 1536 and 1600, 1537 and 1600, 1538 and 1600, 1539 and 1600, 1540 and 1600, 1541 and 1600, 1542 and 1600, 1543 and 1600, 1544 and 1600, 1545 and 1600, 1546 and 1600, 1547 and 1600, 1548 and 1600, 1549 and 1600, 1550 and 1600, 1551 and 1600, 1515 and 1583, 1515 and 1584, 1515 and 1585, 1515 and 1586, 1515 and 1587, 1515 and 1588, 1515 and 1589, 1515 and 1590, 1515 and 1591, 1515 and 1592, 1515 and 1593, 1515 and 1594, 1515 and 1595, 1515 and 1596, 1515 and 1597, 1515 and 1598, or 1515 and 1599 of SEQ ID NO: 1. More particularly, between nucleobase positions 1551 and 1583 of SEQ ID NO: 1, more particularly between nucleobase positions 1552 and 1582, 1553 and 1581, 1554 and 1580, 1555 and 1579, and even more particularly between nucleobase positions 1556 and 1578 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1.

[0134] In more specific embodiments, the target region is defined by SEQ ID NO: 69. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NOs: 63, 64, 65, 66, 67, and / or 68. In most specific embodiments, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NOs: 318, 319, 320, 321, 322, and / or 323.

[0135] In another specific embodiment, the target region is located between nucleobase positions 1580 and 1700 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1 or is contained within the nucleotide subsequence defined by nucleobases 1580 and 1700. Specifically, the target region is located between nucleobase positions 1581 and 1700, 1582 and 1700, 1583 and 1700, 1584 and 1700, 1585 and 1700, 1586 and 1700, 1589 and 1700, 1590 and 1700, 1591 and 1700, 1592 and 1700, 1593 and 1700, 1594 and 1700, 1595 and 1700, 1596 and 1700, 1597 and 1700, 1598 and 1700, 159 ... 7 and 1700, 1598 and 1700, 1580 and 1656, 1580 and 1657, 1580 and 1658, 1580 and 1659, 1580 and 1660, 1580 and 1661, 1580 and 1662, 1580 and 1663, 1580 and 1664, 1580 and 1665, 1580 and 1666, 1580 and 1667, 1580 and 1668, 1580 and 6169, 1580 and 6170, 1580 and 1671, 1580 and 1672, 1580 and 1673, 1580 and 1674, 1580 and 1675, 1580 and 1676, 1580 and 1677, 1580 and 1678, 1580 and 1679, 1580 and 1680, 1580 and 1681, 1580 and 1682, 1580 and 1683, 1580 and 1684, 1580 and 16 85, 1580 and 1686, 1580 and 1687, 1580 and 1688, 1580 and 1689, 1580 and 1690, 1580 and 1691, 1580 and 1692, 1580 and 1693, 1580 and 1694, 1580 and 1695, 1580 and 1696, 1580 and 1697, 1580 and 1698, or 1580 and 1699. More specifically, between nucleobase positions 1598 and 1656 of SEQ ID NO:1, more specifically between nucleobase positions 1599 and 1655, 1600 and 1654, 1601 and 1653, 1602 and 1652, and even more specifically between nucleobase positions 1603 and 1651 of the Syngr-3 mRNA transcript defined by SEQ ID NO:1.

[0136] In more specific embodiments, the target region is defined by SEQ ID NO: 79. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NOs: 70, 71, 72, 73, 74, 75, 76, 77, and / or 78. In most specific embodiments, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NOs: 324, 325, 326, 327, 328, 329, 330, 331, and / or 332.

[0137] In another specific embodiment, the target region is located between nucleobase positions 1680 and 1837 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1 or is contained within the nucleotide subsequence defined by nucleobase positions 1680 and 1837. Specifically, the target region is located between nucleobase positions 1680 and 1837 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Nucleobase positions 1681 and 1837, 1682 and 1837, 1683 and 1837, 1684 and 1837, 1685 and 1837, 1686 and 1837, 1689 and 1837, 1690 and 1837, 1691 and 1837, 1692 and 1837, 1693 and 1837, 1694 and 1837, 1695 and 1837, 1696 and 1837, 1680 and 1777, 1680 and 1778, 1680 and 1779, 1680 and 178 0, 1680 and 1781, 1680 and 1782, 1680 and 1783, 1680 and 1784, 1680 and 1785, 1680 and 1786, 1680 and 1787, 1680 and 1788, 1680 and 1789, 1680 and 1790, 1680 and 1791, 1680 and 1792, 1680 and 1793, 1680 and 1794, 1680 and 1795, 1680 and 1796, 1680 and 1797, 1680 and 1798, 1680 and 1799, 1680 and 1800, 1680 and 1801, 1680 and 1802, 1680 and 1803, 1680 and 1804, 1680 and 1805, 1680 and 1806, 1680 and 1807, 1680 and 1808, 1680 and 1809, 1680 and 1810, 1680 and 1811, 1680 and 1812, 1680 and 1813, 1680 and 1814, 1680 and 1815, 1680 and 1816, 1680 and 1817, 1680 and 1818, 16 It is positioned between 1680 and 1819, 1680 and 1820, 1680 and 1821, 1680 and 1822, 1680 and 1823, 1680 and 1824, 1680 and 1825, 1680 and 1826, 1680 and 1827, 1680 and 1828, 1680 and 1829, 1680 and 1830, 1680 and 1831, 1680 and 1832, 1680 and 1833, 1680 and 1834, 1680 and 1835, or 1680 and 1836.More specifically, the target region is located between nucleobase positions 1696 and 1777 of SEQ ID NO:1, more specifically between nucleobase positions 1697 and 1776, 1698 and 1775, 1699 and 1774, 1700 and 1773, and even more specifically between nucleobase positions 1701 and 1772 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1.

[0138] In more specific embodiments, the target region is defined by SEQ ID NO: 84. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NOs: 80, 81, 82, and / or 83. In most specific embodiments, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NOs: 333, 334, 335, and / or 336.

[0139] In another specific embodiment, the target region is located between or contained within the nucleotide subsequence defined by nucleobase positions 1824 and 1885 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Specifically, the target region is located between nucleobase positions 1825 and 1885, 1826 and 1885, 1827 and 1885, 1828 and 1885, 1829 and 1885, 1830 and 1885, 1831 and 1885, 1832 and 1885, 1833 and 1885, 1834 and 1885, 1835 and 1885, 1836 and 1885, 1824 and 1865, 1824 and 1866, 1824 and 1867, 1824 and 1868, 1824 and 1869, 1824 and 1866, 1824 and 1868, 1824 and 1869 ... It is positioned between 1824 and 1869, 1824 and 1870, 1824 and 1871, 1824 and 1872, 1824 and 1873, 1824 and 1874, 1824 and 1875, 1824 and 1876, 1824 and 1877, 1824 and 1878, 1824 and 1879, 1824 and 1880, 1824 and 1881, 1824 and 1882, 1824 and 1883, or 1824 and 1884. More specifically, the target regions are located between nucleobase positions 1836 and 1865 of SEQ ID NO:1, more specifically between nucleobase positions 1837 and 1864, 1838 and 1863, 1839 and 1862, 1840 and 1861, and even more specifically between nucleobase positions 1841 and 1860 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1.

[0140] In more specific embodiments, the target region is defined by SEQ ID NO: 87. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NOs: 85 and / or 86. In most specific embodiments, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NOs: 337 and / or 338.

[0141] In another specific embodiment, the target region is located between or contained within the nucleotide subsequence defined by nucleobase positions 1850 and 2100 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Specifically, the target region is located between nucleobase positions 1851 and 2100, 1852 and 2100, 1853 and 2100, 1854 and 2100, 1855 and 2100, 1856 and 2100, 1857 and 2100, 1858 and 2100, 1859 and 2100, 1860 and 2100, 1861 and 2100, 1862 and 2100, 1863 and 2100 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. 2100, 1864 and 2100, 1865 and 2100, 1866 and 2100, 1867 and 2100, 1868 and 2100, 1869 and 2100, 1870 and 2100, 1850 and 2067, 1850 and 2068, 1850 and 2069, 1850 and 2070, 1850 and 2071, 1850 and 2072, 1850 and 2073, 1850 and 2074, 1850 and 2075, 1850 and 2076, 1850 and 2077, 1850 and 2078, 1850 and 2079, 1850 and 2080, 1850 and 2081, 1850 and 2082, 1850 and 2083, 1850 and 2084, 1850 and 2085, 1850 and 2086, 1850 and 2087, 1850 and 2088, 1850 and 2089, 1850 and 2090, 1850 and 2091, 1850 and 2092, 1850 and 2093, 1850 and 2094, 1850 and 2095, 1850 and 2096, 1850 and 2097, 1850 and 2098, or 1850 and 2099 of SEQ ID NO:1. More specifically, the target region is located between nucleobase positions 1870 and 2067 of SEQ ID NO:1, more specifically between nucleobase positions 1871 and 2066, 1872 and 2065, 1873 and 2064, 1874 and 2063, and even more specifically between nucleobase positions 1875 and 2062 of the Syngr-3 mRNA transcript set forth in SEQ ID NO:1.

[0142] In a more specific embodiment, the target region is defined by SEQ ID NO:111.

[0143] In another specific embodiment, the target region is located between nucleobase positions 1850 and 1950 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1, or is contained within the nucleotide subsequence defined by nucleobase positions 1850 and 1950. Specifically, the target region is located between nucleobase positions 1850 and 1950 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Nucleic acid base positions 1851 and 1950, 1852 and 1950, 1853 and 1950, 1854 and 1950, 1855 and 1950, 1856 and 1950, 1857 and 1950, 1858 and 1950, 1859 and 1950, 1860 and 1950, 1861 and 1950, 1862 and 1950, 1863 and 1950, 1864 and 1950, 1865 and 1950, 1866 and 1950, 1867 and 1950, 1868 and 1950, 1869 and It can be placed between 1950, 1870 and 1950, 1850 and 1933, 1850 and 1934, 1850 and 1935, 1850 and 1936, 1850 and 1937, 1850 and 1938, 1850 and 1939, 1850 and 1940, 1850 and 1941, 1850 and 1942, 1850 and 1943, 1850 and 1944, 1850 and 1945, 1850 and 1946, 1850 and 1947, 1850 and 1948, or 1850 and 1949. More specifically, the target region is located between nucleobase positions 1870 and 1933 of SEQ ID NO:1, more specifically between nucleobase positions 1871 and 1932, 1872 and 1931, 1873 and 1930, or 1874 and 1929, and even more specifically between nucleobase positions 1875 and 1928 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1.

[0144] In more specific embodiments, the target region is defined by SEQ ID NO: 91. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NOs: 88, 89, and / or 90. In most specific embodiments, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NOs: 339, 340, and / or 341.

[0145] In another specific embodiment, the target region is located between nucleobase positions 1930 and 2000 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1, or is contained within the nucleotide subsequence defined by nucleobase positions 1930 and 2000. Specifically, the target region is located between nucleobase positions 1931 and 2000, 1932 and 2000, 1933 and 2000, 1934 and 2000, 1935 and 2000, 1936 and 2000, 1937 and 2000, 1938 and 2000, 1939 and 2000, 1940 and 2000, 1941 and 2000, 1942 and 2000 of SEQ ID NO: 1. 1992, 1930 and 1993, 1930 and 1994, 1930 and 1995, 1930 and 1996, 1930 and 1997, 1930 and 1998, or 1930 and 1999. More specifically, the target region is located between nucleobase positions 1946 and 1992 of SEQ ID NO:1, more specifically between nucleobase positions 1947 and 1991, 1948 and 1990, 1949 and 1989, or 1950 and 1988, and even more specifically between nucleobase positions 1951 and 1987 of SEQ ID NO:1.

[0146] In more specific embodiments, the target region is defined by SEQ ID NO: 94. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NOs: 92 and / or 93. In most specific embodiments, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NOs: 342 and / or 343.

[0147] In another specific embodiment, the target region is located between or contained within the nucleotide subsequence defined by nucleobase positions 1995 and 2100 of the Syngr-3 mRNA transcript set forth in SEQ ID NO:1. Specifically, the target regions are located at nucleobase positions 1996 and 2100, 1997 and 2100, 1998 and 2100, 1999 and 2100, 2000 and 2100, 2001 and 2100, 2002 and 2100, 2003 and 2100, 2004 and 2100, 2005 and 2100, 2006 and 2100, 2007 and 2100, 2008 and 2100, 1995 and 2067, 1995 and 2068, 1995 and 2069, 1995 and 2070, 1995 and 2071, 1995 and 2072, 1995 and 2073, 1995 and 2074, 1995 and 2075, 1995 and 2076, 1995 and 2077, 1995 and 2078, 1995 and 2079, 1995 and 2080, 1995 and 2081, 1995 and 2082, 1995 and 2083, 1995 and 2084, 1995 and 2085, 1995 and 2086, 1995 and 2087, 1995 and 2088, 1995 and 2089, 1995 and 2090, 1995 and 2091, 1995 and 2092, 1995 and 2093, 1995 and 2094, 1995 It is positioned between 2076, 1995 and 2077, 1995 and 2078, 1995 and 2079, 1995 and 2080, 1995 and 2081, 1995 and 2082, 1995 and 2083, 1995 and 2084, 1995 and 2085, 1995 and 2086, 1995 and 2087, 1995 and 2088, 1995 and 2089, 1995 and 2090, 1995 and 2091, 1995 and 2092, 1995 and 2093, 1995 and 2094, 1995 and 2095, 1995 and 2096, 1995 and 2097, 1995 and 2098, or 1995 and 2099. More specifically, the target region is located between nucleobase positions 2008 and 2067 of SEQ ID NO:1, more specifically between nucleobase positions 2009 and 2066, 2010 and 2065, 2011 and 2064, or 2012 and 2063, and even more specifically between nucleobase positions 2013 and 2062 of SEQ ID NO:1.

[0148] In a more specific embodiment, the target region is defined by SEQ ID NO: 110. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NOs: 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, and / or 109. In a most specific embodiment, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NOs: 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, and / or 358.

[0149] In another specific embodiment, the target region is a subsequence located between nucleobase positions 2100 and 2250 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1, or is contained within the nucleotide subsequence defined by nucleobases 2100 and 2250. Specifically, the target region is nucleobases 2101 and 2250, 2102 and 2250, 2103 and 2250, 2104 and 2250, 2105 and 2250, 2106 and 2250, 2107 and 2250, 2108 and 2250, 2109 and 2250, 2110 and 2250, 2111 and 2250, 2112 and 2250, 2113 and 2250, 2114 and 2250, 2115 and 2250, 2116 and 2250, 2117 and 2250, 2118 and 2250, 2119 and 2250, 2120 and 2250, 2121 and 2250, 2122 and 2250, 2123 and 2250, 2124 and 2250, 2125 and 2250, 2126 and 2250, 2127 and 2250, 2128 and 2250, 2129 and 2250, 2130 and 2250, 2131 and 2250, 2132 and 2250, 2133 and 2250, 2134 and 2250, 2135 and 2250, 2136 and 2250, 2137 and 2250, 2138 and 2250, 2139 and 2250, 2140 and 2250, 2141 and 2250, 2142 and Between 8 and 2250, 2119 and 2250, 2100 and 2233, 2100 and 2234, 2100 and 2235, 2100 and 2236, 2100 and 2237, 2100 and 2238, 2100 and 2239, 2100 and 2240, 2100 and 2241, 2100 and 2242, 2100 and 2243, 2100 and 2244, 2100 and 2245, 2100 and 2246, 2100 and 2247, 2100 and 2248, or 2100 and 2249. More specifically, the target region is located between nucleobase positions 2119 and 2233 of SEQ ID NO:1, more specifically between nucleobase positions 2120 and 2232, 2121 and 2231, 2122 and 2230, or 2123 and 2229, and even more specifically between nucleobases 2124 and 2228 of SEQ ID NO:1.

[0150] In a more specific embodiment, the target region is defined by SEQ ID NO:141.

[0151] In another specific embodiment, the target region is a subsequence located between nucleobase positions 2100 and 2190 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1, or is contained within the nucleotide subsequence defined by nucleobases 2100 and 2190 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Specifically, the target region is a subsequence located between nucleobase positions 2100 and 2190 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Nucleobase positions 2101 and 2190, 2102 and 2190, 2103 and 2190, 2104 and 2190, 2105 and 2190, 2106 and 2190, 2107 and 2190, 2108 and 2190, 2109 and 2190, 2110 and 2190, 2111 and 2190, 2112 and 2190, 2113 and 2190, 2114 and 2190, 2115 and 219 0, 2116 and 2190, 2117 and 2190, 2118 and 2190, 2119 and 2190, 2100 and 2180, 2100 and 2181, 2100 and 2182, 2100 and 2183, 2100 and 2184, 2100 and 2185, 2100 and 2186, 2100 and 2187, 2100 and 2188, or 2100 and 2189. More specifically, the target region is located between nucleobase positions 2119 and 2180 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1, more specifically between nucleobase positions 2120 and 2179, 2121 and 2178, 2122 and 2177, or 2123 and 2176, and even more specifically between nucleobase positions 2124 and 2175 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1.

[0152] In more specific embodiments, the target region is defined by SEQ ID NO: 135. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NOs: 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, and / or 134. In the most specific embodiments, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NO: 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, and / or 381.

[0153] In another specific embodiment, the target region is a subsequence located between nucleobase positions 2180 and 2250 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1, or is contained within the nucleotide subsequence defined by nucleobases 2180 and 2250 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Specifically, the target region is a subsequence located between nucleobase positions 2180 and 2250 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Nucleobase positions 2181 and 2250, 2182 and 2250, 2183 and 2250, 2184 and 2250, 2185 and 2250, 2186 and 2250, 2187 and 2250, 2188 and 2250, 2189 and 2250, 2190 and 2250, 2191 and 2250, 2192 and 2250, 2193 and 2250, 2194 and 2250, 2195 and 2250, 2196 and 2250, 2197 and 2250, 2198 and 2250, 2199 and 2250, 2200 and 2250, 2201 and 2250, 2180 and 2233, 2180 and 2234, 2180 and 2235, 2180 and 2236, 2180 and 2237, 2180 and 2238, 2180 and 2239, 2180 and 2240, 2180 and 2241, 2180 and 2242, 2180 and 2243, 2180 and 2244, 2180 and 2245, 2180 and 2246, 2180 and 2247, 2180 and 2248, or 2180 and 2249. More specifically, the target region is located between nucleobase positions 2201 and 2233 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1, more specifically between nucleobase positions 2202 and 2232, 2203 and 2231, 2204 and 2230, or 2205 and 2229, and even more specifically between nucleobase positions 2206 and 2228 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1.

[0154] In more specific embodiments, the target region is defined by SEQ ID NO: 140. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NOs: 136, 137, 138, and / or 139. In most specific embodiments, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NOs: 382, ​​383, 384, and / or 385.

[0155] In another specific embodiment, the target region is a subsequence located between nucleobase positions 2308 and 2428 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1, or is contained within the nucleotide subsequence defined by nucleobases 2308 and 2428 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Specifically, the target region is a subsequence located between nucleobase positions 2309 and 2428, 2310 and 2428, 2308 and 2417, 2308 and 2418, 2308 and 2419, 2308 and 2420, 2308 and 2421, 2308 and 2422, 2308 and 2423, 2308 and 2424, 2308 and 2425, 2308 and 2426, or 2308 and 2027 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. More specifically, the target region is located between nucleobase positions 2310 and 2417 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1, more specifically between nucleobase positions 2311 and 2416, 2312 and 2415, 2313 and 2414, or 2314 and 2413, and even more specifically between nucleobase positions 2315 and 2412 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1.

[0156] In a more specific embodiment, the target region is defined by SEQ ID NO: 170. In an even more specific embodiment, the target region is defined by (or comprises or consists of) SEQ ID NOs: 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, and / or 169. In the most specific embodiments, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NO: 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, and / or 413.

[0157] In another specific embodiment, the target region is a subsequence located between nucleobase positions 2416 and 2441 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1, or is contained within the nucleotide subsequence defined by nucleobases 2416 and 2441 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Specifically, the target region is a subsequence located between nucleobase positions 2417 and 2441, 2418 and 2441, 2419 and 2441, 2420 and 2441, 2421 and 2441, 2416 and 2436, 2416 and 2437, 2416 and 2438, 2416 and 2439, or 2416 and 2440 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. More specifically, the target region is located between nucleobase positions 2421 and 2436 of the Syngr-3 mRNA transcript as defined in SEQ ID NO:1.

[0158] In more specific embodiments, the target region is defined by SEQ ID NO: 172. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NO: 171. In a most specific embodiment, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NO: 414.

[0159] In another specific embodiment, the target region is a subsequence located between nucleobase positions 2428 and 2625 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1, or is contained within the nucleotide subsequence defined by nucleobases 2428 and 2625 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Specifically, the target region is a subsequence located between nucleobase positions 2428 and 2625 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Nucleobase positions 2429 and 2625, 2430 and 2625, 2431 and 2625, 2432 and 2625, 2433 and 2625, 2434 and 2625, 2435 and 2625, 2436 and 2625, 2437 and 2625, 2438 and 2625, 2439 and 2625, 2440 and 2625, 2441 and 2625, 2442 and 2625, 2443 and 2625, 2444 and 2625, 2445 and 2625, 2446 and 2625, 2447 and 2625 , 2448 and 2625, 2449 and 2625, 2450 and 2625, 2451 and 2625, 2452 and 2625, 2453 and 2625, 2454 and 2625, 2455 and 2625, 2456 and 2625, 2457 and 2625, 2458 and 2625, 2459 and 2625, 2460 and 2625, 2461 and 2625, 2462 and 2625, 2463 and 2625, 2664 and 2625, 2665 and 2625, 2666 and 2625, 2667 and 2625, 266 8 and 2625, 2669 and 2625, 2470 and 2625, 2428 and 2519, 2428 and 2520, 2428 and 2521, 2428 and 2522, 2428 and 2523, 2428 and 2524, 2428 and 2525, 2428 and 2526, 2428 and 2527, 2428 and 2528, 2428 and 2529, 2428 and 2530, 2428 and 2531, 2428 and 2532, 2428 and 2533, 2428 and 2534, 2428 and 2535, 2428 and 2 536, 2428 and 2537, 2428 and 2538, 2428 and 2539, 2428 and 2540, 2428 and 2541, 2428 and 2542, 2428 and 2543, 2428 and 2544, 2428 and 2545, 2428 and 2546, 2428 and 2547, 2428 and 2548, 2428 and 2549, 2428 and 2550, 2428 and 2551, 2428 and 2552, 2428 and 2553, 2428 and 2554, 2428 and 2555, 2428 and 2556,2428 and 2557, 2428 and 2558, 2428 and 2559, 2428 and 2560, 2428 and 2561, 2428 and 2562, 2428 and 2563, 2428 and 2564, 2428 and 2565, 2428 and 2566, 2428 and 2567, 2428 and 2568, 2428 and 2569, 2428 and 2570, 2428 and 2571, 2428 and 2572, 2428 and 2573, 2428 and 2574, 2428 and 2575, 2428 and 2576, 2428 and 2577, 2428 and 2578, 2428 and 2579, 2428 and 2580, 2428 and 2581, 2428 and 2582, 2428 and 2583, 2428 and 2584, 2428 and 2585, 2428 and 2586, 2428 and 2587, 2428 and 2588, 2428 and 2589, 2428 and 2590, 2428 and 2591, 2428 and 2592, 2428 and 2593, 2428 and 2594, 2428 and 2595, 2428 and 2596, 2428 and 2597, 2428 and 2598, 2428 and 2599, 2428 and 2600, 2428 and 2601, 2428 and 2602, 2428 and 2603, 2428 and 2604, 2428 and 2605, 2428 and 2606, 2428 and 2607, 2428 and 2608, 2428 and 2609, 2428 and 2610, 2428 and 2611, 2428 and 2612, 2428 and 2613, 2428 and 2614, 2428 and 2615, 2428 and 2616, 2428 and 2617, 2428 and 2618, 2428 and 2619, 2428 and 2620, 2428 and 2621, 2428 and 2622, 2428 and 2623, or 2428 and 2624. More specifically, the target region is located between nucleobase positions 2470 and 2519 of the Syngr-3 mRNA transcript set forth in SEQ ID NO:1, more specifically between nucleobase positions 2471 and 2518, 2472 and 2517, 2473 and 2516, or 2474 and 2515, and even more specifically, the target region is located between nucleobase positions 2475 and 2514 of SEQ ID NO:1.

[0160] In more specific embodiments, the target region is defined by SEQ ID NO: 179. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NOs: 173, 174, 175, 176, 177, and / or 178. In most specific embodiments, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NOs: 415, 416, 417, 418, 419, and / or 420.

[0161] In another specific embodiment, the target region is a subsequence located between nucleobase positions 2649 and 2796 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1, or is contained within the nucleotide subsequence defined by nucleobases 2649 and 2796 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Specifically, the target region is a subsequence located between nucleobase positions 2649 and 2796 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Nucleobase positions 2650 and 2796, 2651 and 2796, 2652 and 2796, 2653 and 2796, 2654 and 2796, 2655 and 2796, 2656 and 2796, 2657 and 2796, 2658 and 2796, 2659 and 2796, 2670 and 2796, 2671 and 2796, 2672 and 2796, 2673 and 2796, 2674 and 2796, 2675 and 2796, 2676 and 2796, 2677 and 2796, 2678 and 2796 , 2679 and 2796, 2680 and 2796, 2681 and 2796, 2682 and 2796, 2683 and 2796, 2684 and 2796, 2685 and 2796, 2686 and 2796, 2687 and 2796, 2688 and 2796, 2689 and 2796, 2690 and 2796, 2691 and 2796, 2692 and 2796, 2693 and 2796, 2694 and 2796, 2695 and 2796, 2696 and 2796, 2697 and 2796, 2698 and 2796, 269 9 and 2796, 2700 and 2796, 2701 and 2796, 2702 and 2796, 2703 and 2796, 2704 and 2796, 2705 and 2796, 2706 and 2796, 2707 and 2796, 2708 and 2796, 2709 and 2796, 2710 and 2796, 2711 and 2796, 2712 and 2796, 2713 and 2796, 2714 and 2796, 2715 and 2796, 2716 and 2796, 2717 and 2796, 2718 and 2796, 2719 and 2 796, 2720 and 2796, 2721 and 2796, 2722 and 2796, 2723 and 2796, 2724 and 2796, 2725 and 2796, 2726 and 2796, 2727 and 2796, 2649 and 2752, 2649 and 2753, 2649 and 2754, 2649 and 2755, 2649 and 2756, 2649 and 2757, 2649 and 2758, 2649 and 2759, 2649 and 2760, 2649 and 2761, 2649 and 2762, 2649 and 2763,2649 and 2764, 2649 and 2765, 2649 and 2766, 2649 and 2767, 2649 and 2768, 2649 and 2769, 2649 and 2770, 2649 and 2771, 2649 and 2772, 2649 and 2773, 2649 and 2774, 2649 and 2775, 2649 and 2776, 2649 and 2777, 2649 and 2778, 2649 and 2779, 2649 and 2780, 26 and / or 2649 and 2795. More specifically, the target region is located between nucleobase positions 2727 and 2752 of the Syngr-3 mRNA transcript set forth in SEQ ID NO:1, more specifically between nucleobase positions 2728 and 2751, 2729 and 2750, 2730 and 2749, or 2731 and 2748, and even more specifically between nucleobase positions 2732 and 2747 of the Syngr-3 mRNA transcript set forth in SEQ ID NO:1.

[0162] In more specific embodiments, the target region is defined by SEQ ID NO: 181. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NO: 180. In most specific embodiments, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NO: 421.

[0163] In another specific embodiment, the target region is a subsequence located between nucleobase positions 2962 and 3086 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1, or is contained within the nucleotide subsequence defined by nucleobases 2962 and 3086 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Specifically, the target region is a subsequence located between nucleobase positions 2962 and 3086 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Nucleobase positions 2963 and 3086, 2964 and 3086, 2965 and 3086, 2966 and 3086, 2967 and 3086, 2968 and 3086, 2969 and 3086, 2970 and 3086, 2971 and 3086, 2972 ​​and 3086, 2973 and 3086, 2974 and 3086, 2975 and 3086, 2962 and 3066, 2962 and 3067, 2962 and 3068, 2962 and 3069, and / or 2962 and 3085. More specifically, the target region is located between nucleobase positions 2975 and 3066 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1, more specifically between nucleobase positions 2976 and 3065, 2977 and 3064, 2978 and 3063, or 2979 and 3062, and even more specifically between nucleobase positions 2980 and 3061 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1.

[0164] In a more specific embodiment, the target region is defined by SEQ ID NO:194.

[0165] In another specific embodiment, the target region is a subsequence located between nucleobase positions 2962 and 3010 of the Syngr-3 mRNA transcript set forth in SEQ ID NO:1, or is contained within the nucleotide subsequence defined by nucleobases 2962 and 3010 of the Syngr-3 mRNA transcript set forth in SEQ ID NO:1. Specifically, the target region is a subsequence located between nucleobase positions 2963 and 3010, 2964 and 3010, 2965 and 3010, 2966 and 3010, 2967 and 3010, 2968 and 3010, 2969 and 3010, 2970 and 3010, 2971 and 3010, 2972 ​​and 3010, 2973 and 3010, 2974 and 3010, 2975 and 3010, 2962 and 3003, 2962 and 3004, 2962 and 3005, 2962 and 3006, 2962 and 3007, 2962 and 3008, or 2962 and 3009 of the Syngr-3 mRNA transcript set forth in SEQ ID NO:1. More specifically, the target region is located between nucleobase positions 2975 and 3003 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1, more specifically between nucleobase positions 2976 and 3002, 2977 and 3001, 2978 and 3000, or 2979 and 2999, and even more specifically between nucleobase positions 2980 and 2998 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1.

[0166] In more specific embodiments, the target region is defined by SEQ ID NO: 184. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NOs: 182 and / or 183. In most specific embodiments, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NOs: 422 and / or 423.

[0167] In another specific embodiment, the target region is a subsequence located between nucleobase positions 3000 and 3045 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1, or is contained within the nucleotide subsequence defined by nucleobases 3000 and 3045 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1. Specifically, the target region is a subsequence located between nucleobase positions 3001 and 3045, 3002 and 3045, 3003 and 3045, 3004 and 3045, 3005 and 3045, 3006 and 3045, 3000 and 3037, 3000 and 3038, 3000 and 3039, 3000 and 3040, 3000 and 3041, 3000 and 3042, 3000 and 3043, or 3000 and 3044 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1. More specifically, the target region is located between nucleobase positions 3006 and 3037 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1, more specifically between nucleobase positions 3007 and 3036, 3008 and 3035, 3009 and 3034, or 3010 and 3033, and even more specifically between nucleobase positions 3011 and 3032 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1.

[0168] In more specific embodiments, the target region is defined by SEQ ID NO: 188. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NOs: 185, 186, and / or 187. In most specific embodiments, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NOs: 424, 425, and / or 426.

[0169] In another specific embodiment, the target region is a subsequence located between nucleobase positions 3020 and 3086 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1, or is contained within the nucleotide subsequence defined by nucleobases 3020 and 3086 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Specifically, the target region is a subsequence located between nucleobase positions 3020 and 3086 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Nucleobase positions 3021 and 3086, 3022 and 3086, 3023 and 3086, 3024 and 3086, 3025 and 3086, 3026 and 3086, 3027 and 3086, 3028 and 3086, 3029 and 3086, 3020 and 3066, 3020 and 3067, 3020 and 3068, 3020 and 3069, 3020 and 3070, 3020 and 3071 of the mRNA transcript and / or 3020 and 3085. More specifically, the target region is located between nucleobase positions 3029 and 3066 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1, more specifically between nucleobase positions 3030 and 3065, 3031 and 3064, 3032 and 3063, or 3033 and 3062, and even more specifically between nucleobase positions 3034 and 3061 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1.

[0170] In more specific embodiments, the target region is defined by SEQ ID NO: 193. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NOs: 189, 190, 191, and / or 192. In most specific embodiments, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NOs: 427, 428, 429, and / or 430.

[0171] In another specific embodiment, the target region is a subsequence located between nucleobase positions 3153 and 3460 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1, or is contained within the nucleotide subsequence defined by nucleobases 3153 and 3460 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Specifically, the target region is a subsequence located between nucleobase positions 3153 and 3460 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Nucleobase positions 3154 and 3460, 3155 and 3460, 3156 and 3460, 3157 and 3460, 3158 and 3460, 3159 and 3460, 3160 and 3460, 3161 and 3460, 3162 and 3460, 3164 and 3460, 3165 and 3460, 3166 and 3460, 3167 and 3460, 3168 and 3460, 3169 and 3460, 3170 and 3460, 3172 and 3460, 3173 and 3460, 3174 and 3460, 3175 and 3460, 3176 and 3460, 3177 and 3460, 3178 and 3460, 3179 and 3460, 3180 and 3460, 3181 and 3460, 3182 and 3460, 3183 and 3460, 3184 and 3460, 3185 and 3460, 3186 and 3460, 3187 and 3460, 3188 and 3460, 3189 and 3460, 3190 and 3460, 3191 and 3460, 3192 and 3460, 3193 and 3460, 3194 and 3460, 3195 and 3460, 3196 and 3460, 3197 and 3460, 3 73 and 3460, 3174 and 3460, 3175 and 3460, 3176 and 3460, 3177 and 3460, 3178 and 3460, 3179 and 3460, 3180 and 3460, 3181 and 3460, 3182 and 3460, 3183 and 3460, 3153 and 3417, 3153 and 3418, 3153 and 3419, 3153 and 3420, 3153 and 3421, 3153 and 3422, 3153 and 3423, 3153 and 342 4, 3153 and 3425, 3153 and 3426, 3153 and 3427, 3153 and 3428, 3153 and 3429, 3153 and 3430, 3153 and 3431, 3153 and 3432, 3153 and 3433, 3153 and 3434, 3153 and 3435, 3153 and 3436, 3153 and 3437, 3153 and 3438, 3153 and 3439, 3153 and 3440, 3153 and 3441, 3153 and 3442, 3153 and 3443, 3153 and 3444, 3153 and 3445, 3153 and 3446, 3153 and 3447, 3153 and 3448, 3153 and 3449, 3153 and 3450, 3153 and 3451, 3153 and 3452, 3153 and 3453, 3153 and 3454, 3153 and 3455, 3153 and 3456, 3153 and 3457, 3153 and 3458, or 3153 and 3459.More specifically, the target region is located between nucleobase positions 3183 and 3417 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1, more specifically between nucleobase positions 3184 and 3416, 3185 and 3415, 3186 and 3414, or 3187 and 3413, and even more specifically between nucleobase positions 3188 and 3412 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1.

[0172] In a more specific embodiment, the target region is defined by SEQ ID NO:221.

[0173] In another specific embodiment, the target region is a subsequence located between nucleobase positions 3153 and 3270 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1, or is contained within the nucleotide subsequence defined by nucleobases 3153 and 3270 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Specifically, the target region is a subsequence located between nucleobase positions 3153 and 3270 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Nucleobase positions 3154 and 3270, 3155 and 3270, 3156 and 3270, 3157 and 3270, 3158 and 3270, 3159 and 3270, 3160 and 3270, 3161 and 3270, 3162 and 3270, 3164 and 3270, 3165 and 3270, 3166 and 3270, 3167 and 3270, 3168 and 3270, 3169 and 3270, 3170 and 3270, 3172 and 3270, 3173 and 3270, 3174 and 3270, 3175 and 3270, 3176 and 3270, 3177 and 3270, 3178 and 3270, 3179 and 3270, 3180 and 3270, 3181 and 3270, 3182 and 3270, 3183 and 3270, 3184 and 3270, 3185 and 3270, 3186 and 3270, 3187 and 3270, 3188 and 3270, 3189 and 3270, 3190 and 3270, 3191 and 3270, 3192 and 3270, 3193 and 3270, 3194 and 3270, 3195 and 3270, 3196 and 3270, 3197 and 3270, 3 and 3270, 3176 and 3270, 3177 and 3270, 3178 and 3270, 3179 and 3270, 3180 and 3270, 3181 and 3270, 3182 and 3270, 3183 and 3270, 3153 and 3260, 3153 and 3261, 3153 and 3262, 3153 and 3263, 3153 and 3264, 3153 and 3265, 3153 and 3266, 3153 and 3267, 3153 and 3268, or 3153 and 3269. More specifically, the target region is located between nucleobase positions 3183 and 3260 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1, more specifically between nucleobase positions 3184 and 3259, 3185 and 3258, 3186 and 3257, or 3187 and 3256, and even more specifically between nucleobase positions 3188 and 3255 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1.

[0174] In a more specific embodiment, the target region is defined by SEQ ID NO: 210. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NOs: 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, and / or 209. In a most specific embodiment, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NOs: 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, and / or 445.

[0175] In another specific embodiment, the target region is a subsequence located between nucleobase positions 3250 and 3360 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1, or is contained within the nucleotide subsequence defined by nucleobases 3250 and 3360 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Specifically, the target region is a subsequence located between nucleobase positions 3250 and 3360 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Nucleobase positions 3251 and 3360, 3252 and 3360, 3253 and 3360, 3254 and 3360, 3255 and 3360, 3256 and 3360, 3257 and 3360, 3258 and 3360, 3259 and 3360, 3260 and 3360, 3261 and 3360, 3262 and 3360, 3263 and 3360, 3264 and 3360, 3265 and 3360, 3266 and 3360, 3267 and 3360, 3268 and 3360, 3269 and 3360, 3270 and 3360 0, 3271 and 3360, 3250 and 3342, 3250 and 3343, 3250 and 3344, 3250 and 3345, 3250 and 3346, 3250 and 3347, 3250 and 3348, 3250 and 3349, 3250 and 3350, 3250 and 3351, 3250 and 3352, 3250 and 3353, 3250 and 3354, 3250 and 3355, 3250 and 3356, 3250 and 3357, 3250 and 3358, or 3250 and 3359. More specifically, the target region is located between nucleobase positions 3271 and 3342 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1, more specifically between nucleobase positions 3272 and 3341, 3273 and 3340, 3274 and 3339, or 3275 and 3338, and even more specifically between nucleobase positions 3276 and 3337 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1.

[0176] In more specific embodiments, the target region is defined by SEQ ID NO: 216. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NOs: 211, 212, 213, 214, and / or 215. In most specific embodiments, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NOs: 446, 447, 448, 449, and / or 450.

[0177] In another specific embodiment, the target region is a subsequence located between nucleobase positions 3370 and 3460 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1, or is contained within the nucleotide subsequence defined by nucleobases 3370 and 3460 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Specifically, the target region is a subsequence located between nucleobase positions 3370 and 3460 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Nucleobase positions 3371 and 3460, 3372 and 3460, 3373 and 3460, 3374 and 3460, 3375 and 3460, 3376 and 3460, 3377 and 3460, 3378 and 3460, 3379 and 3460, 3380 and 3460, 3381 and 3460, 3382 and 3460, 3383 and 3460, 3384 and 3460, 3385 and 3460, 3386 and 3460, 3387 and 3460, 3388 and 3460, 3389 and 3460, 3390 and 3460, 3391 and 3460, 3392 and 3460, 3393 and 3460, 3394 and 3460, 3395 and 3460, 3396 and 3460, 3397 and 3460, 3398 and 3460, 339 ...9 and 3460, 3 86 and 3460, 3387 and 3460, 3388 and 3460, 3389 and 3460, 3390 and 3460, 3370 and 3417, 3370 and 3418, 3370 and 3419, 3370 and 3420, 3370 and 3421, 3370 and 3422, 3370 and 3423, 3370 and 3424, 3370 and 3425, 3370 and 3426, 3370 and 3427, 3370 and 342 8, 3370 and 3429, 3370 and 3430, 3370 and 3431, 3370 and 3432, 3370 and 3433, 3370 and 3434, 3370 and 3435, 3370 and 3436, 3370 and 3437, 3370 and 3438, 3370 and 3439, 3370 and 3440, 3370 and 3441, 3370 and 3442, 3370 and 3443, 3370 and 3444, 3370 and 3445, 3370 and 3446, 3370 and 3447, 3370 and 3448, 3370 and 3449, 3370 and 3450, 3370 and 3451, 3370 and 3452, 3370 and 3453, 3370 and 3454, 3370 and 3455, 3370 and 3456, 3370 and 3457, 3370 and 3458, or 3370 and 3459.More specifically, the target region is located between nucleobase positions 3390 and 3417 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1, more specifically between nucleobase positions 3391 and 3416, 3392 and 3415, 3393 and 3414, or 3394 and 3413, and even more specifically between nucleobase positions 3395 and 3412 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1.

[0178] In more specific embodiments, the target region is defined by SEQ ID NO: 220. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NOs: 217, 218, and / or 219. In most specific embodiments, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NOs: 451, 452, and / or 453.

[0179] In another specific embodiment, the target region is a subsequence located between nucleobase positions 3450 and 3530 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1, or is contained within the nucleotide subsequence defined by nucleobases 3450 and 3530 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Specifically, the target region is located between nucleobase positions 3451 and 3530, 3452 and 3530, 3453 and 3530, 3454 and 3530, 3455 and 3530, 3456 and 3530, 3457 and 3530, 3458 and 3530, 3459 and 3530, 3460 and 3530, 3461 and 3530, 3462 and 3530, 3463 and 3530 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. and 3530, 3464 and 3530, 3465 and 3530, 3466 and 3530, 3467 and 3530, 3468 and 3530, 3469 and 3530, 3470 and 3530, 3471 and 3530, 3472 and 3530, 3473 and 3530, 3474 and 3530, 3475 and 3530, 3476 and 3530, 347 7 and 3530, 3478 and 3530, 3479 and 3530, 3480 and 3530, 3481 and 3530, 3482 and 3530, 3483 and 3530, 3484 and 3530, 3485 and 3530, 3486 and 3530, 3487 and 3530, 3488 and 3530, 3489 and 3530, 3490 and 3530, 34 and 3518, 3450 and 3519, 3450 and 3520, 3450 and 3521, 3450 and 3522, 3450 and 3523, 3450 and 3524, 3450 and 3525, 3450 and 3526, 3450 and 3527, 3450 and 3528, or 3450 and 3529. More specifically, the target region is located between nucleobase positions 3490 and 3518 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1, more specifically between nucleobase positions 3491 and 3517, 3492 and 3516, 3493 and 3515, or 3494 and 3514, and even more specifically between nucleobase positions 3495 and 3513 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1.

[0180] In more specific embodiments, the target region is defined by SEQ ID NO: 224. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NOs: 222 and / or 223. In most specific embodiments, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NOs: 454 and / or 455.

[0181] In another specific embodiment, the target region is a subsequence located between nucleobase positions 3508 and 3551 of the Syngr-3 mRNA transcript set forth in SEQ ID NO:1, or is contained within the nucleotide subsequence defined by nucleobases 3508 and 3551 of the Syngr-3 mRNA transcript set forth in SEQ ID NO:1. Specifically, the target region is a subsequence located between nucleobase positions 3509 and 3551, 3510 and 3551, 3511 and 3551, 3512 and 3551, 3513 and 3551, 3514 and 3551, 3515 and 3551, 3516 and 3551, 3517 and 3551, 3518 and 3551, 3519 and 3551, 3520 and 3551, 3508 and 3549, or 3508 and 3550 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1. More specifically, the target region is located between nucleobase positions 3520 and 3549 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1, more specifically between nucleobase positions 3521 and 3548, 3522 and 3547, 3523 and 3546, or 3524 and 3545, and even more specifically between nucleobase positions 3525 and 3544 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1.

[0182] In more specific embodiments, the target region is defined by SEQ ID NO: 227. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NOs: 225 and / or 226. In most specific embodiments, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NOs: 456 and / or 457.

[0183] In another specific embodiment, the target region is a subsequence located between nucleobase positions 3538 and 3636 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1, or is contained within the nucleotide subsequence defined by nucleobases 3538 and 3636 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Specifically, the target region is a subsequence located between nucleobase positions 3538 and 3636 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Nucleobase positions 3539 and 3636, 3540 and 3636, 3541 and 3636, 3542 and 3636, 3543 and 3636, 3544 and 3636, 3538 and 3569, 3538 and 3570, 3538 and 3571, 3538 and 3572, 3538 and 3573, 3538 and 3574, 3538 and 3575, 3538 and 3576, 3538 and 3577, 3538 and 3578, 3538 and 3579, 3538 and 3580, 3538 and 3581, 3538 and 3582, 3538 and 3583, 3538 and 3584, 3538 and 3585, 3538 and 3586, 3538 and 3587, 3538 and 3588, 3538 and 3589, 3538 and 3590, 3538 and 3591, 3538 and 3592, 3538 and 3593, 3538 and 3594, 3538 and 3595, 3538 and 3596, 3538 and 3597, 3538 and 3598, 3538 and 3599, 3538 and 3599, 3538 and 3599, 3538 and 3591, 3538 and 3591, 3538 and 3592, 3 80, 3538 and 3581, 3538 and 3582, 3538 and 3583, 3538 and 3584, 3538 and 3585, 3538 and 3586, 3538 and 3587, 3538 and 3588, 3538 and 3589, 3538 and 3590, 3538 and 3591, 3538 and 3592, 3538 and 3593, 3538 and 3594, 3538 and 3595, 3538 and 3596, 3538 and 3597, 3538 and 3598, 3538 and 359 9, 3538 and 3600, 3538 and 3601, 3538 and 3602, 3538 and 3603, 3538 and 3604, 3538 and 3605, 3538 and 3606, 3538 and 3607, 3538 and 3608, 3538 and 3609, 3538 and 3610, 3538 and 3611, 3538 and 3612, 3538 and 3613, 3538 and 3614, 3538 and 3615, 3538 and 3616, 3538 and 3617, 3538 and 3618 , 3538 and 3619, 3538 and 3620, 3538 and 3621, 3538 and 3622, 3538 and 3623, 3538 and 3624, 3538 and 3625, 3538 and 3626, 3538 and 3627, 3538 and 3628, 3538 and 3629, 3538 and 3630, 3538 and 3631, 3538 and 3632, 3538 and 3633, 3538 and 3634, or 3538 and 3635.More specifically, the target region is located between nucleobase positions 3544 and 3569 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1, more specifically between nucleobase positions 3545 and 3568, 3546 and 3567, 3547 and 3566, or 3548 and 3565, and even more specifically between nucleobase positions 3549 and 3564 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1.

[0184] In more specific embodiments, the target region is defined by SEQ ID NO: 229. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NO: 228. In most specific embodiments, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NO: 458.

[0185] In another specific embodiment, the target region is a subsequence located between nucleobase positions 3626 and 4599 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1, or is contained within the nucleotide subsequence defined by nucleobases 3626 and 4599 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Specifically, the target region is a subsequence located between nucleobase positions 3626 and 4599 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Nucleobase positions 3627 and 4599, 3628 and 4599, 3629 and 4599, 3630 and 4599, 3631 and 4599, 3632 and 4599, 3633 and 4599, 3634 and 4599, 3635 and 4599, 3636 and 4599, 3637 and 4599, 3638 and 4599, 3639 and 4599, 3640 and 4599, 3626 and 4567, 3626 and 4568, 3626 and 4569, 3626 and 4570, 3626 and 4571, 3626 and 4572, 3626 and 4573, 3626 and 4574, 3626 and 4575, 3626 and 4576, 3626 and 4577, 3626 and 4578, 3626 and 4579, 3626 and 4580, 3626 and 4581, 3626 and 4582, 3626 and 4583, 3626 and 4584, 3626 and 4585, 3626 and 4586, 3626 and 4587, 3626 and 4588, 3626 and 4589, 3626 and 4590, 3626 and 4591, 3626 and 4592, 3626 and 4593, 3626 and 4594, 3 and 4576, 3626 and 4577, 3626 and 4578, 3626 and 4579, 3626 and 4580, 3626 and 4581, 3626 and 4582, 3626 and 4583, 3626 and 4584, 3626 and 4585, 3626 and 4586, 3626 and 4587, 3626 and 4588, 3626 and 4589, 3626 and 4590, 3626 and 4591, 3626 and 4592, 3626 and 4593, 3626 and 4594, 3626 and 4595, 3626 and 4596, 3626 and 4597, or 3626 and 4598. More specifically, the target region is located between nucleobase positions 3640 and 4567 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1, more specifically between nucleobase positions 3641 and 4566, 3642 and 4565, 3643 and 4564, or 3644 and 4563, and even more specifically between nucleobase positions 3645 and 4562 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1.

[0186] In a more specific embodiment, the target region is defined by SEQ ID NO:269.

[0187] In another specific embodiment, the target region is a subsequence located between nucleobase positions 3626 and 3680 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1, or is contained within the nucleotide subsequence defined by nucleobases 3626 and 3680 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Specifically, the target region is a subsequence located between nucleobase positions 3626 and 3680 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Nucleobase positions 3627 and 3680, 3628 and 3680, 3629 and 3680, 3630 and 3680, 3631 and 3680, 3632 and 3680, 3633 and 3680, 3634 and 3680, 3635 and 3680, 3636 and 3680, 3637 and 3680, 3638 and 3680, 3639 and 3680, 3640 and 3680, 3626 and 366 5, 3626 and 3666, 3626 and 3667, 3626 and 3668, 3626 and 3669, 3626 and 3670, 3626 and 3671, 3626 and 3672, 3626 and 3673, 3626 and 3674, 3626 and 3675, 3626 and 3676, 3626 and 3677, 3626 and 3678, or 3626 and 3679. More specifically, the target region is located between nucleobase positions 3640 and 3665 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1, more specifically between nucleobase positions 3641 and 3664, 3642 and 3663, 3643 and 3662, or 3644 and 3661, and even more specifically between nucleobase positions 3645 and 3660 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1.

[0188] In more specific embodiments, the target region is defined by SEQ ID NO: 231. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NO: 230. In most specific embodiments, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NO: 459.

[0189] In another specific embodiment, the target region is a subsequence located between nucleobase positions 3700 and 3800 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1, or is contained within the nucleotide subsequence defined by nucleobases 3700 and 3800 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Specifically, the target region is located between nucleobase positions 3701 and 3800, 3702 and 3800, 3703 and 3800, 3704 and 3800, 3705 and 3800, 3706 and 3800, 3707 and 3800, 3708 and 3800, 3709 and 3800, 3710 and 3800, 3711 and 3800, 3712 and 3800 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. , 3713 and 3800, 3714 and 3800, 3715 and 3800, 3716 and 3800, 3717 and 3800, 3718 and 3800, 3719 and 3800, 3720 and 3800, 3721 and 3800, 3722 and 3800, 3723 and 3800, 3724 and 3800, 3725 and 3800, 372 6 and 3800, 3727 and 3800, 3728 and 3800, 3729 and 3800, 3730 and 3800, 3700 and 3780, 3700 and 3781, 3700 and 3782, 3700 and 3783, 3700 and 3784, 3700 and 3785, 3700 and 3786, 3700 and 3787, 3700 and 37 3700 and 3799. More specifically, the target region is located between nucleobase positions 3730 and 3780 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1, more specifically between nucleobase positions 3731 and 3779, 3732 and 3778, 3733 and 3777, or 3734 and 3776, and even more specifically between nucleobase positions 3735 and 3775 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1.

[0190] In more specific embodiments, the target region is defined by SEQ ID NO: 235. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NOs: 232, 233, and / or 234. In most specific embodiments, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NOs: 460, 461, and / or 462.

[0191] In another specific embodiment, the target region is a subsequence located between nucleobase positions 3800 and 3910 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1, or is contained within the nucleotide subsequence defined by nucleobases 3800 and 3910 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Specifically, the target region is located between nucleobase positions 3801 and 3910, 3802 and 3910, 3803 and 3910, 3804 and 3910, 3805 and 3910, 3806 and 3910, 3807 and 3910, 3808 and 3910, 3809 and 3910, 3810 and 3910, 3811 and 3910, 3812 and 3910, 3813 and 3910, 3814 and 3910 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. 10, 3815 and 3910, 3816 and 3910, 3817 and 3910, 3818 and 3910, 3819 and 3910, 3820 and 3910, 3821 and 3910, 3822 and 3910, 3823 and 3910, 3824 and 3910, 3825 and 3910, 3826 and 3910, 3827 and 3910, 3828 and 3910, 3829 and 391 0, 3830 and 3910, 3831 and 3910, 3832 and 3910, 3833 and 3910, 3834 and 3910, 3835 and 3910, 3836 and 3910, 3837 and 3910, 3838 and 3910, 3839 and 3910, 3840 and 3910, 3841 and 3910, 3842 and 3910, 3843 and 3910, 3844 and 3910 , 3845 and 3910, 3800 and 3898, 3800 and 3899, 3800 and 3900, 3800 and 3901, 3800 and 3902, 3800 and 3903, 3800 and 3904, 3800 and 3905, 3800 and 3906, 3800 and 3907, 3800 and 3908, or 3800 and 3909. More specifically, the target region is located between nucleobase positions 3845 and 3898 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1, more specifically between nucleobase positions 3846 and 3897, 3847 and 3896, 3848 and 3895, or 3849 and 3894, and even more specifically between nucleobase positions 3850 and 3893 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1.

[0192] In more specific embodiments, the target region is defined by SEQ ID NO: 241. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NOs: 236, 237, 238, 239, and / or 240. In most specific embodiments, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NOs: 463, 464, 465, 466, and / or 467.

[0193] In another specific embodiment, the target region is a subsequence located between nucleobase positions 3900 and 4025 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1, or is contained within the nucleotide subsequence defined by nucleobases 3900 and 4025 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Specifically, the target region is a subsequence located between nucleobase positions 3900 and 4025 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Nucleobase positions 3901 and 4025, 3902 and 4025, 3903 and 4025, 3904 and 4025, 3905 and 4025, 3906 and 4025, 3907 and 4025, 3908 and 4025, 3909 and 4025, 3910 and 4025, 3911 and 4025, 3912 and 4025, 3913 and 4025, 3914 and 4025, 3915 and 4025, 3900 and 4002, 3900 and 4003, 3900 and 4004, 3900 and 4005, 3900 and 4006, 3900 and 4007, 3900 and 4009, 3900 and 4010, 3900 and 4011, 3900 and 4012, 3900 and 4013, 3900 and 4014, 3900 and 4015, 3900 and 4016, 3900 and 4017, 3900 and 4018, 3900 and 4019 ... and 4006, 3900 and 4007, 3900 and 4008, 3900 and 4009, 3900 and 4010, 3900 and 4011, 3900 and 4012, 3900 and 4013, 3900 and 4014, 3900 and 4015, 3900 and 4016, 3900 and 4017, 3900 and 4018, 3900 and 4019, 3900 and 4020, 3900 and 4021, 3900 and 4022, 3900 and 4023, or 3900 and 4024. More specifically, the target region is located between nucleobase positions 3915 and 4002 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1, more specifically between nucleobase positions 3916 and 4001, 3917 and 4000, 3918 and 3999, or 3919 and 3998, and even more specifically between nucleobase positions 3920 and 3997 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1.

[0194] In more specific embodiments, the target region is defined by SEQ ID NO: 246. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NOs: 242, 243, 244, and / or 245. In most specific embodiments, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NOs: 468, 469, 470, and / or 471.

[0195] In another specific embodiment, the target region is a subsequence located between nucleobase positions 4050 and 4150 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1, or is contained within the nucleotide subsequence defined by nucleobases 4050 and 4150 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Specifically, the target region is a subsequence located between nucleobase positions 4050 and 4150 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Nucleobase positions of mRNA transcripts 4051 and 4150, 4052 and 4150, 4053 and 4150, 4054 and 4150, 4055 and 4150, 4056 and 4150, 4057 and 4150, 4058 and 4150, 4059 and 4150, 4060 and 4150, 4061 and 4150, 4062 and 4150, 4063 and 4150, 4064 and 4150, 4065 and 4150, 4066 and 4150, 4067 and 4150, 4068 and 4150, 4069 and 4150, 4070 and 4150, 4071 and 4150, 4072 and 4150, 4073 and 4150, 4074 and 4150, 4075 and 4150, 4076 and 4150, 4077 and 4150, 4078 and 4150, 4079 and 4150, 4080 and 4150, 4081 and 4150, 4082 and 4150, 4083 and 4150, 4084 and 4150, 4085 and 4150, 4086 and 4150, 4087 and 4150, 4088 and 4150, 4089 and 4150, 4090 and 4150, 4091 and 4150, 4092 and 415 69 and 4150, 4070 and 4150, 4071 and 4150, 4072 and 4150, 4073 and 4150, 4074 and 4150, 4075 and 4150, 4076 and 4150, 4077 and 4150, 4078 and 4150, 4079 and 4150, 4080 and 4150, 4081 and 4150, 4082 and 4150, 4083 and 4150, 4084 and 4150, 4085 and 4150, 4086 and 4150, 4087 and 4150, 4088 and 415 0, 4089 and 4150, 4090 and 4150, 4091 and 4150, 4050 and 4116, 4050 and 4117, 4050 and 4118, 4050 and 4119, 4050 and 4120, 4050 and 4121, 4050 and 4122, 4050 and 4123, 4050 and 4124, 4050 and 4125, 4050 and 4126, 4050 and 4127, 4050 and 4128, 4050 and 4129, 4050 and 4130, 4050 and 4131, 4050 and 4132, 4050 and 4133, 4050 and 4134, 4050 and 4135, 4050 and 4136, 4050 and 4137, 4050 and 4138, 4050 and 4139, 4050 and 4140, 4050 and 4141, 4050 and 4142, 4050 and 4143, 4050 and 4144, 4050 and 4145, 4050 and 4146, 4050 and 4147, 4050 and 4148, or 4050 and 4149.More specifically, the target region is located between nucleobase positions 4091 and 4116 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1, more specifically between nucleobase positions 4092 and 4115, 4093 and 4114, 4094 and 4113, or 4095 and 4112, and even more specifically between nucleobase positions 4096 and 4111 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1.

[0196] In more specific embodiments, the target region is defined by SEQ ID NO: 248. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NO: 247. In most specific embodiments, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NO: 472.

[0197] In another specific embodiment, the target region is a subsequence located between nucleobase positions 4150 and 4250 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1, or is contained within the nucleotide subsequence defined by nucleobases 4150 and 4250 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Specifically, the target region is a subsequence located between nucleobase positions 4150 and 4250 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Nucleobase positions of mRNA transcripts 4151 and 4250, 4152 and 4250, 4153 and 4250, 4154 and 4250, 4155 and 4250, 4156 and 4250, 4157 and 4250, 4158 and 4250, 4159 and 4250, 4160 and 4250, 4161 and 4250, 4162 and 4250, 4163 and 4250, 4164 and 4250, 4165 and 4250, 4166 and 4250, 4167 and 4250, 4168 and 4250, 41 69 and 4250, 4170 and 4250, 4171 and 4250, 4172 and 4250, 4173 and 4250, 4174 and 4250, 4175 and 4250, 4176 and 4250, 4177 and 4250, 4178 and 4250, 4179 and 4250, 4180 and 4250, 4181 and 4250, 4182 and 4250, 4183 and 4250, 4184 and 4250, 4185 and 4250, 4186 and 4250, 4187 and 4250, 4188 and 425 0, 4189 and 4250, 4190 and 4250, 4191 and 4250, 4192 and 4250, 4150 and 4217, 4150 and 4218, 4150 and 4219, 4150 and 4220, 4150 and 4221, 4150 and 4222, 4150 and 4223, 4150 and 4224, 4150 and 4225, 4150 and 4226, 4150 and 4227, 4150 and 4228, 4150 and 4229, 4150 and 4230, 4150 and 4231, 4150 and 4232, 4150 and 4233, 4150 and 4234, 4150 and 4235, 4150 and 4236, 4150 and 4237, 4150 and 4238, 4150 and 4239, 4150 and 4240, 4150 and 4241, 4150 and 4242, 4150 and 4243, 4150 and 4244, 4150 and 4245, 4150 and 4246, 4150 and 4247, 4150 and 4248, or 4150 and 4249.More specifically, the target region is located between nucleobase positions 4192 and 4217 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1, more specifically between nucleobase positions 4193 and 4216, 4194 and 4215, 4195 and 4214, or 4196 and 4213, and even more specifically between nucleobase positions 4197 and 4212 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1.

[0198] In more specific embodiments, the target region is defined by SEQ ID NO: 250. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NO: 249. In most specific embodiments, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NO: 473.

[0199] In another specific embodiment, the target region is a subsequence located between nucleobase positions 4250 and 4410 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1, or is contained within the nucleotide subsequence defined by nucleobases 4250 and 4410 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Specifically, the target region is a subsequence located between nucleobase positions 4250 and 4410 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Nucleobase positions 4251 and 4410, 4252 and 4410, 4253 and 4410, 4254 and 4410, 4255 and 4410, 4256 and 4410, 4257 and 4410, 4258 and 4410, 4259 and 4410, 4260 and 4410, 4261 and 4410, 4262 and 4410, 4263 and 4410, 4264 and 4410, 4265 and 4410 10, 4266 and 4410, 4267 and 4410, 4268 and 4410, 4269 and 4410, 4270 and 4410, 4271 and 4410, 4272 and 4410, 4273 and 4410, 4274 and 4410, 4275 and 4410, 4276 and 4410, 4277 and 4410, 4278 and 4410, 4279 and 4410, 4280 and 4410, 4281 and 441 0, 4282 and 4410, 4283 and 4410, 4284 and 4410, 4285 and 4410, 4286 and 4410, 4287 and 4410, 4288 and 4410, 4289 and 4410, 4250 and 4388, 4250 and 4389, 4250 and 4390, 4250 and 4391, 4250 and 4392, 4250 and 4393, 4250 and 4394, 4250 and 4395 , 4250 and 4396, 4250 and 4397, 4250 and 4398, 4250 and 4399, 4250 and 4400, 4250 and 4401, 4250 and 4402, 4250 and 4403, 4250 and 4404, 4250 and 4405, 4250 and 4406, 4250 and 4407, 4250 and 4408, or 4250 and 4409.More specifically, the target region is located between nucleobase positions 4289 and 4388 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1, more specifically between nucleobase positions 4290 and 4287, 4291 and 4386, 4292 and 4385, or 4293 and 4384, and even more specifically between nucleobase positions 4294 and 4383 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1.

[0200] In more specific embodiments, the target region is defined by SEQ ID NO: 259. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NOs: 251, 252, 253, 254, 255, 256, 257, and / or 258. In most specific embodiments, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NOs: 474, 475, 476, 477, 478, 479, 480, and / or 481.

[0201] In another specific embodiment, the target region is a subsequence located between nucleobase positions 4375 and 4599 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1, or is contained within the nucleotide subsequence defined by nucleobases 4375 and 4599 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Specifically, the target region is a subsequence located between nucleobase positions 4375 and 4599 of the Syngr-3 mRNA transcript set forth in SEQ ID NO: 1. Nucleobase positions of mRNA transcripts 4376 and 4599, 4377 and 4599, 4378 and 4599, 4379 and 4599, 4380 and 4599, 4381 and 4599, 4382 and 4599, 4383 and 4599, 4384 and 4599, 4385 and 4599, 4386 and 4599, 4387 and 4599, 4388 and 4599, 4389 and 4599, 4390 and 4599, 4391 and 4599, 4392 and 4599, 4393 and 4599, 4394 and 4599, 4395 and 4599, 4396 and 4599, 4397 and 4599, 4398 and 4599, 4399 and 4599, 4400 and 4599, 4401 and 4599, 4402 and 4599, 4403 and 4599, 4404 and 4599, 4405 and 4599, 4406 and 4599, 4407 and 4599, 4408 and 4599, 4409 and 4599, 441 0 and 4599, 4411 and 4599, 4375 and 4567, 4375 and 4568, 4375 and 4569, 4375 and 4570, 4375 and 4571, 4375 and 4572, 4375 and 4573, 4375 and 4574, 4375 and 4575, 4375 and 4576, 4375 and 4577, 4375 and 4578, 4375 and 4579, 4375 and 4580, 4375 and 4581, 4375 and 4582, 43 and a subsequence located between 4375 and 4583, 4375 and 4584, 4375 and 4585, 4375 and 4586, 4375 and 4587, 4375 and 4588, 4375 and 4589, 4375 and 4590, 4375 and 4591, 4375 and 4592, 4375 and 4593, 4375 and 4594, 4375 and 4595, 4375 and 4596, 4375 and 4597, or 4375 and 4598.More specifically, the target region is located between nucleobase positions 4411 and 4567 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1, more specifically between nucleobase positions 4412 and 4566, 4413 and 4565, 4414 and 4564, or 4415 and 4563, and even more specifically between nucleobase positions 4416 and 4562 of the Syngr-3 mRNA transcript defined in SEQ ID NO:1.

[0202] In more specific embodiments, the target region is defined by SEQ ID NO: 268. In even more specific embodiments, the target region is defined by (or comprises or consists of) SEQ ID NOs: 260, 261, 262, 263, 264, 265, 266, and / or 267. In most specific embodiments, the oligonucleotide (e.g., ASO, siRNA, shRNA) comprises or consists of SEQ ID NOs: 482, 483, 484, 485, 486, 487, 488, and / or 489.

[0203] In a specific embodiment, the oligonucleotide of the present disclosure is complementary (fully or partially complementary) to a target region of synaptogyrin-3 selected from the group consisting of SEQ ID NOs: 66, 97, 126, and 138. In another specific embodiment, the oligonucleotide of the present application comprises or consists of 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 nucleotides in length and comprises or consists of a sequence selected from the list consisting of SEQ ID NOs: 321, 346, 373, and 384, or overlaps with one of said SEQ ID NOs: 321, 346, 373, 384 by at least 12, 13, 14, 15, or 16 nucleotides.

[0204] In a most specific embodiment, the oligonucleotide of the present disclosure is complementary (fully or partially complementary) to a target region of synaptogyrin-3 comprising or consisting of SEQ ID NO: 66. In another most specific embodiment, the oligonucleotide of the present application comprises or consists of SEQ ID NO: 321.

[0205] In another most specific embodiment, the oligonucleotide of the present disclosure is complementary (fully or partially complementary) to a target region of synaptogyrin-3 comprising or consisting of SEQ ID NO: 97. In another most specific embodiment, the oligonucleotide of the present application comprises or consists of SEQ ID NO: 346.

[0206] In another most specific embodiment, the oligonucleotide of the present disclosure is complementary (fully or partially complementary) to a target region of synaptogyrin-3 comprising or consisting of SEQ ID NO: 126. In another most specific embodiment, the oligonucleotide of the present application comprises or consists of SEQ ID NO: 373.

[0207] In a most specific embodiment, the oligonucleotide of the present disclosure is complementary (fully or partially complementary) to a target region of synaptogyrin-3 comprising or consisting of SEQ ID NO: 138. In another most specific embodiment, the oligonucleotide of the present application comprises or consists of SEQ ID NO: 384.

[0208] In some aspects, the present disclosure provides target regions within the human Syngr-3 gene, specifically within the synaptogyrin-3 mRNA transcript set forth in SEQ ID NO: 1, that can be used to design oligonucleotides or RNAi molecules (e.g., ASOs, siRNAs, shRNAs) that can reduce the expression level of synaptogyrin-3 mRNA transcripts in cells, wherein the target region is any of the target regions described above.

[0209] Furthermore, any of the target regions described herein, for example, a target region defined by any of SEQ ID NOs: 2 to 269, a subsequence thereof, or a subsequence of the synaptogyrin-3 mRNA transcript defined by SEQ ID NO: 1 that includes or overlaps with a target region defined by any of SEQ ID NOs: 2 to 269, are provided for designing antisense or RNAi molecules, more specifically siRNA, di-siRNA, or shRNA duplexes, that can statistically significantly reduce the expression level of the synaptogyrin-3 mRNA transcript described by SEQ ID NO: 1, the synaptogyrin-3 protein level, the synaptogyrin-3 activity level, or any combination thereof in cells.

[0210] Antisense oligonucleotides (ASO): In some aspects, the oligonucleotides of the present disclosure are ASOs. Thus, in some aspects, the oligonucleotides of the present disclosure include antisense oligonucleotides (ASOs), such as unconjugated or conjugated ASOs. Antisense oligonucleotides or ASOs are small (generally between about 16 and about 30 nucleotides, or shorter, for example, between about 12 and about 20 nucleotides) synthetic single-stranded nucleic acid polymers of various chemistries, which can be used to regulate gene expression through various mechanisms. ASOs can be subdivided into two major categories: RNase H reactive and steric block ASOs. In some aspects, the oligonucleotides of the present disclosure are RNase H reactive. In some aspects, the oligonucleotides of the present disclosure are steric block ASOs. In some aspects, the oligonucleotides of the present disclosure are gapmers. Gapmer designs are disclosed, for example, in WO 2007 / 146511A2, the entire contents of which are incorporated herein by reference.

[0211] ASOs can also regulate gene expression through steric hindrance or occupancy alone. Steric block oligonucleotides are designed to bind to target transcripts with high affinity but lack RNase H reactivity and therefore do not induce target transcript degradation. Thus, such oligonucleotides contain either nucleotides that do not form RNase H substrates when paired with RNA, or a mixture of nucleotide chemistries that avoids stretches of consecutive DNA-like bases. Steric block oligonucleotides can mask specific sequences within target transcripts, thereby interfering with transcript RNA-RNA and / or RNA-protein interactions. The most widely used application of steric block ASOs is in modulating alternative splicing to selectively exclude or retain specific exon(s) to disrupt target gene translation. ASOs can also be designed to interfere with the maturation and stability of RNA transcripts or block their interaction with the translational apparatus.

[0212] In cases where ASOs can enter the nucleus, mRNA maturation can be regulated by inhibiting 5'-capping, inhibiting mRNA splicing, or activating RNase H (Chan et al 2006 Clin Exp Pharmacol Physiol 33:533-540; this reference also describes some of the software available to assist in ASO design).

[0213] In some aspects, the ASO comprises an antisense oligomer of 12 to 22 contiguous nucleotides in length, wherein the sequence of the antisense oligomer is selected from the group consisting of SEQ ID NOS: 2-9, 11, 13-19, 21-24, 26-28, 32, 34-49, 51-52, 54-57, 60-61, 63-68, 70-78, 80-83, 85-86, 88-90, 90-91, 91-92, 92-93, 93-94, 94-95, 95-96, 96-97, 97-98, 98-99, 99-100, 101-102, 103-104, 105-106, 107-108, 108-109, 109-110, 110-111, 112-113, 114-115, 115-116, 116-117, 117-118, 118-119, 120-121, 122-123, 123-124, 124-125, 125-126, 126-127, 127-128, 128-129, 130-131, 131-132, 132-133, 133-134, 134-135, 135-136, 136-137, 137-138, 138-139, 140-141, 142-143, 1 2-93, 95-109, 112-134, 136-139, 142-169, 171, 173-178, 180, 182-183, 185-187, 189-192, 195-209, 211-215, 217-219, 222-223, 225-226, 228, 230, 232-234, 236-240, 242-245, 247, 249, 251-252 58, and 260-267, or from the group consisting of SEQ ID NOs: 10, 12, 20, 25, 29-31, 33, 50, 53, 58-59, 62, 69, 79, 84, 87, 91, 94, 110-111, 135, 140-141, 170, 172, 179, 181, 184, 188, 193-194, 210, 216, 220-221, 224, 227, 229, The antisense oligomer comprises a contiguous sequence of 12 to 22 (e.g., 16) nucleotides in length that is 100% complementary to a sequence or subsequence of a synaptogyrin-3 target sequence selected from the group consisting of 231, 235, 241, 246, 248, 250, 259, 268, and 269, wherein the antisense oligomer targets an RNA encoding synaptogyrin-3.

[0214] In some aspects, the ASO comprises an antisense oligomer of 10-16 contiguous nucleotides in length, wherein the sequence of the antisense oligomer is selected from the group consisting of SEQ ID NOs: 2-9, 11, 13-19, 21-24, 26-28, 32, 34-49, 51-52, 54-57, 60-61, 63-68, 70-78, 80-83, 85-86, 88-90, and the like. , 92-93, 95-109, 112-134, 136-139, 142-169, 171, 173-178, 180, 182-183, 185-187, 189-192, 195-209, 211-215, 217-219, 222-223, 225-226, 228, 230, 232-234, 236-240, 242-245, 247, 249, 2 51 to 258, and 260 to 267, or SEQ ID NOs: 10, 12, 20, 25, 29 to 31, 33, 50, 53, 58 to 59, 62, 69, 79, 84, 87, 91, 94, 110 to 111, 135, 140 to 141, 170, 172, 179, 181, 184, 188, 193 to 194, 210, 216, 220 to 221, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 2 and a contiguous sequence of 10 to 25 nucleotides in length that is 100% complementary to a sequence or subsequence of a synaptogyrin-3 target sequence selected from the group consisting of: 7, 229, 231, 235, 241, 246, 248, 250, 259, 268, and 269, wherein the antisense oligomer targets an RNA encoding synaptogyrin-3.

[0215] In some aspects, the ASO comprises an antisense oligomer 10-16 contiguous nucleotides in length, wherein the antisense oligomer is at least 90%, at least 95%, or 100% identical to a subsequence of any of SEQ ID NOs: 270-489. In some aspects, the ASO is a gapmer. In some aspects, the ASO is conjugated to a targeting moiety, e.g., a GalNAc moiety.

[0216] Gapmer: In specific embodiments, the antisense oligonucleotide or its contiguous nucleotide sequence of the present invention is a gapmer. A gapmer or gapmer oligonucleotide comprises at least three distinct structural regions: a 5' flank, a gap, and a 3' flank, or FG-F', in a 5->3' orientation. The "gap" region (G) comprises a stretch of contiguous DNA nucleotides that allows the oligonucleotide to recruit RNase H. The gap region is flanked by a 5' flanking region (F) containing one or more sugar-modified nucleosides and a 3' flanking region (F') containing one or more sugar-modified nucleosides. One or more sugar-modified nucleosides in regions F and F' enhance the affinity of the oligonucleotide for the target nucleic acid (i.e., are affinity-enhancing sugar-modified nucleosides). In some embodiments, one or more sugar-modified nucleosides in regions F and F' are 2' sugar-modified nucleosides independently selected from, for example, LNA and 2'-MOE.

[0217] In gapmer design, the 5'- and 3'-most nucleosides of the gap region are DNA nucleosides, located adjacent to sugar-modified nucleosides in the 5' (F) or 3' (F') regions, respectively. Flanks can be further defined by having at least one sugar-modified nucleoside at the end furthest from the gap region, i.e., at the 5' end of the 5' flank and at the 3' end of the 3' flank. The region FG-F' forms a contiguous nucleotide sequence. The antisense oligonucleotide of the present invention, or a contiguous nucleotide sequence thereof, can comprise a gapmer region of the formula FG-F'.

[0218] Regions F and F' independently comprise 1 to 8 consecutive nucleosides, 1 to 5 of which may be independently 2'-sugar modified, and define the 5' and 3' ends of the F and F' regions. Region F is located immediately adjacent to the 5' DNA nucleoside of region G. In one embodiment, the 3'-most nucleoside of region F is a sugar-modified nucleoside, e.g., a 2'-substituted nucleoside, e.g., an MOE nucleoside or an LNA nucleoside. Region F' is located immediately adjacent to the 3' DNA nucleoside of region G. In one embodiment, the 5'-most nucleoside of region F' is a sugar-modified nucleoside, e.g., a 2'-substituted nucleoside, e.g., an MOE nucleoside or an LNA nucleoside.

[0219] In one embodiment, region F is between 1 and 8 contiguous nucleotides in length, e.g., 2 to 6, e.g., 3 to 4 contiguous nucleotides in length. In a specific embodiment, the 5'-most nucleoside of region F is a sugar-modified nucleoside. In some embodiments, the two 5'-most nucleosides of region F are sugar-modified nucleosides. In some embodiments, the 5'-most nucleosides of region F are LNA nucleosides. In some embodiments, the two 5'-most nucleosides of region F are LNA nucleosides. In some embodiments, the two 5'-most nucleosides of region F are 2'-substituted nucleosides, such as two 3'MOE nucleosides. In some embodiments, the 5'-most nucleoside of region F is a 2'-substituted nucleoside, such as an MOE nucleoside.

[0220] In one embodiment, region F' is between 2 and 8 contiguous nucleotides in length, e.g., 3 to 6, e.g., 4 to 5 contiguous nucleotides in length. Specifically, embodiments provide that the 3'-most nucleosides of region F' are sugar-modified nucleosides. In some embodiments, the two 3'-most nucleosides of region F' are sugar-modified nucleosides. In some embodiments, the two 3'-most nucleosides of region F' are LNA nucleosides. In some embodiments, the 3'-most nucleosides of region F' are LNA nucleosides. In some embodiments, the two 3'-most nucleosides of region F' are 2'-substituted nucleosides, such as two 3' MOE nucleosides. In some embodiments, the 3'-most nucleosides of region F' are 2'-substituted nucleosides, such as MOE nucleosides.

[0221] It should be noted that when the length of region F or F' is 1, it is preferably an LNA nucleoside.

[0222] In some embodiments, regions F and F' independently consist of or comprise a contiguous sequence of sugar-modified nucleosides. In some embodiments, the sugar-modified nucleosides of region F can be independently selected from 2'-O-alkyl-RNA units, 2'-O-methyl-RNA, 2'-amino-DNA units, 2'-fluoro-DNA units, 2'-alkoxy-RNA, MOE units, LNA units, arabinonucleic acid (ANA) units, and 2'-fluoro-ANA units. In some embodiments, regions F and F' independently comprise both LNA and 2'-substituted modified nucleosides. In some embodiments, regions F and F' consist of only one type of sugar-modified nucleoside, for example, only MOE, or only beta-D-oxyLNA, or only ScET. Such designs are also referred to as uniform flank or uniform gapmer designs.

[0223] In some embodiments, all nucleosides in regions F or F', or F and F', are LNA nucleosides, e.g., independently selected from beta-D-oxyLNA, ENA, or ScET nucleosides. In some embodiments, region F consists of 1 to 5, e.g., 2 to 4, e.g., 3 to 4, e.g., 1, 2, 3, 4, or 5 consecutive LNA nucleosides. In some embodiments, all nucleosides in regions F and F' are LNA nucleosides or beta-D-oxyLNA nucleosides.

[0224] In some embodiments, all nucleosides in regions F or F', or F and F', are 2'-substituted nucleosides, such as OMe or MOE nucleosides. In some embodiments, region F consists of 1, 2, 3, 4, 5, 6, 7, or 8 consecutive OMe or MOE nucleosides. In some embodiments, only one of the flanking regions can consist of a 2'-substituted nucleoside, such as an OMe or MOE nucleoside. In some embodiments, it is the 5' (F) flanking region that consists of a 2'-substituted nucleoside, such as an OMe or MOE nucleoside, and the 3' (F') flanking region comprises at least one LNA nucleoside, such as a beta-D-oxyLNA nucleoside or a cET nucleoside. In some embodiments, it is the 3' (F') flanking region that consists of 2' substituted nucleosides, such as OMe or MOE nucleosides, and the 5' (F) flanking region comprises at least one LNA nucleoside, such as a beta-D-oxyLNA nucleoside or a cET nucleoside.

[0225] In some embodiments, the 5'-most and 3'-most nucleosides of regions F and F' are LNA nucleosides, such as beta-D-oxyLNA nucleosides or ScET nucleosides.

[0226] Region G comprises or consists of between 5 and 18 nucleosides capable of recruiting RNase H. Preferably, the gapmer may have a gap region of at least 5 or 6 consecutive DNA nucleosides in length, e.g., 5 to 16 consecutive DNA nucleosides, e.g., 6 to 15 consecutive DNA nucleosides, e.g., 7 to 14 consecutive DNA nucleosides, e.g., 8 to 12 consecutive DNA nucleotides, e.g., 8 to 12 consecutive DNA nucleotides. Gap region G may, in some embodiments, consist of 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 consecutive DNA nucleosides. One or more cytosine (C) DNA residues in the gap region may be methylated in some cases (e.g., when DNA c is followed by DNA g). Both such residues are annotated as 5-methyl-cytosine (meC). In some embodiments, the gap region G can consist of 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 consecutive phosphorothioate-linked DNA nucleosides. In some embodiments, all internucleoside linkages across the gap are phosphorothioate linkages.

[0227] The overall length of the gapmer design FG-F' can be, for example, 12 to 32 nucleosides, such as 13 to 24, such as 14 to 22 nucleosides, such as 14 to 17, such as 16 to 18 nucleosides.

[0228] In some embodiments, the internucleoside linkage between region F and region G is a phosphorothioate internucleoside linkage. In some embodiments, the internucleoside linkage between region F' and region G is a phosphorothioate internucleoside linkage. In some embodiments, the internucleoside linkage between the nucleosides of regions F or F', F and F' is a phosphorothioate internucleoside linkage.

[0229] In some embodiments, gapmers of the invention are LNA gapmers. An LNA gapmer is a gapmer in which either one or both of regions F and F' comprise or consist of LNA nucleosides. A beta-D-oxy gapmer is a gapmer in which either one or both of regions F and F' comprise or consist of beta-D-oxy LNA nucleosides.

[0230] In other embodiments, the gapmer of the present invention is an MOE gapmer. An MOE gapmer is a gapmer in which regions F and F' consist of MOE nucleosides. In some embodiments, the MOE gapmer has the design [MOE]1-8-[region G]-[MOE]1-8, e.g., [MOE]2-7-[region G]5-16-[MOE]2-7, e.g., [MOE]3-6-[region G]-[MOE]3-6, where region G is as defined in the gapmer definition. MOE gapmers with the 5-10-5 design (MOE-DNA-MOE) are widely used in the art.

[0231] In specific embodiments, gapmers of the invention may also contain regions D' and / or D" which refer to additional 5' and / or 3' nucleosides which may or may not be perfectly complementary to the target nucleic acid. The addition of region D' or D" can be used for the purpose of joining a contiguous nucleotide sequence, such as a gapmer, to a conjugate moiety or another functional group. When used to join a conjugate moiety to a conjugate moiety, it can serve as a biologically cleavable linker. Alternatively, it can be used to provide exonuclease protection or for ease of synthesis or manufacturing. Regions D' and D" can be attached to the 5' end of region F or the 3' end of region F', respectively, to generate designs of the following formula D'-FG-F', FG-F'-D" or D'-FG-F'-D" where FG-F' is the gapmer portion of the oligonucleotide and region D' or D" constitutes a separate part of the oligonucleotide.

[0232] Region D' or D" can independently comprise or consist of 1, 2, 3, 4, or 5 additional nucleotides, which can be complementary or non-complementary to the target nucleic acid. The nucleotides adjacent to the F or F' region are not sugar-modified nucleotides, e.g., DNA or RNA, or base-modified versions thereof. The D' or D' region can serve as a nuclease-sensitive biologically cleavable linker (see definition of linker). In some embodiments, the additional 5' and / or 3' terminal nucleotides are linked by phosphodiester linkages and are DNA or RNA.

[0233] RNAi using double-stranded silencer: In some aspects, the oligonucleotide of the present disclosure is an RNAi molecule, specifically an RNAi duplex or double-stranded RNAi oligonucleotide, more specifically the antisense part or antisense strand of an RNAi duplex (double-stranded RNA).In some aspects, the oligonucleotide of the present disclosure comprises an RNAi molecule, more specifically an siRNA, for example, unconjugated or conjugated siRNA.RNA interference (RNAi) is a mechanism by which double-stranded RNA induces the loss of homologous RNA molecules.Small interfering RNA (siRNA) molecules are the effector molecules of RNAi, and are classically composed of an RNA duplex (or alternatively referred to as the double strand of an RNA molecule) with a length of 21 nucleotides, i.e., 19 complementary bases and two terminal 3' overhangs.One strand of siRNA (guide or antisense strand) is complementary to target transcript, and the other strand is designated as passenger or sense strand. As part of the RNA-induced silencing complex (RISC), siRNAs act to guide the Argonaute 2 protein (AGO2) to complementary target transcripts. Perfect complementarity between the siRNA and the target transcript results in cleavage of the guide strand at the opposite position of the target, catalyzed by AGO2, leading to gene silencing.

[0234] In siRNA, the sense strand fulfills the formal definition of a drug delivery device: it is non-covalently bound, enhances the stability of the antisense strand, and must be removed by the Ago2-loaded complex before the antisense strand of the pharmacophore becomes active.

[0235] Numerous variations of the prototypical siRNA designs have been developed with the aim of reduced passenger strand activity and / or improved potency, including Dicer substrate siRNAs, small internally segmented siRNAs, self-delivering siRNAs (asymmetric and hydrophobic), single-stranded siRNAs, and bivalent siRNAs.

[0236] In some aspects, the oligonucleotide of the present disclosure is the antisense part of shRNA.Short hairpin RNA (shRNA) is an artificial RNA molecule that is transcribed as single-stranded RNA, but forms a loop or hairpin-like structure due to internal complementarity.The hairpin is then processed into siRNA, and leads to the degradation of mRNA in a sequence-specific manner that depends on the complementary binding of target mRNA.shRNA is slightly larger than siRNA molecules, and unlike siRNA, it is produced in the nucleus within cells.

[0237] Other non-limiting examples of double-stranded silencers mediated by RNAi are miRNAs and di-siRNAs. MicroRNAs (miRNAs) are endogenous non-coding RNA molecules that trigger RNAi and are involved in numerous physiological and pathophysiological processes. The miRNA hairpin embedded within a long primary miRNA transcript is sequentially processed by two RNase III family enzymes, DICER1 (Dicer) and DROSHA, which release the hairpin and cleave the loop sequence, respectively. The resulting double-stranded RNA, similar to siRNA, is then loaded onto an Argonaute protein (e.g., AGO2), and one strand is discarded to generate a mature single-stranded miRNA species. Like siRNAs, miRNAs guide RISC to target sequences where they initiate gene silencing. In contrast to siRNAs, miRNAs typically bind via partial complementarity and induce silencing via a Dicer-independent mechanism.

[0238] In some aspects, the oligonucleotide of the present disclosure is di-siRNA. Bivalent siRNA (di-siRNA) is a recently developed alternative to RNA silencing drugs, and has been shown to support high-potency and sustained gene silencing in the central nervous system of mice and non-human primates after a single injection into cerebrospinal fluid (Alterman et al. 2019 Nature Biotech 37, 884-894). Di-siRNA is composed of two fully chemically modified phosphorothioate-containing siRNAs connected by a linker.

[0239] In some aspects, the siRNA of the present disclosure comprises an antisense strand of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 consecutive nucleotides in length, wherein the sequence of the antisense strand is set forth in SEQ ID NOs: 2-9, 11, 13-19, 21-24, 26-28, 32, 34-49, 51-52, 54-57, 60-65, 61-62, 62-63, 63-64, 64-65, 65-66, 66-67, 67-68, 68-69, 69-70, 71-72, 73-74, 75-76, 77-78, 78-79, 79-80, 81-82, 83-84, 85-86, 87-88, 89-90, 91-92, 93-94, 95-96, 96-97, 97-98, 98-99, 99-100, 100-101, 102-103, 104-105, 105-106, 106-107, 107-108, 108-109, 110-111, 112-113, 114-115, 116-117, 118-119, 119-120, 120-121, 1, 63-68, 70-78, 80-83, 85-86, 88-90, 92-93, 95-109, 112-134, 136-139, 142-169, 171, 173-178, 180, 182-183, 185-187, 189-192, 195-209, 211-215, 217-219, 222-223, 225-226, 228, 230, 232-234, 236-240, 242-245, 247, 249, 251 to 258, and 260 to 267, or from the group consisting of SEQ ID NOs: 10, 12, 20, 25, 29 to 31, 33, 50, 53, 58 to 59, 62, 69, 79, 84, 87, 91, 94, 110 to 111, 135, 140 to 141, 170, 172, 179, 181, 184, 188, 193 to 194, 210, 216, 220 to 221, 224, 227, 229, 231, 235, 241, 246, 248, 25 The siRNA comprises a contiguous sequence of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length that is 100% complementary to a sequence or subsequence of a synaptogyrin-3 target sequence selected from the group consisting of 0, 259, 268, and 269, wherein the siRNA targets an RNA encoding synaptogyrin-3. In some aspects, the siRNA of the present disclosure is conjugated to a targeting moiety, such as a GalNAc moiety.

[0240] CRISPR gRNA: Another recent genome editing technology is the CRISPR / Cas system, which can be used to achieve RNA-guided genome engineering. CRISPR interference is a genetic technique that allows sequence-specific control of gene expression in prokaryotic and eukaryotic cells. It is based on the CRISPR (clustered regularly interspaced palindromic repeats) pathway, derived from the bacterial immune system. Recently, it has been demonstrated that the CRISPR-Cas editing system can also be used to target RNA. It has been shown that the class 2 type VI-A CRISPR-Cas effector C2c2 can be programmed to cleave single-stranded RNA targets bearing a complementary protospacer (Abudayyeh et al., 2016, Science 353 / science.aaf5573). C2c2 is a single-effector endoRNase that mediates ssRNA cleavage once it is guided toward the target RNA by a single crRNA guide. Therefore, the invention disclosed herein can also be applied to develop gRNA that specifically reduces the expression of synaptogyrin-3 using CRISPR / Cas system.Therefore, the present application also provides that any of the oligonucleotides provided herein can be used as gRNA or CRISPR gRNA.More specifically, there is provided gRNA or CRISPR gRNA that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or about 100% complementarity with the same length of the target region of synaptogyrin-3 described in SEQ ID NO: 1, wherein the target region is selected from the target region of the present application or any of its subsequences.

[0241] In some aspects, a gRNA or CRISPR gRNA provided herein has at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100% complementarity to an equal length of a target region of synaptogyrin-3 set forth in SEQ ID NO:1, wherein the target region is between nucleobase positions 449 and 531, 549 and 653, 640 and 733, 720 and 875, 915 and 1108, 1197 and 1271, 1258 and 1344, 1332 and 1450, 1451 and 1452 of SEQ ID NO:1. The amino acid sequence may be located between or be a subsequence of 0 and 1527, 1515 and 1600, 1580 and 1700, 1680 and 1837, 1824 and 1885, 1850 and 2100, 2100 and 2250, 2308 and 2428, 2416 and 2441, 2428 and 2625, 2649 and 2796, 2962 and 3086, 3153 and 3460, 3450 and 3530, 3508 and 3551, 3538 and 3636, or 3626 and 4599, wherein the endpoints are inclusive.

[0242] In some aspects, the gRNA or CRISPR provided herein The gRNA has at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100% complementarity to an equivalent length of the target region of synaptogyrin-3 set forth in SEQ ID NO: 1, wherein the target region is set forth in SEQ ID NOs: 10, 12, 20, 25, 29-31, 33, 50, 53, 58-59, 62, 69, 79, 84, 87, 91, 94, 110-111, 135, 140-141, 170, 172, 179, 181, 184, 188, 193-194, 210, 216, 220-221, 224, 227, 229, 231, 235, 241, 246, 248, 250, 259, 268, or 269. 69, more specifically, the target region is selected from SEQ ID NOs: 2 to 9, 11, 13 to 19, 21 to 24, 26 to 28, 32, 34 to 49, 51 to 52, 54 to 57, 60 to 61, 63 to 68, 70 to 78, 80 to 83, 85 to 86, 88 to 90, 92 to 93, 95 to 109, 112 to 134, 136 to 139, 142 to 169, Selected from any of 171, 173-178, 180, 182-183, 185-187, 189-192, 195-209, 211-215, 217-219, 222-223, 225-226, 228, 230, 232-234, 236-240, 242-245, 247, 249, 251-258, or 260-267.

[0243] In some aspects, the gRNA is selected from the group consisting of SEQ ID NOs: 2-9, 11, 13-19, 21-24, 26-28, 32, 34-49, 51-52, 54-57, 60-61, 63-68, 70-78, 80-83, 85-86, 88-90, 92-93, 95-109, 112-134, 136-139, 142-169, 171, 173-178, 180, 182-183, 185-187, 189-192, 195-209, 211-215, 217-219, 222-223, 225-226, 228, 230, 232-234, 236-240, 242-245, 247, 249, 251-258, or 260-267. In some aspects, the gRNA comprises or consists of a sequence comprising a subsequence selected from the target region defined by SEQ ID NO: 10, 12, 20, 25, 29-31, 33, 50, 53, 58-59, 62, 69, 79, 84, 87, 91, 94, 110-111, 135, 140-141, 170, 172, 179, 181, 184, 188, 193-194, 210, 216, 220-221, 224, 227, 229, 231, 235, 241, 246, 248, 250, 259, 268, or 269.

[0244] In specific embodiments, the gRNA is 10 to 50, 10 to 40, or 10 to 30 nucleotides in length, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 nucleotides in length.

[0245] In another specific embodiment, the gRNA comprises a contiguous nucleotide sequence of at least 10 contiguous nucleotides in length comprising a sequence selected from the group consisting of SEQ ID NOs: 270-489.

[0246] In yet another specific embodiment, a gRNA of the present disclosure comprises a sequence that overlaps with a 9, 10, 11, 12, 13, 14, 15, or 16 nucleobase subsequence from a sequence selected from the group consisting of SEQ ID NOs: 270-489. chemical modification

[0247] In some aspects, the oligonucleotides of the present disclosure comprise non-naturally occurring nucleotide analogs, such as nucleotides with modified sugar moieties, e.g., bicyclic nucleotides or 2'-modified nucleotides, e.g., 2'-substituted nucleotides. An essential step in the evolution of antisense technology has been the creation, innovation, and evaluation of oligonucleotide medicinal chemistry. The goals have been to enhance affinity for target sequences (thereby increasing potency), ensure effective distribution to peripheral tissues, enhance duration of action by increasing resistance to nuclease degradation, improve pharmacokinetic characteristics, reduce class-specific (chemically based) toxicity of chemical classes commonly used in therapeutic drugs, and create designs that support multiple post-binding mechanisms, thereby broadening the utility of the technology.

[0248] Within the field of antisense technology, extensive work has been initiated to modify essentially every position on a dinucleotide, with the exception of those required for Watson-Crick base pairing. Thousands of analogs have been synthesized and evaluated to date, and new analogs continue to be explored. Three major classes of modifications can be distinguished: modification of the internucleotide linkage, modulation of the ribose sugar, and bioconjugation, for example with GalNAc. phosphorothioate

[0249] In some aspects, the oligonucleotide of the present disclosure comprises one or more non-cleavable internucleotide linkages, for example, phosphorothioate linkages.The phosphodiester backbone of unmodified DNA and RNA oligonucleotides is highly susceptible to degradation by nuclease in vivo.Therefore, in order to develop the oligonucleotide for therapeutic drug application, it is necessary to identify the backbone modification that reduces their susceptibility to nuclease degradation, but does not too much damage other key characteristics, such as RNase H1 activation and RNA binding.

[0250] In phosphorothioate (PS) linkages, the non-bridging oxygen on the phosphate group is replaced by sulfur. PS moieties provide significant protection from nucleases. Importantly, due to the greater size impact of sulfur compared to oxygen, the negative charge of PS moieties at physiological pH is more widely distributed than that of phosphodiester (PO) moieties. This increases the lipophilicity of oligonucleotides containing PS moieties, facilitating protein binding, thereby preventing rapid excretion of oligonucleotides by the kidney and facilitating their uptake into cells and tissues. PS moieties are the most widely used backbone modification in RNAi molecules such as ASOs and siRNAs. Ribose sugar modification

[0251] In some aspects, the oligonucleotides of the present disclosure include non-naturally occurring nucleotide analogs, such as nucleotides with modified sugar moieties, such as bicyclic nucleotides or 2'-modified nucleotides, e.g., 2'-substituted nucleotides. Oligonucleotides are frequently modified at the ribose sugar, primarily to improve properties such as affinity and / or nuclease resistance. Such modifications include those in which the ribose ring structure is modified (e.g., locked nucleic acids or LNAs), those in which the sugar moiety is replaced with a non-sugar moiety (e.g., peptide nucleic acids or PNAs), or those in which the substituents on the ribose ring are altered to groups other than hydrogen or the 2' and OH groups naturally found on DNA and RNA nucleosides.

[0252] Non-limiting examples of ring structure modifications include HNA (hexitol nucleic acid), in which the ribose ring is replaced by a hexose ring; UNA (unlocked nucleic acid), in which the unlinked ribose ring lacks a bond between the C2 and C3 carbons; or locked nucleic acid (LNA), in which the C2' and C4' of the ribose sugar ring are linked by a methylene bridge (also referred to as a "2'-4' bridge"), which restricts or locks the conformation of the ribose ring. Locking the ribose conformation (also referred to as bridged nucleic acid or BNA) is associated with enhanced hybridization affinity (duplex stabilization) when LNA is incorporated into the oligonucleotide of a complementary RNA or DNA molecule. Non-limiting examples of LNA nucleosides include beta-D-oxy-LNA, 6'-methyl-beta-D-oxy-LNA, such as (S)-6'-methyl-beta-D-oxy-LNA (ScET), and 2'-O,4'-C-ethylene bridged nucleic acids (ENA), or the nucleic acids described in WO 1999 / 014226, WO 2000 / 66604, WO 1998 / 039352, WO 2004 / 046160, WO 2000 / 047599, WO 2007 / 134181, WO 2010 / 077578, WO 2010 / 036698, WO 2007 / 090071, WO 2009 / 006478, WO 2011 / 156202, WO 2008 / 154401, WO 2009 / 067647, and WO 2008 / 150729, all of which are incorporated herein by reference in their entirety.

[0253] Because BNA modifications enhance both nuclease stability and the affinity of oligonucleotides for target RNA, they have been incorporated into the flanking regions of gapmers to improve target binding. Thus, cET-flanked 3-10-3 gapmers are more potent than MOE 5-10-5 equivalents. Importantly, BNAs are excluded from DNA gap regions because they are not compatible with RNase H-mediated cleavage. LNA modifications have also been utilized in steric-blocking ASOs, such as miRNA inhibitors.

[0254] Non-limiting examples of 2'-substituted modified nucleosides include 2'-O-alkyl-RNA, 2'-O-methyl-RNA (2'-OMe), 2'-alkoxy-RNA, 2'-O-methoxyethyl-RNA (MOE), 2'-amino-DNA, 2'-fluoro-RNA (2'-F), and 2'-F-ANA nucleosides. These modifications increase the nuclease resistance of oligonucleotides by replacing the nucleophilic 2'-hydroxyl group of unmodified RNA, leading to improved stability in plasma, increased tissue half-life, and ultimately prolonged drug efficacy. These modifications also enhance the binding affinity of oligonucleotides to complementary RNA, and some 2' modifications reduce pro-inflammatory effects. 2'-ribose modifications are not compatible with RNase H activity, meaning they are typically used in steric block oligonucleotides or in flanking sequences on gapmer ASOs. Although most work has been done in modifying the 2' position, substituents can also be introduced at the 3', 4', or 5' positions.

[0255] The present disclosure provides oligonucleotides comprising or consisting of a simple sequence of naturally occurring nucleotides, preferably 2'-deoxynucleotides (commonly referred to herein as "DNA"), but possibly also ribonucleotides (commonly referred to herein as "RNA"), or a combination of such naturally occurring nucleotides with one or more non-naturally occurring nucleotides, i.e., "nucleotide analogs," such as nucleotides having the ribose sugar modifications disclosed above.

[0256] In some aspects, an oligonucleotide (e.g., ASO, siRNA, or shRNA) of the present disclosure comprises at least two nucleotide analogs. In some aspects, an oligonucleotide of the present disclosure comprises 3, 4, 5, 6, 7, or 8 nucleotide analogs, for example, 6 or 7 nucleotide analogs. In some aspects, all nucleotide analogs are the same. In some aspects, some nucleotide analogs are different. In some aspects, all nucleotides on an oligonucleotide of the present disclosure are nucleotide analogs, i.e., an oligonucleotide (e.g., ASO, siRNA, or shRNA) of the present disclosure is fully modified. In some aspects, when all nucleotides on an oligonucleotide of the present disclosure are nucleotide analogs, all nucleotide analogs are the same. In some aspects, when all nucleotides on an oligonucleotide of the present disclosure are nucleotide analogs, some of the nucleotide analogs are different. In some aspects, all nucleotides on an oligonucleotide (e.g., ASO, siRNA, or shRNA) of the present disclosure are 2'-modified. In some aspects, all nucleotides on an oligonucleotide (e.g., ASO, siRNA, or shRNA) of the present disclosure are 2'-fluoride and 2'-O-methyl nucleotides. In some aspects, all nucleotides on the oligonucleotides (e.g., ASO, siRNA, or shRNA) of the present disclosure are 2'-fluoride and 2'-O-methyl nucleotides in an alternating pattern.In some aspects, all nucleotides on the double strands (e.g., siRNA or shRNA) of the present disclosure are 2'-fluoride and 2'-O-methyl nucleotides in an alternating pattern, wherein all or substantially all of the 2'-fluoride modified nucleotides on the sense strand are complementary to all or substantially all of the 2'-O-methyl modified nucleotides on the antisense strand.In some aspects, the double stranded oligonucleotides (e.g., siRNA or shRNA) of the present disclosure comprise nucleotide overhangs.In some aspects, the nucleotide overhangs are dinucleotide overhangs.In some aspects, the dinucleotide overhang is on the antisense strand. In some aspects, the dinucleotide overhang is at the 3' end of the antisense strand. In some aspects, the overhang sequence follows the modification pattern (e.g., an alternating pattern) of the rest of the strand. In some aspects, the overhang is complementary to the synaptogyrin-3 mRNA target sequence. In some aspects, the oligonucleotide of the present disclosure has the structure shown in Figure 1 or includes a modification motif defined in Figure 2A or 2B.

[0257] In some aspects, the nucleic acids or oligonucleotides (e.g., ASOs, siRNAs, or shRNAs) of the present disclosure comprise modification motifs (e.g., patterns of distribution of nucleotide analogs, internucleoside linkages, conjugate moieties, etc. along the sense and antisense sequences) disclosed in U.S. Patent Nos. 8,110,674; 8,420,799; 8,809,516; 9,222,091; 9,708,615; 10,273,477; 9,290,760; 10,233,448; or 9,796,974; U.S. Application Publication Nos. 2018 and 0258427A1; or International Publication WO2018098328A1, all of which are incorporated by reference herein in their entireties.

[0258] In some aspects, nucleic acids or oligonucleotides (e.g., ASOs, siRNAs, or shRNAs) of the present disclosure comprise at least one chiral internucleoside linkage. In some aspects, all internucleoside linkages are chiral internucleoside linkages. In some aspects, nucleic acids or oligonucleotides (e.g., ASOs, siRNAs, or shRNAs) of the present disclosure comprise at least one 8-oxo-deoxyadenosine. In some aspects, nucleic acids or oligonucleotides (e.g., ASOs, siRNAs, or shRNAs) of the present disclosure comprise at least one phosphoryl DMI amidate diester internucleoside linkage (PN). In some aspects, nucleic acids or oligonucleotides (e.g., ASOs, siRNAs, or shRNAs) of the present disclosure comprise at least one 8-oxo-deoxyadenosine. In some aspects, nucleic acids or oligonucleotides (e.g., ASOs, siRNAs, or shRNAs) of the present disclosure comprise at least one phosphoramidite internucleoside linkage. In some aspects, the nucleic acids or oligonucleotides (e.g., ASOs, siRNAs, or shRNAs) of the present disclosure comprise at least one phosphoramidate internucleoside linkage. In some aspects, the nucleic acids or oligonucleotides (e.g., ASOs, siRNAs, or shRNAs) of the present disclosure comprise at least one pseudouridine. In some aspects, the nucleic acids or oligonucleotides (e.g., ASOs, siRNAs, or shRNAs) of the present disclosure comprise at least one isouridine. See, e.g., WO2022 / 099159 and WO2021 / 071858, which are incorporated herein by reference in their entireties. In some aspects, the nucleic acids or oligonucleotides (e.g., ASOs, siRNAs, or shRNAs) of the present disclosure comprise at least one glycol nucleic acid (GNA). In some aspects, the nucleic acids or oligonucleotides (e.g., ASOs, siRNAs, or shRNAs) of the present disclosure comprise a loop. In some aspects, the nucleic acids or oligonucleotides (e.g., ASOs, siRNAs, or shRNAs) of the present disclosure comprise a cleavable loop. Conjugation

[0259] In some aspects, the oligonucleotides of the present disclosure are conjugated, for example, GalNAc conjugates. The delivery potential of RNAi molecules such as ASOs and siRNAs can be enhanced through direct covalent conjugation with various moieties that promote cellular uptake, target the drug to specific cells / tissues, or reduce clearance from the circulation. Non-limiting examples include lipids, peptides, aptamers, antibodies, and sugars. Bioconjugates constitute discrete, homogeneous, single-component molecular entities with precise stoichiometry, meaning that high-scale synthesis is relatively simple and their pharmacokinetic properties are well-defined. Furthermore, bioconjugates are typically small, meaning that they generally exhibit favorable biodistribution profiles. For example, conjugating ASOs or siRNAs with the sugar moiety GalNAc results in more efficient delivery to hepatocytes, without a significant shift in distribution to other tissues, resulting in a 15- to 30-fold increase in potency against RNA targets in these cells.

[0260] RNAi molecules such as ASOs and siRNAs can also be loaded into exosomes. Exosomes are heterogeneous lipid bilayer-enclosed vesicles approximately 100 nm in diameter that are generated as a result of the inward budding of multivesicular bodies. Exosomes are thought to be released by all cells into the extracellular space, where they facilitate intercellular communication through the transfer of their complex macromolecular cargo. Exosomes present several advantageous properties in terms of oligonucleotide drug delivery, making their ability to cross biological membranes, such as the blood-brain barrier (BBB), highly relevant for the treatment of CNS disorders. The method of the present application

[0261] In one embodiment, the oligonucleotide(s) of the present invention, such as the RNAi molecule(s) of the present invention, are artificial and / or chemically synthesized and / or typically purified or isolated.Therefore, the present disclosure provides the method for producing the nucleic acid molecule(s) of the present invention or the oligonucleotide(s), comprising chemically synthesizing the nucleic acid molecule(s) of the present invention or the oligonucleotide(s).In some aspects, the method comprises conjugating a delivery moiety, for example, a GalNAc moiety.

[0262] The present disclosure also provides methods for designing or manufacturing oligonucleotides (e.g., ASOs or siRNAs) of the present disclosure that can inhibit human synaptogyrin-3 (hSYNGR3) gene transcripts and / or hSYNGR3 protein expression and / or activity in a cell, tissue, or subject, wherein the oligonucleotides of the present disclosure are complementary (partially or fully complementary) to any of the target regions of the present application described above. In some aspects, the complementary sequence of an oligonucleotide of the present disclosure comprises or consists of a subsequence of a nucleotide sequence set forth in SEQ ID NOs: 10, 12, 20, 25, 29-31, 33, 50, 53, 58-59, 62, 69, 79, 84, 87, 91, 94, 110-111, 135, 140-141, 170, 172, 179, 181, 184, 188, 193-194, 210, 216, 220-221, 224, 227, 229, 231, 235, 241, 246, 248, 250, 259, 268, or 269. In some aspects, the complementary sequence of an oligonucleotide of the present disclosure partially overlaps with a nucleotide sequence set forth in SEQ ID NOs: 270-489. In some aspects, the complementarity is at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% complementary.

[0263] As used herein, the term "manufacturing" refers to chemically synthesizing the oligonucleotides of the present disclosure, for example, using solid-phase synthesis. In some aspects, manufacturing further includes chemically attaching or conjugating a moiety, such as a delivery moiety (e.g., a GalNAc moiety) and / or a targeting moiety.

[0264] The present disclosure also provides a method for producing the oligonucleotide of the present disclosure, the method comprising using continuous solid-phase oligonucleotide synthesis to chemically synthesize the oligonucleotide of the present disclosure.The present disclosure also provides a method for producing the oligonucleotide of the present disclosure that comprises a conjugate moiety, wherein the method comprises covalently attaching a conjugate moiety (for example, at least one non-nucleotide or non-polynucleotide moiety) to the oligonucleotide disclosed herein.In some aspects, the conjugate moiety (for example, a non-nucleotide or non-polynucleotide moiety, for example, a carbohydrate conjugate moiety such as a GalNAc moiety) is attached to the oligonucleotide disclosed herein directly or via a linker located between the oligonucleotide sequence and the conjugate moiety.

[0265] In some aspects, the non-nucleotide or non-polynucleotide moiety is a liver-targeting moiety attached to the 5' or 3' end of the oligonucleotide disclosed herein. In some aspects, the liver-targeting moiety is linked to the oligonucleotide via a linker. In some aspects, the liver-targeting moiety comprises a carbohydrate-conjugate moiety comprising a carbohydrate selected from the group consisting of galactose, lactose, N-acetylgalactosamine (GalNAc), mannose, mannose-6-phosphate, and combinations thereof. In some aspects, the carbohydrate-conjugate moiety is not a linear carbohydrate polymer. In some aspects, the carbohydrate-conjugate moiety is a carbohydrate group comprising 1, 2, 3, or 4 carbohydrate moieties. In some aspects, all carbohydrate moieties are identical. In some aspects, at least one carbohydrate moiety is different (non-identical) from the other carbohydrate moieties. In some aspects, the carbohydrate-conjugate moiety comprises at least one asialoglycoprotein receptor-targeting conjugate moiety. In some aspects, the asialoglycoprotein receptor-targeting conjugate moiety comprises a monovalent, divalent, trivalent, or tetravalent GalNAc cluster. In some aspects, each GalNAc in the GalNAc cluster is attached to the branch point group via a spacer. In some aspects, the branch point group comprises a dilysine. In some aspects, the spacer comprises a PEG spacer. In some aspects, the linker comprises a C6-C12 aminoalkyl group or a biologically cleavable phosphate nucleotide linker comprising between 1 and 6 nucleotides.

[0266] In some aspects, covalently attaching a conjugate moiety (e.g., a non-nucleotide or non-polynucleotide moiety such as a GalNAc moiety) to an oligonucleotide comprises: (i) chemically synthesizing the oligonucleotide; and (ii) adding a conjugate moiety to the oligonucleotide by chemical synthesis or conjugation to produce an oligonucleotide conjugate. In some aspects, adding a conjugate moiety (e.g., a non-nucleotide or non-polynucleotide moiety, such as a GalNAc moiety) to an oligonucleotide by chemical synthesis or conjugation to produce an oligonucleotide conjugate includes: (i) incorporating at least one conjugate moiety (e.g., a non-nucleotide or non-polynucleotide moiety, such as a GalNAc moiety) into the oligonucleotide by chemical synthesis or conjugation; (ii) incorporating at least one linker into the oligonucleotide or conjugate moiety (e.g., a non-nucleotide or non-polynucleotide moiety, such as a GalNAc moiety) by chemical synthesis or conjugation; (iii) incorporating at least one branch point into the oligonucleotide or conjugate moiety (e.g., a non-nucleotide or non-polynucleotide moiety, such as a GalNAc moiety) by chemical synthesis or conjugation; (iv) incorporating at least one spacer into the oligonucleotide or conjugate moiety (e.g., a non-nucleotide or non-polynucleotide moiety, such as a GalNAc moiety) by chemical synthesis or conjugation; or (v) combinations thereof.In some aspects, (i) at least one linker is inserted between the oligonucleotide and the branch point; (ii) at least one branch point is inserted between the linker and the conjugate moiety (e.g., a non-nucleotide or non-polynucleotide moiety, such as a GalNAc moiety); (iii) at least one, two, or three conjugate moieties (e.g., a non-nucleotide or non-polynucleotide moiety, such as a GalNAc moiety) are attached to the branch point; (iv) at least one polymer spacer (e.g., a PEG spacer) is inserted between the conjugate moiety (e.g., a non-nucleotide or non-polynucleotide moiety, such as a GalNAc moiety) and the branch point; or (v) any combination thereof. Pharmaceutical salts

[0267] The nucleic acid molecules or oligonucleotides according to the present invention can exist in the form of their pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to conventional acid addition salts or base addition salts formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases that retain the biological effectiveness and properties of the nucleic acid molecules or oligonucleotides of the present invention. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid, as well as those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. Base addition salts include those derived from ammonium, potassium, sodium, and quaternary ammonium hydroxides, such as tetramethylammonium hydroxide. Chemical conversion of pharmaceutical compounds into salts is a well-known technique for medicinal chemists to improve the physical and chemical stability, hygroscopicity, flowability, and solubility of compounds. It is described, for example, by Bastin (2000 Organic Process Research & Development 4:427-435) or Ansel (1995 In: Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th ed., pp.196 and 1456-1457).For example, the pharmaceutically acceptable salt of the nucleic acid molecule or oligonucleotide provided herein can be sodium salt.Provided herein is the pharmaceutically acceptable salt of the nucleic acid molecule or oligonucleotide described herein.In one embodiment, the pharmaceutically acceptable salt is sodium or potassium salt. Pharmaceutical Composition

[0268] In another aspect, the present invention provides pharmaceutical compositions comprising any of the nucleic acid molecules or oligonucleotides or salts thereof described herein and a pharmaceutically acceptable diluent, carrier, salt, and / or adjuvant. Pharmaceutically acceptable diluents include phosphate-buffered saline (PBS), and pharmaceutically acceptable salts include, but are not limited to, sodium and potassium salts. In some embodiments, the pharmaceutically acceptable diluent is sterile phosphate-buffered saline. In some embodiments, the nucleic acid molecules or oligonucleotides of the present application are used in a 50-300 mM solution in a pharmaceutically acceptable diluent.

[0269] Suitable formulations for use in the present invention can be found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa., 17th ed., 1985. For a brief review of methods for drug delivery, see, e.g., Langer (1990 Science 249:1527-1533). Non-limiting examples of pharmaceutically acceptable diluents, carriers, adjuvants, suitable dosages, formulations, administration routes, compositions, dosage forms, combinations with other therapeutic agents, and prodrug formulations are provided in WO2007 / 031091. The nucleic acid molecules or oligonucleotides of the present application or their salts can be mixed with pharmaceutically acceptable active or inactive substances to prepare pharmaceutical compositions or formulations. The composition and method for formulating pharmaceutical compositions depend on several criteria, including, but not limited to, the route of administration, the extent of the disease, or the dose to be administered. Pharmaceutical compositions containing the nucleic acid molecules or oligonucleotides of the present application or their salts can be sterilized by conventional sterilization techniques or can be sterile filtered. The resulting aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.

[0270] The pH of the preparation will typically be between 3 and 11, more particularly between 5 and 9 or between 6 and 8, most particularly between 7 and 8, e.g., 7 to 7.5. The resulting solid form of the composition can be packaged in a sealed package of multiple single-dose units, each containing a fixed amount of the nucleic acid molecule or oligonucleotide of the present application or a salt thereof, for example, tablets or capsules. The solid form of the composition can also be packaged in flexible quantity containers. Tauopathy disorders

[0271] It has previously been shown that SYNGR-3 interacts with pathological tau in presynapses, and that reducing the level of SYNGR-3 rescues the tau-induced defects in vesicle mobility and neurotransmitter release.Inhibiting the expression of synaptogyrin-3 to reduce the binding between synaptogyrin-3 and (the N-terminal sequence of) tau protein is therefore at the heart of the present invention.Therefore, in a second aspect, any of the nucleic acid molecules or oligonucleotides described in this application are provided for use as pharmaceuticals.More specifically, for use in treating tauopathy.

[0272] Tauopathies are a diverse group of disorders that all share their association with the prominent accumulation of intracellular tau protein, which is abundantly expressed in the central nervous system. The group of tauopathies is growing with the recent addition of Huntington's disease (Fernandez-Nogales et al. 2014 Nat Med 20:881-885) and chronic traumatic encephalopathy (CTE; McKee et al. 2009 J Neuropathol Exp Neurol 68,709-735).

[0273] Different classifications of tauopathies exist. In one classification system, tauopathic disorders are divided into those with predominant tau pathology, those associated with amyloid deposition, and those associated with other pathologies (Williams et al. 2006 Intern Med J 36:652-660). Predominant tau pathologies include progressive supranuclear palsy (PSP), progressive supranuclear palsy-parkinsonism (PSP-P), Richardson's syndrome, argyrophilic grain disease, corticobasal degeneration, Pick's disease, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), postencephalitic parkinsonism, Guam Parkinson's disease complex, and Guadeloupe Parkinsonism. Tauopathic disorders associated with amyloid deposition include Alzheimer's disease, Down's syndrome, dementia pugilistica, familial British dementia, and familial Danish dementia. Tauopathy disorders associated with different pathologies include myotonic dystrophy, Hallervorden-Spatz disease, and Niemann-Pick type C.

[0274] Another classification is based on the isoform types found in the aggregates, although overlap may exist: 4R tauopathies include progressive supranuclear palsy (PSP), corticobasal degeneration, tangle-predominant dementia, and argyrophilic grain disease. 3R tauopathies include Pick's disease, and 3R+4R tauopathies include Alzheimer's disease (Dickson et al., 2011, J Mol Neurosci. 45:384-389; Murray et al., 2014, Alzheimer's Res. Ther. 6:1). Tau protein is discussed in more detail further below.

[0275] Additional tauopathies include tangle-only dementia, white matter tauopathy with globular glial inclusions, subacute sclerosing panencephalitis, SLC9A6-associated mental retardation, non-Guam motor neuron disease with neurofibrillary tangles, neurodegeneration with cerebral iron accumulation, Gerstmann-Straussler-Scheinker disease, frontotemporal lobar degeneration, diffuse neurofibrillary tangles with calcifications, chronic traumatic encephalopathy, amyotrophic lateral sclerosis of Guam, amyotrophic lateral sclerosis / Parkinsonism dementia complex, prion protein cerebral amyloid angiopathy, and progressive subcortical gliosis (Murray et al. 2014 Alzheimer's Res Ther 6:1; Spillantini & Goedert 2013 Lancet Neurol 12:609-622).

[0276] Symptoms of tauopathy disorders include clinical or pathological symptoms such as mild cognitive impairment, dementia, cognitive decline (e.g., apathy, impaired abstract thinking), motor decline (e.g., causing postural instability, tremor, or dystonia), and oculomotor and bulbar dysfunction. Criteria for diagnosing dementia are outlined, for example, in the Diagnostic and Statistical Manual of Mental Disorders (DSM) or the International Classification of Diseases (ICD) and are subject to periodic updates. The type of clinical manifestation depends on which brain regions are affected by the tauopathy, explaining why Alzheimer's disease is primarily a dementing disorder and why Parkinson's disease primarily affects movement. The stereotypical spatiotemporal propagation of tau inclusions creates consistent patterns of brain pathology in at least Alzheimer's disease and argyrophilic grain disease. Spreading may occur, in part, in a transsynaptic manner (Spillantini & Goedert 2013 Lancet Neurol 12:609-622; Liu et al 2012 PloS One 7:e31802). Molecular symptoms of tauopathy disorders include synaptic dysfunction (specifically presynaptic dysfunction), neurotoxicity, neurodegeneration, neuronal dysfunction, synaptic loss, and amyloid deposition.

[0277] Since the nucleic acid molecules or oligonucleotides described herein can target synaptogyrin-3 and reduce its expression, the nucleic acid molecules or oligonucleotides described herein can therefore be used as pharmaceuticals.In one embodiment thereof, the nucleic acid molecules or oligonucleotides described herein are provided for use in (methods for) treating or inhibiting the progression of tauopathy disorders, or for use in (methods for) treating or inhibiting the symptoms of tauopathy disorders.Specifically, the nucleic acid molecules or oligonucleotides of the present invention are inhibitors of human synaptogyrin-3 expression.The expression or function of synaptogyrin-3 is (partially) inhibited, for example, to restore presynaptic dysfunction induced by pathological tau. In methods for treating or inhibiting the progression of a tauopathy disorder or a symptom of a tauopathy disorder, any of the nucleic acid molecules or oligonucleotides described herein is administered to a subject in need thereof (a subject suffering from or exhibiting a tauopathy or a symptom thereof) in an effective amount, i.e., an amount sufficient to treat or inhibit the progression of a tauopathy disorder or a symptom of a tauopathy disorder.

[0278] For the purpose of treating, preventing, or inhibiting (the progression of) the intended disease or disorder, and in methods for treating, preventing, or inhibiting (the progression of) the intended disease or disorder, an effective amount of a therapeutic compound is administered to a subject in need thereof. An "effective amount" of an active agent in a composition is the amount of said agent required and sufficient to elicit a sufficient response in treating, preventing, or inhibiting (the progression of) the intended or targeted medical indication. It will be apparent to those skilled in the art that such a response may require continuous administration (over time) of the composition as part of an administration scheme. The effective amount may vary depending on the properties of the compound, the route of administration of the compound (passing the blood-brain barrier and cell membrane are potential barriers to be overcome by the oligonucleotides described herein), the health and physical condition of the individual to be treated, the age of the individual to be treated (e.g., dosages for infants may be lower than those for adults), the taxonomic group of the individual to be treated (e.g., humans, non-human primates, primates, etc.), the capacity of the individual's system to respond effectively, the desired degree of response, the formulation of the active substance, the evaluation of the attending physician, and other relevant factors.The effective amount may also vary depending on whether it is used in monotherapy or combination therapy.Determination of the effective amount of a compound usually comes from preclinical studies in representative animal or in vitro models (if available) and / or dose-finding studies in early clinical trials.

[0279] Any of the nucleic acid molecules or oligonucleotides described herein are provided for use in (a method for) treating or inhibiting progression of a tauopathy disorder, wherein the tauopathy disorder is selected from the group consisting of Alzheimer's disease, progressive supranuclear palsy (PSP), progressive supranuclear palsy-parkinsonism (PSP-P), Richardson's syndrome, argyrophilic grain disease, corticobasal degeneration, Pick's disease, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), postencephalitic parkinsonism, Parkinson's disease complex of Guam, Parkinson's disease of Guadeloupe, Huntington's disease, Down's syndrome, dementia pugilistica, familial British dementia, familial idiopathic dementia, and familial idiopathic dementia. The disease is selected from the group consisting of Danish dementia, myotonic dystrophy, Hallervorden-Spatz disease, Niemann-Pick type C, chronic traumatic encephalopathy, tangle-only dementia, white matter tauopathy with globular glial inclusions, subacute sclerosing panencephalitis, SLC9A6-associated mental retardation, non-Guam motor neuron disease with neurofibrillary tangles, neurodegeneration with cerebral iron accumulation, Gerstmann-Straussler-Scheinker disease, frontotemporal lobar degeneration, diffuse neurofibrillary tangles with calcifications, chronic traumatic encephalopathy, amyotrophic lateral sclerosis of Guam, amyotrophic lateral sclerosis / Parkinsonism-dementia complex, prion protein cerebral amyloid angiopathy, and progressive subcortical gliosis.

[0280] Therefore, any of the nucleic acid molecules or oligonucleotides described herein can be used in the treatment or inhibition of the progression of symptoms of tauopathy disorders selected from the group consisting of mild cognitive impairment, dementia, cognitive decline, motor function decline, oculomotor and bulbar dysfunction, synaptic dysfunction, neurotoxicity, neurodegeneration, neuronal dysfunction, synaptic loss, and amyloid deposition. Specifically, with regard to synaptic dysfunction, it relates to presynaptic dysfunction.

[0281] "Treatment" refers to a reduction or delay in any rate of progression of a disease or disorder compared to the progression or expected progression of the disease or disorder if left untreated. More desirably, treatment results in no / zero progression of the disease or disorder (i.e., "inhibition" or "inhibition of progression"), or even regression of any rate of an already developed disease or disorder. Tauopathies are generally progressive disorders, and progression can imply the spread of pathological tau protein (Asai et al. 2015 Nat Neurosci 18:1584-1593; deCalignon et al. 2012 Neuron 73:685-697).

[0282] As used herein, "reduction" or "reducing" refers to a statistically significant reduction. More specifically, a statistically significant reduction by administering an inhibitor of the present invention compared to a control situation in which the inhibitor is not administered. In specific embodiments, the statistically significant reduction is at least a 25%, 30%, 35%, 40%, 45%, or 50% reduction compared to a control situation.

[0283] The present application also provides a method of treating or inhibiting the progression of symptoms of a tauopathic disorder, the method comprising administering to a subject in need thereof any of the nucleic acid molecules or oligonucleotides described herein.

[0284] In one aspect, there is provided a method of reducing the expression level of synaptogyrin-3 in a subject comprising administering to the subject any of the nucleic acid molecules or oligonucleotides described herein. Diagnosis of Tauopathy Disorders

[0285] The nucleic acid molecules or oligonucleotides of the present disclosure can also be used for diagnostic purposes.Magnetic resonance imaging (MRI) itself allows the radiological determination of brain atrophy.Signs of midbrain atrophy, such as hummingbird or penguin silhouette, are indicators of, for example, progressive supranuclear palsy (PSP).Determining the tau protein content in cerebrospinal fluid (CSF) can also be used as an indicator of tauopathy.For example, the ratio between 33kDa / 55kDa tau forms in CSF has been found to be reduced in patients with PSP (Borroni et al. 2008 Neurology 71:1796-1803).

[0286] Recently, in vivo imaging techniques for neurodegeneration have become available. Such techniques can clearly support the clinical diagnosis of neurodegenerative diseases in general, and tauopathies in particular. In vivo diagnosis of tauopathies benefits from the existence of tau imaging ligands detectable by positron emission tomography (PET), and can be visualized using the radioactive tracer 2-(1-(6-((2-[ 18 F]fluoroethyl)(methyl)amino)-2-naphthyl)ethylidene)malononitrile([ 18 F]FDDNP), 2-(4-aminophenyl)-6-(2-([ 18 F]fluoroethoxy))quinolone ([ 18 F]THK523), and [ 18 F]T807 and [ 18 [F]T808 (Murray et al 2014 Alzheimer's Res Ther 6:1). In addition, MRI can be used to detect tauopathies, and fluorodeoxyglucose (FDG, 18PET imaging with florbetapir (or other amyloid markers) indicates synaptic activity (Murray et al., 2014 Alzheimer's Res Ther 6:1). For example, beta-amyloid, which can be detected in vivo by using florbetapir (or other amyloid markers) in combination with PET, has been found to be an accurate biomarker for at least Alzheimer's disease (Clark et al., 2011 J Am Med Assoc 305:275-283), and florbetapir-PET technology received FDA approval in 2012. The availability of in vivo tauopathy detection technology further supports the selection of subjects who may benefit from synaptogyrin-3 inhibition therapy as described herein.

[0287] Thus, the present disclosure provides nucleic acid molecules or oligonucleotides of the present disclosure conjugated to a detectable moiety, such as a radioactive tracer, a fluorescent moiety (e.g., a fluorescent protein), or any detectable moiety known in the art. Methods for the diagnosis or prognosis of a tauopathy disorder, for monitoring the efficacy of treatment, for selecting patients for treatment, or for selecting or excluding subjects for a clinical trial involving administering a nucleic acid molecule or oligonucleotide of the present disclosure are also provided. Inhibition of synaptogyrin-3

[0288] By using the oligonucleotide of the present disclosure, inhibition of synaptogyrin-3 can be achieved at the expression level.In other words, administration of the oligonucleotide of the present disclosure can reduce the mRNA level encoding synaptogyrin-3, which in turn will result in a lower protein expression level of synaptogyrin-3.In some aspects, such reduction in the expression level of synaptogyrin-3 can result in the reduction of synaptogyrin-3 activity.As previously demonstrated (see WO2019 / 016123 and US 20220403021A1, the entire contents of which are incorporated herein by reference), partial inhibition of synaptogyrin-3 is sufficient to restore the presynaptic dysfunction induced by pathological tau.Therefore, inhibition of synaptogyrin-3 expression and / or activity implies several possible levels of inhibition.

[0289] In some aspects, administration of an oligonucleotide of the present disclosure may result in a reduction in synaptogyrin-3 mRNA levels by at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least 95%, or even about 100% relative to control conditions (e.g., prior to administration of an oligonucleotide of the present disclosure). In some aspects, administration of an oligonucleotide of the present disclosure may result in a reduction in synaptogyrin-3 protein levels of at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least a...

Claims

1. and a target region within the synaptogyrin-3 nucleotide sequence set forth in SEQ ID NO:1, the target region comprising a contiguous nucleotide sequence of at least 10 contiguous nucleotides in length, the contiguous nucleotide sequence being at least 90% complementary to an equal length portion of a target region within the synaptogyrin-3 nucleotide sequence set forth in SEQ ID NO:1, the target region ... , 1515 and 1600, 1580 and 1700, 1680 and 1837, 1824 and 1885, 1850 and 2100, 2100 and 2250, 2308 and 2428, 2416 and 2441, 2428 and 2625, 2649 and 2796, 2962 and 3086, 3153 and 3460, 3450 and 3530, 3508 and 3551, 3538 and 3636, or between 3626 and 4599, where the endpoints are inclusive.

2. 2. The oligonucleotide of claim 1, wherein the oligonucleotide is capable of binding to the synaptogyrin-3 transcript set forth in SEQ ID NO:

1.

3. The oligonucleotide according to any one of claims 1 to 2, wherein the oligonucleotide is capable of statistically significantly reducing the level of synaptogyrin-3 transcript in a cell compared to a control condition in the absence of the oligonucleotide.

4. The oligonucleotide of any one of claims 1 to 3, wherein the oligonucleotide is a single-stranded nucleic acid molecule.

5. The oligonucleotide of claim 4, wherein the single-stranded oligonucleotide is an antisense oligonucleotide (ASO) or the antisense portion of an RNAi molecule.

6. The oligonucleotide of any one of claims 1 to 5, wherein the contiguous nucleotide sequence is at least 16 nucleotides in length.

7. 7. The oligonucleotide of any one of claims 1 to 6, wherein the target region is selected from SEQ ID NOs: 10, 12, 20, 25, 29-31, 33, 50, 53, 58-59, 62, 69, 79, 84, 87, 91, 94, 110-111, 135, 140-141, 170, 172, 179, 181, 184, 188, 193-194, 210, 216, 220-221, 224, 227, 229, 231, 235, 241, 246, 248, 250, 259, 268, or 269.

8. The target region is selected from SEQ ID NOs: 2-9, 11, 13-19, 21-24, 26-28, 32, 34-49, 51-52, 54-57, 60-61, 63-68, 70-78, 80-83, 85-86, 88-90, 92-93, 95-109, 112-134, 136-139, 142-169, 171, 173-178, 180, 182-183, 184-185, 186-187, 187-188, 188-189, 190-191, 191-192, 192-193, 193-194, 194-195, 195-196, 196-197, 197-198, 198-199, 199-200, 200-201, 201-202, 202-203, 203-204, 204-205, 205-206, 206-207, 207-208, 208-210, 209-211, 210-212, 211-213, 212-214, 213-215, 214-216, 215-217, 216-218, 217-219, 218-220, 219-221, 222-223, 223-224, 224-225 8. The oligonucleotide of any one of claims 1 to 7, selected from: 3, 185-187, 189-192, 195-209, 211-215, 217-219, 222-223, 225-226, 228, 230, 232-234, 236-240, 242-245, 247, 249, 251-258, or 260-267.

9. 9. The oligonucleotide of any one of claims 1 to 8, wherein a contiguous nucleotide sequence of at least 10 contiguous nucleotides in length exhibits at least 90% sequence identity to any of SEQ ID NOs: 270 to 489.

10. 10. The oligonucleotide of any one of claims 1 to 9, wherein a contiguous nucleotide sequence of at least 10 contiguous nucleotides in length exhibits at least 90% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 321, SEQ ID NO: 346, SEQ ID NO: 373, SEQ ID NO:

384.

11. The oligonucleotide of any one of claims 1 to 10, wherein the contiguous nucleotide sequence is 100% complementary to one of the target regions.

12. The oligonucleotide of any one of claims 1 to 11, wherein the oligonucleotide comprises one or more internucleoside linkages and / or one or more 2' sugar-modified nucleosides.

13. 13. The oligonucleotide of claim 12, wherein the internucleoside linkage is a phosphorothioate internucleoside linkage and / or the 2' sugar modified nucleoside is selected from the group consisting of 2'-O-methyl-, 2'-O-methoxyethyl-, 2'-O-alkyl-, 2'-alkoxy, 2'-amino-, 2'-fluoro-, and LNA nucleosides.

14. 14. The oligonucleotide of any one of claims 1 to 13, wherein the oligonucleotide comprises a gapmer of the formula 5'-FG-F'-3', wherein regions F and F' independently comprise between 1 and 8 nucleosides, 1 to 5 of which are independently 2' sugar-modified nucleosides, defining the 5' and 3' ends of the F and F' regions, and G is a region of between 5 and 18 nucleosides for recruiting RNase H.

15. 15. The oligonucleotide of claim 14, wherein the internucleoside linkages between one or more nucleosides of regions F and / or F' and / or between F and G and / or between F' and G are phosphorothioate internucleoside linkages.

16. A pharmaceutical composition comprising the oligonucleotide of any one of claims 1 to 15.

17. An oligonucleotide according to any one of claims 1 to 14 or a pharmaceutical composition according to claim 15 for use as a medicament.

18. 17. The oligonucleotide of any one of claims 1 to 15 or the pharmaceutical composition of claim 16 for use in treating or inhibiting the progression of a tauopathy disorder or for use in treating or inhibiting a symptom of a tauopathy disorder.

19. Tauopathy disorders include Alzheimer's disease, progressive supranuclear palsy (PSP), progressive supranuclear palsy-Parkinsonism (PSP-P), Richardson's syndrome, argyrophilic grain disease, corticobasal degeneration, Pick's disease, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), postencephalitic parkinsonism, Guam Parkinson's disease complex, Guadeloupe Parkinson's disease, Huntington's disease, Down's syndrome, dementia pugilistica, familial British dementia, familial Danish dementia, myotonic dystrophy, Hallervorden-Spatz disease, Niemann-Pick type C, chronic traumatic encephalopathy, tangle-only dementia, and bulbar dementia.

19. The oligonucleotide of any one of claims 1 to 15 or the pharmaceutical composition of claim 16 for use according to claim 18, wherein the oligonucleotide is selected from the group consisting of leukotauopathy with glial inclusions, subacute sclerosing panencephalitis, SLC9A6-associated mental retardation, non-Guam motor neuron disease with neurofibrillary tangles, neurodegeneration with cerebral iron accumulation, Gerstmann-Straussler-Scheinker disease, frontotemporal lobar degeneration, diffuse neurofibrillary tangles with calcifications, chronic traumatic encephalopathy, amyotrophic lateral sclerosis of Guam, amyotrophic lateral sclerosis / Parkinsonism-dementia complex, prion protein cerebral amyloid angiopathy, and progressive subcortical gliosis.

20. 19. The oligonucleotide of any one of claims 1 to 15 or the pharmaceutical composition of claim 16 for use according to claim 18, wherein the symptoms of a tauopathy disorder are selected from the group consisting of mild cognitive impairment, dementia, cognitive decline, motor function decline, oculomotor and bulbar dysfunction, synaptic dysfunction, neurotoxicity, neurodegeneration, neuronal dysfunction, synapse loss, and amyloid deposition.

21. The oligonucleotide of any one of claims 1 to 15 or the pharmaceutical composition of claim 16 for use according to claim 20, wherein the synaptic dysfunction is presynaptic dysfunction.

22. A nucleic acid sequence selected from SEQ ID NOs: 10, 12, 20, 25, 29-31, 33, 50, 53, 58-59, 62, 69, 79, 84, 87, 91, 94, 110-111, 135, 140-141, 170, 172, 179, 181, 184, 188, 193-194, 210, 216, 220-221, 224, 227, 229, 231, 235, 241, 246, 248, 250, 259, 268, or 269 for designing an antisense or RNAi molecule capable of reducing the level of synaptogyrin-3 transcripts in a cell by at least 45% compared to the control situation in the absence of the antisense or RNAi molecule.

23. 17. A method for treating or inhibiting the progression of a tauopathy disorder or treating or inhibiting a symptom of a tauopathy disorder, comprising administering to a subject in need thereof an effective dose of the oligonucleotide of any of claims 1 and 15 or the pharmaceutical composition of claim 16.

24. Tauopathy disorders include Alzheimer's disease, progressive supranuclear palsy (PSP), progressive supranuclear palsy-Parkinsonism (PSP-P), Richardson's syndrome, argyrophilic grain disease, corticobasal degeneration, Pick's disease, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), postencephalitic parkinsonism, Guam Parkinson's disease complex, Guadeloupe Parkinson's disease, Huntington's disease, Down's syndrome, dementia pugilistica, familial British dementia, familial Danish dementia, myotonic dystrophy, Hallervorden-Spatz disease, and Niemann-Pick C.

24. The method of claim 23, wherein the dementia is selected from the group consisting of: chronic traumatic encephalopathy, tangle-only dementia, white matter tauopathy with globular glial inclusions, subacute sclerosing panencephalitis, SLC9A6-associated mental retardation, non-Guam motor neuron disease with neurofibrillary tangles, neurodegeneration with cerebral iron accumulation, Gerstmann-Straussler-Scheinker disease, frontotemporal lobar degeneration, diffuse neurofibrillary tangles with calcifications, chronic traumatic encephalopathy, amyotrophic lateral sclerosis of Guam, amyotrophic lateral sclerosis / Parkinsonism dementia complex, prion protein cerebral amyloid angiopathy, and progressive subcortical gliosis.

25. 25. The method of claim 24, wherein the symptoms of the tauopathy disorder are selected from the group consisting of mild cognitive impairment, dementia, cognitive decline, motor function decline, oculomotor and bulbar dysfunction, synaptic dysfunction, neurotoxicity, neurodegeneration, neuronal dysfunction, synaptic loss, and amyloid deposition.

26. 26. The method of claim 25, wherein the synaptic dysfunction is presynaptic dysfunction.

27. Synaptogyrin-3 in cells by at least 45% compared to the control situation in the absence of antisense or RNAi molecules The level of mRNA, synaptogyrin-3 protein, synaptogyrin-3 activity, or a combination thereof can be reduced, wherein the nucleic acid sequence of the antisense oligonucleotide or RNAi molecule targets a subsequence of mRNA encoding synaptogyrin-3 selected from the group consisting of SEQ ID NOs: 10, 12, 20, 25, 29-31, 33, 50, 53, 58-59, 62, 69, 79, 84, 87, 91, 94, 110-111, 135, 140-141, 170, 172, 179, 181, 184, 188, 193-194, 210, 216, 220-221, 224, 227, 229, 231, 235, 241, 246, 248, 250, 259, 268, or 269.

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