Antisense Oligomers and Their Use in the Treatment of Duchenne Muscular Dystrophy

Description

"Antisense Oligomers and Their Use in the Treatment of Duchenne Muscular Dystrophy" Split order BR 11 2021 001575 2, filed on 07 / 25 / 2019. RELATED ORDERS

[001] This application claims the benefit of U.S. Provisional Application No. 62 / 711215, filed July 27, 2018, and U.S. Provisional Application No. 62 / 868003, filed June 28, 2019. The full teachings of the aforementioned applications are incorporated by reference in their entirety. SEQUENCE LISTING

[002] The instant request contains a Sequence Listing that was sent electronically in ASCII format and is incorporated herein by reference in its entirety. The said ASCII copy, created on July 3, 2019, is named 8166_02_WO00_SL.txt and is 28,526 bytes in size. FIELD OF DISSEMINATION

[003] This disclosure relates to novel antisense oligomers suitable for exon 2 skipping in the human dystrophin gene and their pharmaceutical compositions. The disclosure also provides methods for inducing exon 2 skipping using the novel antisense oligomers, methods for producing dystrophin in an individual with a dystrophin gene mutation that is susceptible to exon 2 skipping, and methods for treating an individual with a dystrophin gene mutation that is susceptible to exon 2 skipping. Fundamentals of Disclosure

[004] Duchenne muscular dystrophy (DMD) is caused by a defect in the expression of the dystrophin protein. The gene that codes for the protein contains 79 exons spread over more than 2 million nucleotides of DNA. Any exonic mutation that alters the reading frame of the exon, duplicates an exon, introduces a stop codon, or is characterized by the removal of an entire exon or exons out of the frame, Petition 870260074072, dated 07 / 24 / 2026, page 9 / 448 2 / 207, or duplications of one or more exons, have the potential to disrupt the production of functional dystrophin, resulting in DMD. Exon 2 is the most commonly duplicated exon in DMD.

[005] A less severe form of muscular dystrophy, Becker muscular dystrophy (BMD) arises where a mutation, typically a skip of one or more exons, results in a correct reading frame throughout the dystrophin transcript, so that mRNA translation into protein is not prematurely terminated. If the joining of upstream and downstream exons in the processing of a mutant dystrophin pre-mRNA maintains the correct reading frame of the gene, the result is an mRNA encoding a protein with a short internal deletion that retains some activity, resulting in a Becker phenotype.

[006] There is a need for antisense oligomers that are suitable for exon 2 skipping and corresponding pharmaceutical compositions that are useful for therapeutic methods for dystrophin production and DMD treatment. SUMMARY OF THE DISCLOSURE

[007] The antisense oligomers, or their pharmaceutically acceptable salts, provided herein comprise a base sequence that is 8 to 50 morpholino subunits and hybridize with a target region of exon 2, intron 1 or intron 2 of the human dystrophin premRNA that is a region within exon 2, intron 1 or intron 2. In one aspect, the antisense oligomer, or its pharmaceutically acceptable salt, induces exon skipping in the human dystrophin gene. In one aspect, the antisense oligomer, or its pharmaceutically acceptable salt, contains 16 to 32 morpholino subunits. In another aspect, the antisense oligomer, or its pharmaceutically acceptable salt, contains 19 to 25 morpholino subunits.

[08] In certain embodiments, the antisense oligomer is conjugated to one or more cell-penetrating peptides (referred to in this document as CPPs). In certain embodiments, one or more CPPs are attached to a terminal of the oligomer. Petition 870260074072, dated 07 / 24 / 2026, p. 10 / 448 3 / 207 antisense. In certain embodiments, at least one CPP is attached to the 5' end of the antisense oligomer. In certain embodiments, at least one CPP is attached to the 3' end of the antisense oligomer. In certain embodiments, a first CPP is attached to the 5' end and a second CPP is attached to the 3' end of the antisense oligomer.

[09] In some embodiments, the CPP is an arginine-rich peptide. The term arginine-rich refers to a CPP with at least 2, and preferably 2, 3, 4, 5, 6, 7 or 8 arginine residues, each optionally separated by one or more uncharged hydrophobic residues and optionally containing about 6-14 amino acid residues. As explained below, a CPP is preferably linked at its carboxy terminus to the 3' and / or 5' end of an antisense oligonucleotide via a linker, which may also be one or more amino acids, and is preferably also limited at its amino terminus by a Racom Raselecionado substituent of H, acyl, acetyl, benzoyl or stearoyl. In some embodiments, Raé acetyl.

[010] As can be seen in the table below, non-limiting examples of CPPs for use in this document include -(RXR)4-Ra(SEQ ID NO: 40), -R-(FFR)3-Ra(SEQ ID NO: 41), -BX-(RXR)4-Ra(SEQ ID NO: 42), -BXR-(FFR)3-Ra(SEQ ID NO: 43), -GLY-R-(FFR)3-Ra(SEQ ID NO: 44), -GLY-R5-Ra(SEQ ID NO: 45), -R5-Ra(SEQ ID NO: 46), -GLY-R6-Ra(SEQ ID NO: 47) and -R6-Ra(SEQ ID NO: 48), wherein Ra is selected from H, acyl, acetyl, benzoyl and stearoyl, and wherein R is arginine, X is 6-aminohexanoic acid, B is β-alanine, F is phenylalanine and GLY (or G) is glycine. CPP R5 (SEQ ID NO: 46) is intended to indicate a peptide of five (5) arginine residues linked together by amide bonds (and not a single substituent, for example, R5(SEQ ID NO: 46)). CPP R6 (SEQ ID NO: 48) is intended to indicate a peptide of six (6) arginine residues linked together by amide bonds (not a Petition 870260074072, dated 07 / 24 / 2026, p. 11 / 448 4 / 207 single substituent, for example R6(SEQ ID NO: 48)). In some embodiments, Raé acetyl.

[011] Exemplary CPPs are provided in Table 1 (SEQ ID NOS. 40-46). Table 1: Exemplary Cell Penetrating Peptides Name Sequence SEQ ID NO: (RXR)4 RXRRXRRXRRXR 40 (RFF)3R RFFRFFRFFR 41 (RXR)4XB RXRRXRRXRRXRXB 42 (RFF)3RXB RFFRFFRFFRXB 43 (RFF)3RG RFFRFFRFFRG 44 R5G RRRRRG 45 R5 RRRRR 46 R6G RRRRRRG 47 R6 RRRRRR 48 R is arginine; X is 6-aminohexanoic acid; B is β-alanine; F is phenylalanine; G is glycine.

[012] CPPs, their synthesis and methods of conjugation to an oligomer are further described in U.S. Patent Publication 2012 / 0289457 and International Patent Publication Nos. WO 2004 / 097017, WO 2009 / 005793 and WO 2012 / 150960, disclosures of which are incorporated herein by reference in their entirety.

[013] In some embodiments, an antisense oligonucleotide comprises a Z substituent, defined as the combination of a CPP and a linker. The linker links the CPP at its carboxy terminus to the 3' and / or 5' end of the oligonucleotide. In several embodiments, an antisense oligonucleotide may comprise only a CPP linked to the 3' end of the oligomer. In other embodiments, an antisense oligonucleotide may comprise only a CPP linked to the 5' end of the oligomer.

[014] The linker within Z may comprise, for example, 1, 2, 3, 4 or 5 amino acids.

[015] In particular modalities, Z is selected from:

[016] -C(O)(CH2)5NH-CPP;

[017] -C(O)(CH2)2NH-CPP;

[018] -C(O)(CH2)2NHC(O)(CH2)5NH-CPP; Petition 870260074072, dated 07 / 24 / 2026, p. 12 / 448 5 / 207

[019] -C(O)CH2NH-CPP; and the formula:

[020] in which the CPP is linked to the linking portion by an amide linkage at the carboxy terminus of the CPP.

[021] In several embodiments, CPP is an arginine-rich peptide, as described herein and seen in Table 1. In several embodiments, the arginine-rich CPP is -R5-Ra, (i.e., five arginine residues; SEQ ID NO:46), wherein Ra is selected from H, acyl, acetyl, benzoyl, and stearoyl. In certain embodiments, Ra is acetyl. In several embodiments, the CPP is SEQ ID NO:46, and the linker is selected from the group consisting of -C(O)(CH2)5NH-, -C(O)(CH2)2NH-, -C(O)(CH2)2NHC(O)(CH2)5NH-, -C(O)CH2NH-,0CPP and ' . In some embodiments, the linker comprises 1, 2, 3, 4, or 5 amino acids.

[022] In some embodiments, the CPP is SEQ ID NO:46 and the binder is Gly. In some embodiments, the CPP is SEQ ID NO:45.

[023] In certain embodiments, the arginine-rich CPP is -R6-Ra, (i.e., six arginine residues; SEQ ID NO:48), wherein Ra is selected from H, acyl, acetyl, benzoyl, and stearoyl. In certain embodiments, Ra is acetyl. In several embodiments, the CPP is selected from SEQ ID NOS. 40, 41, or 48, and the ligand is selected from the group consisting of -C(O)(CH2)5NH-, -C(O)(CH2)2NH-, -C(O)(CH2)2NHC(O)(CH2)5NH-, -C(O)CH2NH-, Petition 870260074072, dated 07 / 24 / 2026, p. 13 / 448 6 / 207 amino acids. In some forms, the linker comprises 1, 2, 3, 4 or 5

[024] In some embodiments, CPP is SEQ ID NO:48 and the linker is Gly. In some embodiments, CPP is SEQ ID NO:47.

[025] In certain embodiments, Z is -C(O)CH2NH-R6-Ra('Wdisclosed as SEQ ID NO: 48) covalently linked to an antisense oligomer of disclosure at the 5' and / or 3' end of the oligomer, wherein Ra is H, acyl, acetyl, benzoyl or stearoyl to cover the amino terminus of R6 (SEQ ID NO: 48). In certain embodiments, Ra is acetyl. In these non-limiting examples, CPP is -R6-Ra(SEQ ID NO: 48) and the linker is -C(O)CH2NH-, (i.e., GLY). This particular example of Z = -C(O)CH2NH-R6-Ra(R6 disclosed as SEQ ID NO: 48) is also exemplified by the following structure:

[026] where Raé is selected from H, acyl, acetyl, benzoyl and stearoyl. In some embodiments, Raé is acetyl.

[027] In several modalities, the CPP is -R6-Ra(SEQ ID NO: 48), also exemplified as the following formula: Petition 870260074072, dated 07 / 24 / 2026, p. 14 / 448 7 / 207

[028] in which Raé selected from H, acyl, acetyl, benzoyl and stearoyl. In certain modalities, CPP is SEQ ID NO:47. In some modalities, Raé acetil.

[029] In some modalities, the CPP is -(RXR)4-Ra(SEQ ID NO: 40), also exemplified as the following formula:

[030] In several modalities, the CPP is -R-(FFR)s-Ra(SEQ ID NO: 41), also exemplified as the following formula:

[031] In several modalities, Z is selected from: Petition 870260074072, dated 07 / 24 / 2026, p. 15 / 448 8 / 207 -C(O)(CH2)5NH-CPP; -C(O)(CH2)2NH-CPP; -C(O)(CH2)2NHC(O)(CH2)5NH-CPP; -C(O)CH2NH-CPP and the formula:

[032] wherein the CPP is linked to the ligand moiety by an amide linkage at the carboxy terminus of the CPP and wherein the CPP is selected from: , (-R-(FFR)3-Ra(SEQ ID NO: 41)), Petition 870260074072, dated 07 / 24 / 2026, p. 16 / 448 9 / 207 , and (-Re-Ra(SEQ ID NO: 48)). In some modes, Raé acetil.

[033] In one aspect, the disclosure provides a modified antisense oligomer, or a pharmaceutically acceptable salt thereof, capable of binding to a selected target to induce exon skipping in the human dystrophin gene, wherein the modified antisense oligomer comprises a base sequence that is complementary to an exon 2, target region of intron 1 or intron 2 of dystrophin pre-mRNA designated as an annealing site; wherein the base sequence and / or annealing site are selected from one of the following: Sítio de anelamento Sequência base [5' a 3'] SEQ ID NO: H2.SA.(-20+05) TTC ATC TAA AAT GCA AAA TAA AAA A SEQ ID NO:1 H2.SA.(-14+11) TTC TCT TTC ATC TAA AAT GCA AAA T SEQ ID NO:2 H2.SA.(-11+14) ATC TTC TCT TTC ATC TAA AAT GCA A SEQ ID NO:3 H2.SA.(-08+17) AAC ATC TTC TCT TTC ATC TAA AAT G SEQ ID NO:4 H2.SA.(-05+20) TTG AAC ATC TTC TCT TTC ATC TAA A SEQ ID NO:5 H2.SA.(-02+23) CTT TTG AAC ATC TTC TCT TTC ATC T SEQ ID NO:6 H2.SA.(+02+26) TTT CTT TTG AAC ATC TTC TCT TTC A SEQ ID NO:7 H2.SA.(+05+29) TGT TTT CTT TTG AAC ATC TTC TCT T SEQ ID NO:8 H2.SA.(+08+32) GAA TGT TTT CTT TTG AAC ATC TTC T SEQ ID NO:9 H2.SA.(+11+35) TGT GAA TGT TTT CTT TTG AAC ATC T SEQ ID NQ:10 H2.SA.(+14+38) TTT TGT GAA TGT TTT CTT TTG AAC A SEQ ID NO:11 H2.SA.(+17+41) CCA TTT TGT GAA TGT TTT CTT TTG A SEQ ID NO:12 H2.SA.(+20+44) TAG CCA TTT TGT GAA TGT TTT CTT T SEQ ID NO:13 H2.SA.(+23+47) ATT TAG CCA TTT TGT GAA TGT TTT C SEQ ID NO:14 H2.SA.(+26+50) TGC ATT TAG CCA TTT TGT GAA TGT T SEQ ID NO:15 H2.SA.(+29+53) TTG TGC ATT TAG CCA TTT TGT GAA T SEQ ID NO:16 H2.SA.(+32+56) AAA TTG TGC ATT TAG CCA TTT TGT G SEQ ID NO:17 H2.SA.(+35+59) AGA AAA TTG TGC ATT TAG CCA TTT T SEQ ID NO:18 H2.SA.(+38+62) CTT AGA AAA TTG TGC ATT TAG CCA T SEQ ID NO:19 H2.SD.(+22-03) TAG CTT AGA AAA TTG TGC ATT TAG C SEQ ID NQ:20 H2.SD.(+19-06) TCT TAG CTT AGA AAA TTG TGC ATT T SEQ ID NO:21 H2.SD.(+16-09) CAT TCT TAG CTT AGA AAA TTG TGC ATT T SEQ ID NO:22. Petition 870260074072, de 24 / 07 / 2026, pág. 17 / 448 10 / 207 H2.SD.(+13-12) AAC CAT TCT TAC CTT AGA AAA TTG T SEQ ID NO:23 H2.SD.(+10-15) ACA AAC CAT TCT TAC CTT AGA AAA T SEQ ID NO:24 H2A(+06+30) ATG TTT TCT TTT GAA CAT CTT CTC T SEQ ID NO:25 H2A(+07+31) AAT GTT TTC TTT TGA ACA TCT TCT C SEQ ID NO:26 H2A(+09+33) TGA ATG TTT TCT TTT GAA CAT CTT C SEQ ID NO:27 H2A(+10+34) GTG AAT GTT TTC TTT TGA ACA TCT T SEQ ID NO:28 H2A(-23+02) ATC TAA AAT GCA AAA TAA AAA AAT A SEQ ID NO:29 H2A(-26-02) TAA AAT GCA AAA TAA AAA AAT AAA A SEQ ID NO:30 H2A(-29-05) AAT GCA AAA TAA AAA AAT AAA AGT T SEQ ID NO:31 H2A(-32-08) GCA AAA TAA AAA AAT AAA AGT TAG G SEQ ID NO:32 H2A(-35-11) AAA TAA AAA AAT AAA AGT TAG GAA G SEQ ID NO:33 H2A(-38-14) TAA AAA AAT AAA AGT TAG GAA GCA A SEQ ID NO:34 H2A(-41-17) AAA AAT AAA AGT TAG GAA GCA ACT T SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36 H2D(+15-08) ATT CTT ACC TTA GAA AAT TGT GC SEQ ID NO:37 H2A(+46+62) CTT AGA AAA TTG TGC AT SEQ ID NO:38 H2D(+08-09) CAT TCT TAC CTT AGA AA SEQ ID NO:39 where A is adenine, C is cytosine, G is guanine, and T is thymine or uracil. In certain modalities, T is thymine.

[034] In certain embodiments, the modified antisense oligomer is capable of binding to a selected target to induce exon skipping in the human dystrophin gene, wherein the modified antisense oligomer comprises a base sequence that is complementary to a target region of exon 2, intron 1, or intron 2 of the dystrophin premRNA designated as an annealing site; wherein the base sequence and / or annealing site are selected from one of the following: Sítio de anelamento Sequência base [5' a 3'] SEQ ID NO: H2.SA.(-20+05) TTC ATC TAA AAT GCA AAA TAA AAA A SEQ ID NO:1 H2.SA.(-14+11) TTC TCT TTC ATC TAA AAT GCA AAA T SEQ ID NO:2 H2.SA.(-11+14) ATC TTC TCT TTC ATC TAA AAT GCA A SEQ ID NO:3 H2.SA.(-08+17) AAC ATC TTC TCT TTC ATC TAA AAT G SEQ ID NO:4 H2.SA.(-05+20) TTG AAC ATC TTC TCT TTC ATC TAA A SEQ ID NO:5 H2.SA.(-02+23) CTT TTG AAC ATC TTC TCT TTC ATC T SEQ ID NO:6 H2.SA.(+02+26) TTT CTT TTG AAC ATC TTC TCT TTC A SEQ ID NO:7 H2.SA.(+05+29) TGT TTT CTT TTG AAC ATC TTC TCT T SEQ ID NO:8 H2.SA.(+08+32) GAA TGT TTT CTT TTG AAC ATC TTC T SEQ ID NO:9 H2.SA.(+11+35) TGT GAA TGT TTT CTT TTG AAC ATC T SEQ ID NO:10 H2.SA.(+14+38) TTT TGT GAA TGT TTT CTT TTG AAC A SEQ ID NO:11 H2.SA.(+17+41) CCA TTT TGT GAA TGT TTT CTT TTG A SEQ ID NO:12 H2.SA.(+20+44) TAC CCA TTT TGT GAA TGT TTT CTT T SEQ ID NO:13 H2.SA.(+23+47) ATT TAC CCA TTT TGT GAA TGT TTT C SEQ ID NO:14 Petição 870260074072, de 24 / 07 / 2026, pág. 18 / 448 11 / 207H2.SA.(+26+50) TGC ATT TAC CCA TTT TGT GAA TGT T SEQ ID NO:15 H2.SA.(+29+53) TTG TGC ATT TAC CCA TTT TGT GAA T SEQ ID NO:16 H2.SA.(+32+56) AAA TTG TGC ATT TAC CCA TTT TGT G SEQ ID NO:17 H2.SA.(+35+59) AGA AAA TTG TGC ATT TAC CCA TTT T SEQ ID NO:18 H2.SD.(+22-03) TAC CTT AGA AAA TTG TGC ATT TAC C SEQ ID NO:20 H2.SD.(+19-06) TCT TAC CTT AGA AAA TTG TGC ATT T SEQ ID NO:21 H2.SD.(+16-09) CAT TCT TAC CTT AGA AAA TTG TGC A SEQ ID NO:22 H2.SD.(+13-12) AAC CAT TCT TAC CTT AGA AAA TTG T SEQ ID NO:23 H2.SD.(+10-15) ACA AAC CAT TCT TAC CTT AGA AAA T SEQ ID NO:24 H2A(+06+30) ATG TTT TCT TTT GAA CAT CTT CTC T SEQ ID NO:25 H2A(+07+31) AAT GTT TTC TTT TGA ACA TCT TCT C SEQ ID NO:26 H2A(+09+33) TGA ATG TTT TCT TTT GAA CAT CTT C SEQ ID NO:27 H2A(+10+34) GTG AAT GTT TTC TTT TGA ACA TCT T SEQ ID NO:28 H2A(-23+02) ATC TAA AAT GCA AAA TAA AAA AAT A SEQ ID NO:29 H2A(-26-02) TAA AAT GCA AAA TAA AAA AAT AAA A SEQ ID NO:30 H2A(-29-05) AAT GCA AAA TAA AAA AAT AAA AGT T SEQ ID NO:31 H2A(-32-08) GCA AAA TAA AAA AAT AAA AGT TAG G SEQ ID NO:32 H2A(-35-11) AAA TAA AAA AAT AAA AGT TAG GAA G SEQ ID NO:33 H2A(-38-14) TAA AAA AAT AAA AGT TAG GAA GCA A SEQ ID NO:34 H2A(-41-17) AAA AAT AAA AGT TAG GAA GCA ACT T SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36 H2A(+46+62) CTT AGA AAA TTG TGC AT SEQ ID NO:38 H2D(+08-09) CAT TCT TAC CTT AGA AA SEQ ID NO:39. em que A é adenina, C é citosina, G é guanina e T é timina ou uracila. Em certas modalidades, T é timina.

[035] In certain embodiments, the modified antisense oligomer is capable of binding to a selected target to induce exon skipping in the human dystrophin gene, wherein the modified antisense oligomer comprises a base sequence that is complementary to a target region of exon 2, intron 1, or intron 2 of the dystrophin premRNA designated as an annealing site; wherein the base sequence and / or annealing site are selected from one of the following: Annealing site Base sequence [5' to 3'] SEQ ID NO: H2.SA.(-20+05) TTC ATC TAA AAT GCA AAA TAA AAA A SEQ ID NO:1 H2.SA.(-14+11) TTC TCT TTC ATC TAA AAT GCA AAA T SEQ ID NO:2 H2.SA.(-11+14) ATC TTC TCT TTC ATC TAA AAT GCA A SEQ ID NO:3 H2.EN.(-08+17) AAC ATC TTC TCT TTC ATC TAA AAT G SEQ ID NO:4 H2.EN.(-05+20) TTG AAC ATC TTC TCT TTC ATC TAA A SEQ ID NO:5 H2.EN.(-02+23) CTT TTG AAC ATC TTC TCT TTC ATC T SEQ ID NO:6 H2.EN.(+02+26) TTT CTT TTG AAC ATC TTC TCT TTC A SEQ ID NO:7 H2.EN.(+05+29) TGT TTT CTT TTG AAC ATC TTC TCT T SEQ ID NO:8 Petition 870260074072, 07 / 24 / 2026, p. 19 / 4 12 / 2 H2.SA.(+08+32) GAA TGT TTT CTT TTG AAC ATC TTC T SEQ ID NO:9 H2.SA.(+11+35) TGT GAA TGT TTT CTT TTG AAC ATC T SEQ ID NO:10 H2.SA.(+14+38) TTT TGT GAA TGT TTT CTT TTG AAC A SEQ ID NO:11 H2.SA.(+17+41) CCA TTT TGT GAA TGT TTT CTT TTG A SEQ ID NO:12 H2.SA.(+20+44) TAC CCA TTT TGT GAA TGT TTT CTT T SEQ ID NO:13 H2.SA.(+38+62) CTT AGA AAA TTG TGC ATT TAC CCA T SEQ ID NO:19 H2.SD.(+22-03) TAC CTT AGA AAA TTG TGC ATT TAC C SEQ ID NO:20 H2.SD.(+19-06) TCT TAC CTT AGA AAA TTG TGC ATT T SEQ ID NO:21 H2A(+06+30) ATG TTT TCT TTT GAA CAT CTT CTC T SEQ ID NO:25 H2A(+07+31) AAT GTT TTC TTT TGA ACA TCT TCT C SEQ ID NO:26 H2A(+09+33) TGA ATG TTT TCT TTT GAA CAT CTT C SEQ ID NO:27 H2A(+10+34) GTG AAT GTT TTC TTT TGA ACA TCT T SEQ ID NO:28 H2A(-38-14) TAA AAA AAT AAA AGT TAG GAA GCA A SEQ ID NO:34 H2A(-41-17) AAA AAT AAA AGT TAG GAA GCA ACT SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36

[036] where A is adenine, C is cytosine, G is guanine and T is thymine or uracil. In certain embodiments, T is thymine.

[037] In certain embodiments, the modified antisense oligomer is capable of binding to a selected target to induce exon skipping in the human dystrophin gene, wherein the modified antisense oligomer comprises a base sequence that is complementary to a target region of exon 2, intron 1, or intron 2 of the dystrophin premRNA designated as an annealing site; wherein the base sequence and / or annealing site are selected from one of the following: Sítio de anelamento Sequência base [5' a 3'] SEQ ID NO: H2.SA.(-20+05) TTC ATC TAA AAT GCA AAA TAA AAA A SEQ ID NO:1 H2.SA.(-14+11) TTC TCT TTC ATC TAA AAT GCA AAA T SEQ ID NO:2 H2.SA.(-11+14) ATC TTC TCT TTC ATC TAA AAT GCA A SEQ ID NO:3 H2.SA.(-08+17) AAC ATC TTC TCT TTC ATC TAA AAT G SEQ ID NO:4 H2.SA.(-05+20) TTG AAC ATC TTC TCT TTC ATC TAA A SEQ ID NO:5 H2.SA.(-02+23) CTT TTG AAC ATC TTC TCT TTC ATC T SEQ ID NO:6 H2.SA.(+02+26) TTT CTT TTG AAC ATC TTC TCT TTC A SEQ ID NO:7 H2.SA.(+05+29) TGT TTT CTT TTG AAC ATC TTC TCT T SEQ ID NO:8 H2.SA.(+08+32) GAA TGT TTT CTT TTG AAC ATC TTC T SEQ ID NO:9 H2.SA.(+11+35) TGT GAA TGT TTT CTT TTG AAC ATC T SEQ ID NO:10 H2.SA.(+14+38) TTT TGT GAA TGT TTT CTT TTG AAC A SEQ ID NO:11 H2.SA.(+17+41) CCA TTT TGT GAA TGT TTT CTT TTG A SEQ ID NO:12 H2.SA.(+20+44) TAC CCA TTT TGT GAA TGT TTT CTT T SEQ ID NO:13 H2.SD.(+22-03) TAC CTT AGA AAA TTG TGC ATT TAC C SEQ ID NO:20 H2.SD.(+19-06) TCT TAC CTT AGA AAA TTG TGC ATT T SEQ ID NO:21 H2A(+06+30) ATG TTT TCT TTT GAA CAT CTT CTC T SEQ ID NO:25 H2A(+07+31) AAT GTT TTC TTT TGA ACA TCT CCT: SEQ ID NO:2. Petition 870260074072, of 24 / 07 / 2026, p. 20 / 448 13 / 207 H2A(+09+33) TGA ATG TTT TCT TTT GAA CAT CTT C SEQ ID NO:27 H2A(+10+34) GTG AAT GTT TTC TTT TGA ACA TCT T SEQ ID NO:28 H2A(-38-14) TAA AAA AAT AAA AGT TAG GAA GAA SEQ ID NO:34 H2A(-41-17) AAA AAT AAA AGT TAG GAA GCA ACT T SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36

[038] wherein A is adenine, C is cytosine, G is guanine and T is thymine or uracil. In some modalities, T is thymine.

[039] In some forms, the base sequence corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, or SEQ ID NO:35. In some modes, the base sequence corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, or SEQ ID NO:28. In some modes, the base sequence corresponds to one of the following: SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:25, or SEQ ID NO:28.

[040] In some forms, T is thymine and the base sequence corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, or SEQ ID NO:35. In some modalities, T is thymine and the base sequence corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, or SEQ ID NO:28. In some modalities, T is thymine and the base sequence corresponds to one of the following: SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:25, or SEQ ID NO:28. In some modalities, T is thymine and the base sequence corresponds to SEQ ID NO:19. In some modalities, T is thymine and the base sequence corresponds to SEQ ID NO:27. Petition 870260074072, dated 07 / 24 / 2026, p. 21 / 448 14 / 207

[041] In some embodiments, the antisense oligonucleotide or antisense oligonucleotide conjugate contains a T' portion attached to the end. 5' of the nucleic acid analog, wherein the T' portion is selected from: r200 I; and, where R200 is hydrogen or a cell-penetrating peptide and R1 is C1-C6 alkyl. In certain respects, R200 is hydrogen.

[042] In some respects, the nucleobases of the modified antisense oligomer are linked to morpholino ring structures, wherein the morpholino ring structures are joined by phosphorus-containing intersubunit linkages that link a morpholino nitrogen of one ring structure to a 5' exocyclic carbon of an adjacent ring structure.

[043] In some respects, the bases of the modified antisense oligomer are peptide nucleic acids (PNA), in which the sugar-phosphate polynucleotide structure is replaced by a flexible pseudo-peptide polymer to which the nucleobases are attached.

[044] In some respects, the bases of the modified antisense oligomer are blocked nucleic acids (LNA), where the blocked nucleic acid structures are nucleotide analogs that are chemically modified where the ribose portion has an extra bridge connecting the 2' oxygen and the 4' carbon.

[045] In some respects, the bases of the modified antisense oligomer are bridging nucleic acids (BNA), in which the sugar conformation is restricted or blocked by the introduction of an additional bridging structure into the backbone of Petition 870260074072, dated 07 / 24 / 2026, page 22 / 448 15 / 207 furanose. In some respects, the bases of the antisense oligomer are 2'-O,4'-C-ethylene (ENA) bridged nucleic acids.

[046] In some respects, the modified antisense oligomer may contain unlocked nucleic acid (UNA) subunits. UNA and UNAs oligomers are RNA analogs in which the C2-C3' linkage of the subunit has been cleaved.

[047] In some aspects, the modified antisense oligomer contains one or more phosphorothioates (or S-oligos), in which one of the non-bridge oxygens is replaced by a sulfur. In some aspects, the modified antisense oligomer contains one or more 2'O-Methyl, 2'O-MOE, MCE and 2'-F in which the 2'-OH of ribose is replaced by a methyl, methoxyethyl, 2-(N-methylcarbamoyl)ethyl, or fluoro group, respectively.

[048] In some respects, the modified antisense oligomer is a tricycloDNA (tc-DNA) which is a restricted DNA analogue in which each nucleotide is modified by the introduction of a cyclopropane ring to restrict the conformational flexibility of the structure and to optimize the geometry of the γ torsion angle structure.

[049] In several respects, the disclosure provides antisense oligomers according to Formula (I): Petition 870260074072, dated 07 / 24 / 2026, page 23 / 448 16 / 207 5' (I)

[050] or a pharmaceutically acceptable salt thereof, characterized in that:

[051] each Nu is a nucleobase, which together form a targeting sequence;

[052] T is a selected portion from: Petition 870260074072, dated 07 / 24 / 2026, page 24 / 448 17 / 207

[053] R100 and R200 are each independently hydrogen or a cell-penetrating peptide and R1 is C1-C6 alkyl;

[054] each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Sítio de anelamento Sequência base [5' a 3'] SEQ ID NO: H2.SA.(-20+05) TTC ATC TAA AAT GCA AAA TAA AAA A SEQ ID NO:1 H2.SA.(-14+11) TTC TCT TTC ATC TAA AAT GCA AAA T SEQ ID NO:2 H2.SA.(-11+14) ATC TTC TCT TTC ATC TAA AAT GCA A SEQ ID NO:3 H2.SA.(-08+17) AAC ATC TTC TCT TTC ATC TAA AAT G SEQ ID NO:4 H2.SA.(-05+20) TTG AAC ATC TTC TCT TTC ATC TAA A SEQ ID NO:5 H2.SA.(-02+23) CTT TTG AAC ATC TTC TCT TTC ATC T SEQ ID NO:6 H2.SA.(+02+26) TTT CTT TTG AAC ATC TTC TCT TTC A SEQ ID NO:7 H2.SA.(+05+29) TGT TTT CTT TTG AAC ATC TTC TCT T SEQ ID NO:8 H2.SA.(+08+32) GAA TGT TTT CTT TTG AAC ATC TTC T SEQ ID NO:9 H2.SA.(+11+35) TGT GAA TGT TTT CTT TTG AAC ATC T SEQ ID NO:10 H2.SA.(+14+38) TTT TGT GAA TGT TTT CTT TTG AAC A SEQ ID NO:11 H2.SA.(+17+41) CCA TTT TGT GAA TGT TTT CTT TTG A SEQ ID NO:12 H2.SA.(+20+44) TAC CCA TTT TGT GAA TGT TTT CTT T SEQ ID NO:13 H2.SA.(+23+47) ATT TAC CCA TTT TGT GAA TGT TTT C SEQ ID NO:14 H2.SA.(+26+50) TGC ATT TAC CCA TTT TGT GAA TGT T SEQ ID NO:15 H2.SA.(+29+53) TTG TGC ATT TAC CCA TTT TGT GAA T SEQ ID NO:16 H2.SA.(+32+56) AAA TTG TGC ATT TAC CCA TTT TGT G SEQ ID NO:17 H2.SA.(+35+59) AGA AAA TTG TGC ATT TAC CCA TTT T SEQ ID NO:18 H2.SA.(+38+62) CTT AGA AAA TTG TGC ATT TAC CCA T SEQ ID NO:19 H2.SD.(+22-03) TAC CTT AGA AAA TTG TGC ATT TAC C SEQ ID NO:20 H2.SD.(+19-06) TCT TAC CTT AGA AAA TTG TGC ATT T SEQ ID NO:21 H2.SD.(+16-09) CAT TCT TAC CTT AGA AAA TTG TGC ATT T SEQ ID NO:22 H2.SD.(+13-12) AAC CAT TCT TAC CTT AGA AAA TTG T SEQ ID NO:23 H2.SD.(+10-15) ACA AAC CAT TCT TAC CTT AGA AAA T SEQ ID NO:24 H2A(+06+30) ATG TTT TCT TTT GAA CAT CTT CTC T SEQ ID NO:25 H2A(+07+31) AAT GTT TTC TTT TGA ACA TCT TCT C SEQ ID NO:26 H2A(+09+33) TGA ATG TTT TCT TTT GAA CAT CTT C SEQ ID NO:27. Petition 870260074072, de 24 / 07 / 2026, pág. 25 / 448 18 / 207 H2A(+10+34) GTG AAT GTT TTC TTT TGA ACA TCT T SEQ ID NO:28 H2A(-23+02) ATC TAA AAT GCA AAA TAA AAA AAT A SEQ ID NO:29 H2A(-26-02) TAA AAT GCA AAA TAA AAA AAT AAA A SEQ ID NO:30 H2A(-29-05) AAT GCA AAA TAA AAA AAT AAA AGT T SEQ ID NO:31 H2A(-32-08) GCA AAA TAA AAA AAT AAA AGT TAG G SEQ ID NO:32 H2A(-35-11) AAA TAA AAA AAT AAA AGT TAG GAA G SEQ ID NO:33 H2A(-38-14) TAA AAA AAT AAA AGT TAG GAA GCA A SEQ ID NO:34 H2A(-41-17) AAA AAT AAA AGT TAG GAA GCA ACT T SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36 H2D(+15-08) ATT CTT ACC TTA GAA AAT TGT GC SEQ ID NO:37 H2A(+46+62) CTT AGA AAA TTG TGC AT SEQ ID NO:38 H2D(+08-09) CAT TCT TAC CTT AGA AA SEQ ID NO:39

[055] where A is adenine, C is cytosine, G is guanine and T is thymine or uracil. In certain modalities, T is thymine.

[056] In some embodiments of Formula (I), each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Sítio de anelamento Sequência base [5' a 3'] SEQ ID NO: H2.SA.(-20+05) TTC ATC TAA AAT GCA AAA TAA AAA A SEQ ID NO:1 H2.SA.(-14+11) TTC TCT TTC ATC TAA AAT GCA AAA T SEQ ID NO:2 H2.SA.(-11+14) ATC TTC TCT TTC ATC TAA AAT GCA A SEQ ID NO:3 H2.SA.(-08+17) AAC ATC TTC TCT TTC ATC TAA AAT G SEQ ID NO:4 H2.SA.(-05+20) TTG AAC ATC TTC TCT TTC ATC TAA A SEQ ID NO:5 H2.SA.(-02+23) CTT TTG AAC ATC TTC TCT TTC ATC T SEQ ID NO:6 H2.SA.(+02+26) TTT CTT TTG AAC ATC TTC TCT TTC A SEQ ID NO:7 H2.SA.(+05+29) TGT TTT CTT TTG AAC ATC TTC TCT T SEQ ID NO:8 H2.SA.(+08+32) GAA TGT TTT CTT TTG AAC ATC TTC T SEQ ID NO:9 H2.SA.(+11+35) TGT GAA TGT TTT CTT TTG AAC ATC T SEQ ID NO:10 H2.SA.(+14+38) TTT TGT GAA TGT TTT CTT TTG AAC A SEQ ID NO:11 H2.SA.(+17+41) CCA TTT TGT GAA TGT TTT CTT TTG A SEQ ID NO:12 H2.SA.(+20+44) TAC CCA TTT TGT GAA TGT TTT CTT T SEQ ID NO:13 H2.SA.(+23+47) ATT TAC CCA TTT TGT GAA TGT TTT C SEQ ID NO:14 H2.SA.(+26+50) TGC ATT TAC CCA TTT TGT GAA TGT T SEQ ID NO:15 H2.SA.(+29+53) TTG TGC ATT TAC CCA TTT TGT GAA T SEQ ID NO:16 H2.SA.(+32+56) AAA TTG TGC ATT TAC CCA TTT TGT G SEQ ID NO:17 H2.SA.(+35+59) AGA AAA TTG TGC ATT TAC CCA TTT T SEQ ID NO:18 H2.SD.(+22-03) TAC CTT AGA AAA TTG TGC ATT TAC C SEQ ID NO:20 H2.SD.(+19-06) TCT TAC CTT AGA AAA TTG TGC ATT T SEQ ID NO:21 H2.SD.(+16-09) CAT TCT TAC CTT AGA AAA TTG TGC A SEQ ID NO:22 H2.SD.(+13-12) AAC CAT TCT TAC CTT AGA AAA TTG TGC A SEQ ID NO:23 H2.SD.(+10-15) ACA AAC CAT TCT TAC CTT AGA AAA T SEQ ID NO:24 H2A(+06+30) ATG TTT TCT TTT GAA CAT CTT CTC T SEQ ID NO:25 H2A(+07+31) AAT GTT TTC TTT TGA ACA TCT TCT C SEQ ID NO:26. Petition 870260074072, de 24 / 07 / 2026, pág. 26 / 448 19 / 207 H2A(+09+33) TGA ATG TTT TCT TTT GAA CAT CTT C SEQ ID NO:27 H2A(+10+34) GTG AAT GTT TTC TTT TGA ACA TCT T SEQ ID NO:28 H2A(-23+02) ATC TAA AAT GCA AAA TAA AAA AAT A SEQ ID NO:29 H2A(-26-02) TAA AAT GCA AAA TAA AAA AAT AAA A SEQ ID NO:30 H2A(-29-05) AAT GCA AAA TAA AAA AAT AAA AGT T SEQ ID NO:31 H2A(-32-08) GCA AAA TAA AAA AAT AAA AGT TAG G SEQ ID NO:32 H2A(-35-11) AAA TAA AAA AAT AAA AGT TAG GAA G SEQ ID NO:33 H2A(-38-14) TAA AAA AAT AAA AGT TAG GAA GCA A SEQ ID NO:34 H2A(-41-17) AAA AAT AAA AGT TAG GAA GCA ACT T SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36 H2A(+46+62) CTT AGA AAA TTG TGC AT SEQ ID NO:38 H2D(+08-09) CAT TCT TAC CTT AGA AA SEQ ID NO:39

[057] where A is adenine, C is cytosine, G is guanine and T is thymine or uracil. In certain modalities, T is thymine.

[058] In some embodiments of Formula (I), each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Sítio de anelamento Sequência base [5' a 3'] SEQ ID NO: H2.SA.(-20+05) TTC ATC TAA AAT GCA AAA TAA AAA A SEQ ID NO:1 H2.SA.(-14+11) TTC TCT TTC ATC TAA AAT GCA AAA T SEQ ID NO:2 H2.SA.(-11+14) ATC TTC TCT TTC ATC TAA AAT GCA A SEQ ID NO:3 H2.SA.(-08+17) AAC ATC TTC TCT TTC ATC TAA AAT G SEQ ID NO:4 H2.SA.(-05+20) TTG AAC ATC TTC TCT TTC ATC TAA A SEQ ID NO:5 H2.SA.(-02+23) CTT TTG AAC ATC TTC TCT TTC ATC T SEQ ID NO:6 H2.SA.(+02+26) TTT CTT TTG AAC ATC TTC TCT TTC A SEQ ID NO:7 H2.SA.(+05+29) TGT TTT CTT TTG AAC ATC TTC TCT T SEQ ID NO:8 H2.SA.(+08+32) GAA TGT TTT CTT TTG AAC ATC TTC T SEQ ID NO:9 H2.SA.(+11+35) TGT GAA TGT TTT CTT TTG AAC ATC T SEQ ID NO:10 H2.SA.(+14+38) TTT TGT GAA TGT TTT CTT TTG AAC A SEQ ID NO:11 H2.SA.(+17+41) CCA TTT TGT GAA TGT TTT CTT TTG A SEQ ID NO:12 H2.SA.(+20+44) TAC CCA TTT TGT GAA TGT TTT CTT T SEQ ID NO:13 H2.SA.(+38+62) CTT AGA AAA TTG TGC ATT TAC CCA T SEQ ID NO:19 H2.SD.(+22-03) TAC CTT AGA AAA TTG TGC ATT TAC C SEQ ID NO:20 H2.SD.(+19-06) TCT TAC CTT AGA AAA TTG TGC ATT T SEQ ID NO:21 H2A(+06+30) ATG TTT TCT TTT GAA CAT CTT CTC T SEQ ID NO:25 H2A(+07+31) AAT GTT TTC TTT TGA ACA TCT TCT C SEQ ID NO:26 H2A(+09+33) TGA ATG TTT TCT TTT GAA CAT CTT C SEQ ID NO:27 H2A(+10+34) GTG AAT GTT TTC TTT TGA ACA TCT T SEQ ID NO:28 H2A(-38-14) TAA AAA AAT AAA AGT TAG GAA GCA A SEQ ID NO:34 H2A(-41-17) AAA AAT AAA AGT TAG GAA GCA ACT T SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36. Petition 870260074072, dated 07 / 24 / 2026, p. 27 / 448 20 / 207

[059] where A is adenine, C is cytosine, G is guanine and T is thymine or uracil. In certain modalities, T is thymine.

[060] In some embodiments of Formula (I), each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Sítio de anelamento Sequência base [5' a 3'] SEQ ID NO: H2.SA.(-20+05) TTC ATC TAA AAT GCA AAA TAA AAA A SEQ ID NO:1 H2.SA.(-14+11) TTC TCT TTC ATC TAA AAT GCA AAA T SEQ ID NO:2 H2.SA.(-11+14) ATC TTC TCT TTC ATC TAA AAT GCA A SEQ ID NO:3 H2.SA.(-08+17) AAC ATC TTC TCT TTC ATC TAA AAT G SEQ ID NO:4 H2.SA.(-05+20) TTG AAC ATC TTC TCT TTC ATC TAA A SEQ ID NO:5 H2.SA.(-02+23) CTT TTG AAC ATC TTC TCT TTC ATC T SEQ ID NO:6 H2.SA.(+02+26) TTT CTT TTG AAC ATC TTC TCT TTC A SEQ ID NO:7 H2.SA.(+05+29) TGT TTT CTT TTG AAC ATC TTC TCT T SEQ ID NO:8 H2.SA.(+08+32) GAA TGT TTT CTT TTG AAC ATC TTC T SEQ ID NO:9 H2.SA.(+11+35) TGT GAA TGT TTT CTT TTG AAC ATC SEQ ID NO:10 H2.SA.(+14+38) TTT TGT GAA TGT TTT CTT TTG AAC A SEQ ID NO:11 H2.SA.(+17+41) CCA TTT TGT GAA TGT TTT CTT TTG A SEQ ID NO:12 H2.SA.(+20+44) TAC CCA TTT TGT GAA TGT TTT CTT T SEQ ID NO:13 H2.SD.(+22-03) TAC CTT AGA AAA TTG TGC ATT TAC C SEQ ID NO:20 H2.SD.(+19-06) TCT TAC CTT AGA AAA TTG TGC ATT T SEQ ID NO:21 H2A(+06+30) ATG TTT TCT TTT GAA CAT CTC T SEQ ID NO:25 H2A(+07+31) AAT GTT TTC TTT TGA ACA TCT CCT: SEQ TTC TTC TGA TGA ACA TCT C620 TGA+ IDA+3 ATG TTT TCT TTT GAA CAT CTT C SEQ ID NO:27 H2A(+10+34) GTG AAT GTT TTC TTT TGA ACA TCT T SEQ ID NO:28 H2A(-38-14) TAA AAA AAT AAA AGT TAG GAA GCA A SEQ ID NO:34 H2A-11 AAG AGT GAA AGT-41 AGT AAA GCA ACT T SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36.

[061] wherein A is adenine, C is cytosine, G is guanine and T is thymine or uracil. In some modalities, T is thymine.

[062] In some embodiments, each Nu from 1 to (n+1) and 5' to 3' of Formula (I) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, or SEQ ID NO:35. In some modalities, each Nu from 1 to (n+1) and 5' to 3' of Formula (I) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, Petition 870260074072, dated 07 / 24 / 2026, p. 28 / 448 21 / 207 SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27 or SEQ ID NO:28. In some embodiments, each Nu from 1 to (n+1) and 5' to 3' of Formula (I) corresponds to one of the following: SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:25 or SEQ ID NO:28.

[063] In some embodiments, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (I) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, or SEQ ID NO:35. In some modalities, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (I) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27 or SEQ ID NO:28. In some modalities, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (I) corresponds to one of the following: SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:25 or SEQ ID NO:28. In some forms, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (I) corresponds to SEQ ID NO:19.In some forms, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (I) corresponds to SEQ ID NO:37.

[064] In another aspect, the disclosure provides antisense oligomers of Formula (II): [5'] [3'] (II)

[065] or a pharmaceutically acceptable salt thereof,

[066] R200 is hydrogen or a cell-penetrating peptide; and where each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Petition 870260074072, dated 07 / 24 / 2026, p. 29 / 448 22 / 207 Sítio de anelamento Sequência base [5' a 3'] SEQ ID NO: H2.SA.(-20+05) TTC ATC TAA AAT GCA AAA TAA AAA A SEQ ID NO:1 H2.SA.(-14+11) TTC TCT TTC ATC TAA AAT GCA AAA T SEQ ID NO:2 H2.SA.(-11+14) ATC TTC TCT TTC ATC TAA AAT GCA A SEQ ID NO:3 H2.SA.(-08+17) AAC ATC TTC TCT TTC ATC TAA AAT G SEQ ID NO:4 H2.SA.(-05+20) TTG AAC ATC TTC TCT TTC ATC TAA A SEQ ID NO:5 H2.SA.(-02+23) CTT TTG AAC ATC TTC TCT TTC ATC T SEQ ID NO:6 H2.SA.(+02+26) TTT CTT TTG AAC ATC TTC TCT TTC A SEQ ID NO:7 H2.SA.(+05+29) TGT TTT CTT TTG AAC ATC TTC TCT T SEQ ID NO:8 H2.SA.(+08+32) GAA TGT TTT CTT TTG AAC ATC TTC T SEQ ID NO:9 H2.SA.(+11+35) TGT GAA TGT TTT CTT TTG AAC ATC T SEQ ID NO:10 H2.SA.(+14+38) TTT TGT GAA TGT TTT CTT TTG AAC A SEQ ID NO:11 H2.SA.(+17+41) CCA TTT TGT GAA TGT TTT CTT TTG A SEQ ID NO:12 H2.SA.(+20+44) TAC CCA TTT TGT GAA TGT TTT CTT T SEQ ID NO:13 H2.SA.(+23+47) ATT TAC CCA TTT TGT GAA TGT TTT C SEQ ID NO:14 H2.SA.(+26+50) TGC ATT TAC CCA TTT TGT GAA TGT T SEQ ID NO:15 H2.SA.(+29+53) TTG TGC ATT TAC CCA TTT TGT GAA T SEQ ID NO:16 H2.SA.(+32+56) AAA TTG TGC ATT TAC CCA TTT TGT G SEQ ID NO:17 H2.SA.(+35+59) AGA AAA TTG TGC ATT TAC CCA TTT T SEQ ID NO:18 H2.SA.(+38+62) CTT AGA AAA TTG TGC ATT TAC CCA T SEQ ID NO:19 H2.SD.(+22-03) TAC CTT AGA AAA TTG TGC ATT TAC C SEQ ID NO:20 H2.SD.(+19-06) TCT TAC CTT AGA AAA TTG TGC ATT T SEQ ID NO:21 H2.SD.(+16-09) CAT TCT TAC CTT AGA AAA TTG TGC ATT T SEQ ID NO:22 H2.SD.(+13-12) AAC CAT TCT TAC CTT AGA AAA TTG T SEQ ID NO:23 H2.SD.(+10-15) ACA AAC CAT TCT TAC CTT AGA AAA T SEQ ID NO:24 H2A(+06+30) ATG TTT TCT TTT GAA CAT CTT CTC T SEQ ID NO:25 H2A(+07+31) AAT GTT TTC TTT TGA ACA TCT TCT C SEQ ID NO:26 H2A(+09+33) TGA ATG TTT TCT TTT GAA CAT CTT C SEQ ID NO:27 H2A(+10+34) GTG AAT GTT TTC TTT TGA ACA TCT T SEQ ID NO:28 H2A(-23+02) ATC TAA AAT GCA AAA TAA AAA AAT A SEQ ID NO:29 H2A(-26-02) TAA AAT GCA AAA TAA AAA AAT AAA A SEQ ID NO:30 H2A(-29-05) AAT GCA AAA TAA AAA AAT AAA AGT T SEQ ID NO:31 H2A(-32-08) GCA AAA TAA AAA AAT AAA AGT TAG G SEQ ID NO:32 H2A(-35-11) AAA TAA AAA AAT AAA AGT TAG GAA G SEQ ID NO:33 H2A(-38-14) TAA AAA AAT AAA AGT TAG GAA GCA A SEQ ID NO:34 H2A(-41-17) AAA AAT AAA AGT TAG GAA GCA ACT T SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36 H2D(+15-08) ATT CTT ACC TTA GAA AAT TGT GC SEQ ID NO:37 H2A(+46+62) CTT AGA AAA TTG TGC AT SEQ ID NO:38 H2D(+08-09) CAT TCT TAC CTT AGA AA SEQ ID NO:39.

[067] em que A é adenina, C é citosina, G é guanina e T é timina ou uracila. In certain modalities, T is thymine.

[068] In some Formula (II) modalities, each Nu from 1 to (n+1) and 5' to 3' Petition 870260074072, dated 07 / 24 / 2026, p. 30 / 448 23 / 207 corresponds to the nucleobases in one of the following: Sítio de anelamento Sequência base [5' a 3'] NO: SEQ ID H2.SA.(-20+05) AAA A TTC ATC TAA AAT GCA AAA TAA NO:1 SEQ ID H2.SA.(-14+11) AAA T TTC TCT TTC ATC TAA AAT GCA NO:2 SEQ ID H2.SA.(-11+14) GCA A ATC TTC TCT TTC ATC TAA AAT NO:3 SEQ ID H2.SA.(-08+17) G AAC ATC TTC TCT TTC ATC TAA AAT NO:4 SEQ ID H2.SA.(-05+20) A TTG AAC ATC TTC TCT TTC ATC TAA NO:5 SEQ ID H2.SA.(-02+23) T CTT TTG AAC ATC TTC TCT TTC ATC NO:6 SEQ ID H2.SA.(+02+26) A TTT CTT TTG AAC ATC TTC TCT TTC NO:7 SEQ ID H2.SA.(+05+29) T TGT TTT CTT TTG AAC ATC TTC TCT NO:8 SEQ ID H2.SA.(+08+32) TTC T GAA TGT TTT CTT TTG AAC ATC NO:9 SEQ ID H2.SA.(+11+35) ATC T TGT GAA TGT TTT CTT TTG AAC NO:10 SEQ ID H2.SA.(+14+38) A TTT TGT GAA TGT TTT CTT TTG AAC NO:11 SEQ ID H2.SA.(+17+41) A CCA TTT TGT GAA TGT TTT CTT TTG NO:12 SEQ ID H2.SA.(+20+44) T TAC CCA TTT TGT GAA TGT TTT CTT NO:13 SEQ ID H2.SA.(+23+47) C ATT TAC CCA TTT TGT GAA TGT TTT NO:14 SEQ ID H2.SA.(+26+50) TGT T TGC ATT TAC CCA TTT TGT GAA NO:15 SEQ ID H2.SA.(+29+53) GAA T TTG TGC ATT TAC CCA TTT TGT NO:16 SEQ ID H2.SA.(+32+56) TGT G AAA TTG TGC ATT TAC CCA TTT NO:17 SEQ ID H2.SA.(+35+59) TTT T AGA AAA TTG TGC ATT TAC CCA NO:18 SEQ ID H2.SD.(+22-03) TAC C TAC CTT AGA AAA TTG TGC ATT NO:20 SEQ ID H2.SD.(+19-06) ATT T TCT TAC CTT AGA AAA TTG TGC NO:21 SEQ ID H2.SD.(+16-09) TGC A CAT TCT TAC CTT AGA AAA TTG NO:22 SEQ ID H2.SD.(+13-12) TTG T AAC CAT TCT TAC CTT AGA AAA NO:23 SEQ ID H2.SD.(+10-15) AAA T ACA AAC CAT TCT TAC CTT AGA NO:24 SEQ ID H2A(+06+30) T ATG TTT TCT TTT GAA CAT CTT CTC NO:25 SEQ ID H2A(+07+31) C AAT GTT TTC TTT TGA ACA TCT TCT NO:26 SEQ ID H2A(+09+33) C TGA ATG TTT TCT TTT GAA CAT CTT NO:27 SEQ ID. Petition 870260074072, de 24 / 07 / 2026, pág. 31 / 448 24 / 207 H2A(+10+34) GTG AAT GTT TTC TTT TGA ACA TCT T SEQ ID NO:28 H2A(-23+02) ATC TAA AAT GCA AAA TAA AAA AAT A SEQ ID NO:29 H2A(-26-02) TAA AAT GCA AAA TAA AAA AAT AAA A SEQ ID NO:30 H2A(-29-05) AAT GCA AAA TAA AAA AAT AAA AGT T SEQ ID NO:31 H2A(-32-08) GCA AAA TAA AAA AAT AAA AGT TAG G SEQ ID NO:32 H2A(-35-11) AAA TAA AAA AAT AAA AGT TAG GAA G SEQ ID NO:33 H2A(-38-14) TAA AAA AAT AAA AGT TAG GAA GCA A SEQ ID NO:34 H2A(-41-17) AAA AAT AAA AGT TAG GAA GCA ACT T SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36 H2A(+46+62) CTT AGA AAA TTG TGC AT SEQ ID NO:38 H2D(+08-09) CAT TCT TAC CTT AGA AA SEQ ID NO:39

[069] where A is adenine, C is cytosine, G is guanine and T is thymine or uracil. In certain modalities, T is thymine.

[070] In some embodiments of Formula (II), each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Sítio de anelamento Sequência base [5' a 3'] NO: SEQ ID H2.SA.(-20+05) A TTC ATC TAA AAT GCA AAA TAA AAA NO:1 SEQ ID H2.SA.(-14+11) T TTC TCT TTC ATC TAA AAT GCA AAA NO:2 SEQ ID H2.SA.(-11+14) A ATC TTC TCT TTC ATC TAA AAT GCA NO:3 SEQ ID H2.SA.(-08+17) G AAC ATC TTC TCT TTC ATC TAA AAT NO:4 SEQ ID H2.SA.(-05+20) A TTG AAC ATC TTC TCT TTC ATC TAA NO:5 SEQ ID H2.SA.(-02+23) T CTT TTG AAC ATC TTC TCT TTC ATC NO:6 SEQ ID H2.SA.(+02+26) A TTT CTT TTG AAC ATC TTC TCT TTC NO:7 SEQ ID H2.SA.(+05+29) T TGT TTT CTT TTG AAC ATC TTC TCT NO:8 SEQ ID H2.SA.(+08+32) T GAA TGT TTT CTT TTG AAC ATC TTC NO:9 SEQ ID H2.SA.(+11+35) T TGT GAA TGT TTT CTT TTG AAC ATC NO:10 SEQ ID H2.SA.(+14+38) A TTT TGT GAA TGT TTT CTT TTG AAC NO:11 SEQ ID H2.SA.(+17+41) A CCA TTT TGT GAA TGT TTT CTT TTG NO:12 SEQ ID H2.SA.(+20+44) T TAC CCA TTT TGT GAA TGT TTT CTT NO:13 SEQ ID Petição 870260074072, de 24 / 07 / 2026, pág. 32 / 448 25 / 207 H2.SA.(+38+62) CCA T CTT AGA AAA TTG TGC ATT TAC NO:19 SEQ ID H2.SD.(+22-03) C TAC CTT AGA AAA TTG TGC ATT TAC NO:20 SEQ ID H2.SD.(+19-06) T TCT TAC CTT AGA AAA TTG TGC ATT NO:21 SEQ ID H2A(+06+30) T ATG TTT TCT TTT GAA CAT CTT CTC NO:25 SEQ ID H2A(+07+31) C AAT GTT TTC TTT TGA ACA TCT TCT NO:26 SEQ ID H2A(+09+33) C TGA ATG TTT TCT TTT GAA CAT CTT NO:27 SEQ ID H2A(+10+34) T GTG AAT GTT TTC TTT TGA ACA TCT NO:28 SEQ ID H2A(-38-14) GCA A TAA AAA AAT AAA AGT TAG GAA NO:34 SEQ ID H2A(-41-17) ACT T AAA AAT AAA AGT TAG GAA GCA NO:35 SEQ ID H2A(+11+29) TGT TTT CTT TTG AAC ATC T NO:36 SEQ ID

[071] where A is adenine, C is cytosine, G is guanine and T is thymine or uracil. In certain modalities, T is thymine.

[072] In some embodiment of Formula (II), each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Sítio de anelamento Sequência base [5' a 3'] ID NO: SEQ H2.SA.(-20+05) A TTC ATC TAA AAT GCA AAA TAA AAA ID NO:1 SEQ H2.SA.(-14+11) T TTC TCT TTC ATC TAA AAT GCA AAA ID NO:2 SEQ H2.SA.(-11+14) A ATC TTC TCT TTC ATC TAA AAT GCA ID NO:3 SEQ H2.SA.(-08+17) G AAC ATC TTC TCT TTC ATC TAA AAT ID NO:4 SEQ H2.SA.(-05+20) A TTG AAC ATC TTC TCT TTC ATC TAA ID NO:5 SEQ H2.SA.(-02+23) T CTT TTG AAC ATC TTC TCT TTC ATC ID NO:6 SEQ H2.SA.(+02+26) A TTT CTT TTG AAC ATC TTC TCT TTC ID NO:7 SEQ H2.SA.(+05+29) T TGT TTT CTT TTG AAC ATC TTC TCT ID NO:8 SEQ H2.SA.(+08+32) T GAA TGT TTT CTT TTG AAC ATC TTC ID NO:9 SEQ H2.SA.(+11+35) T TGT GAA TGT TTT CTT TTG AAC ATC ID NO:10 SEQ H2.SA.(+14+38) A TTT TGT GAA TGT TTT CTT TTG AAC ID NO:11 SEQ H2.SA.(+17+41) A CCA TTT TGT GAA TGT TTT CTT TTG ID NO:12 SEQ H2.SA.(+20+44) T TAC CCA TTT TGT GAA TGT TTT CTT ID NO:13 SEQ H2.SD.(+22-03) C TAC CTT AGA AAA TTG TGC ATT TAC ID NO:20 SEQ Petição 870260074072, de 24 / 07 / 2026, pág. 33 / 448 26 / 207 H2.SD.(+19-06) T TCT TAC CTT AGA AAA TTG TGC ATT SEQ ID NO:21 H2A(+06+30) T ATG TTT TCT TTT GAA CAT CTT CTC SEQ ID NO:25 H2A(+07+31) C AAT GTT TTC TTC TGA ACA TCT SEQ ID NO:26 H2A(+09+33) C TGA ATG TTT TCT TTT GAA CAT CTT SEQ ID NO:27 H2A(+10+34) T GTG AAT GTT TTC TGA ACA TCT SEQ ID NO:28 H2A(-38-14) GCA A TAA AAA AAT AAA AAA SEQ TAG GAA ID NO: 317 H2-41 H2A(+10+34) ACT T AAA AAT AAA AGT TAG GAA GCA SEQ ID NO:35 H2A(+11+29) TGT 1 1 1 CTT TTG AAC ATC T SEQ ID NO:36

[073] wherein A is adenine, C is cytosine, G is guanine and T is thymine or uracil. In some modalities, T is thymine.

[074] In some embodiments, each Nu from 1 to (n+1) and 5' to 3' of Formula (II) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, or SEQ ID NO:35. In some modalities, each Nu from 1 to (n+1) and 5' to 3' of Formula (II) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27 or SEQ ID NO:28. In some modalities, each Nu from 1 to (n+1) and 5' to 3' of Formula (II) corresponds to one of the following: SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:25 or SEQ ID NO:28.

[075] In some embodiments, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (II) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, or SEQ ID NO:35. In some forms, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (II) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ Petition 870260074072, dated 07 / 24 / 2026, p. 34 / 448 27 / 207 ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27 or SEQ ID NO:28. In some modalities, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (II) corresponds to one of the following: SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:25 or SEQ ID NO:28. In some modalities, each Nu from 1 to (n+1) and 5' to 3' of Formula (II) corresponds to SEQ ID NO:19. In some modalities, each Nu from 1 to (n+1) and 5' to 3' of Formula (II) corresponds to SEQ ID NO:37.

[076] In another aspect, the disclosure provides antisense oligomers of Formula (III): (III)

[077] or a pharmaceutically acceptable salt thereof,

[078] R200 is hydrogen or a cell-penetrating peptide and each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Sítio de anelamento Sequência base [5' a 3'] NO: SEQ ID H2.SA.(-20+05) AAA A TTC ATC TAA AAT GCA AAA TAA NO:1 SEQ ID H2.SA.(-14+11) AAA T TTC TCT TTC ATC TAA AAT GCA NO:2 SEQ ID H2.SA.(-11+14) GCA A ATC TTC TCT TTC ATC TAA AAT NO:3 SEQ ID H2.SA.(-08+17) AAT G AAC ATC TTC TCT TTC ATC TAA NO:4 SEQ ID H2.SA.(-05+20) TAA A TTG AAC ATC TTC TCT TTC ATC NO:5 SEQ ID H2.SA.(-02+23) ATC T CTT TTG AAC ATC TTC TCT TTC NO:6 SEQ ID H2.SA.(+02+26) TTC A TTT CTT TTG AAC ATC TTC TCT NO:7 SEQ ID H2.SA.(+05+29) TCT T TGT TTT CTT TTG AAC ATC TTC NO:8 SEQ ID H2.SA.(+08+32) TTC T GAA TGT TTT CTT TTG AAC ATC NO:9 SEQ ID Petição 870260074072, de 24 / 07 / 2026, pág. 35 / 448 28 / 207 H2.SA.(+11+35) ATC T TGT GAA TGT TTT CTT TTG AAC NO:10 SEQ ID H2.SA.(+14+38) AAC A TTT TGT GAA TGT TTT CTT TTG NO:11 SEQ ID H2.SA.(+17+41) TTG A CCA TTT TGT GAA TGT TTT CTT NO:12 SEQ ID H2.SA.(+20+44) CTT T TAC CCA TTT TGT GAA TGT TTT NO:13 SEQ ID H2.SA.(+23+47) TTT C ATT TAC CCA TTT TGT GAA TGT NO:14 SEQ ID H2.SA.(+26+50) TGT TGC ATT TAC CCA TTT TGT GAA NO:15 SEQ ID H2.SA.(+29+53) GAA T TTG TGC ATT TAC CCA TTT TGT NO:16 SEQ ID H2.SA.(+32+56) TGT G AAA TTG TGC ATT TAC CCA TTT NO:17 SEQ ID H2.SA.(+35+59) TTT T AGA AAA TTG TGC ATT TAC CCA NO:18 SEQ ID H2.SA.(+38+62) CCA T CTT AGA AAA TTG TGC ATT TAC NO:19 SEQ ID H2.SD.(+22-03) TAC C TAC CTT AGA AAA TTG TGC ATT NO:20 SEQ ID H2.SD.(+19-06) ATT T TCT TAC CTT AGA AAA TTG TGC NO:21 SEQ ID H2.SD.(+16-09) TGC A CAT TCT TAC CTT AGA AAA TTG NO:22 SEQ ID H2.SD.(+13-12) TTG T AAC CAT TCT TAC CTT AGA AAA NO:23 SEQ ID H2.SD.(+10-15) AAA T ACA AAC CAT TCT TAC CTT AGA NO:24 SEQ ID H2A(+06+30) CTC T ATG TTT TCT TTT GAA CAT CTT NO:25 SEQ ID H2A(+07+31) TCT C AAT GTT TTC TTT TGA ACA TCT NO:26 SEQ ID H2A(+09+33) CTT C TGA ATG TTT TCT TTT GAA CAT NO:27 SEQ ID H2A(+10+34) TCT T GTG AAT GTT TTC TTT TGA ACA NO:28 SEQ ID H2A(-23+02) AAT A ATC TAA AAT GCA AAA TAA AAA NO:29 SEQ ID H2A(-26-02) AAA A TAA AAT GCA AAA TAA AAA AAT NO:30 SEQ ID H2A(-29-05) AGT T AAT GCA AAA TAA AAA AAT AAA NO:31 SEQ ID H2A(-32-08) TAG G GCA AAA TAA AAA AAT AAA AGT NO:32 SEQ ID H2A(-35-11) GAA G AAA TAA AAA AAT AAA AGT TAG NO:33 SEQ ID H2A(-38-14) GCA A TAA AAA AAT AAA AGT TAG GAA NO:34 SEQ ID H2A(-41-17) ACT T AAA AAT AAA AGT TAG GAA GCA NO:35 SEQ ID H2A(+11+29) TGT TTT CTT TTG AAC ATC T NO:36 SEQ ID H2D(+15-08) GC ATT CTT ACC TTA GAA AAT TGT NO:37 SEQ ID. Petição 870260074072, de 24 / 07 / 2026, pág. 36 / 448 29 / 207 H2A(+46+62) CTT AGA AAA TTG TGC AT SEQ ID NO:38 H2D(+08-09) CAT TCT TAC CTT AGA AA SEQ ID NO:39

[079] where A is adenine, C is cytosine, G is guanine and T is thymine or uracil. In certain modalities, T is thymine.

[080] In some Formula (III) modalities, each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Sítio de anelamento Sequência base [5' a 3'] ID NO: SEQ H2.SA.(-20+05) A TTC ATC TAA AAT GCA AAA TAA AAA ID NO:1 SEQ H2.SA.(-14+11) T TTC TCT TTC ATC TAA AAT GCA AAA ID NO:2 SEQ H2.SA.(-11+14) A ATC TTC TCT TTC ATC TAA AAT GCA ID NO:3 SEQ H2.SA.(-08+17) G AAC ATC TTC TCT TTC ATC TAA AAT ID NO:4 SEQ H2.SA.(-05+20) A TTG AAC ATC TTC TCT TTC ATC TAA ID NO:5 SEQ H2.SA.(-02+23) T CTT TTG AAC ATC TTC TCT TTC ATC ID NO:6 SEQ H2.SA.(+02+26) TTT CTT TTG AAC ATC TTC TCT TTC A ID NO:7 SEQ H2.SA.(+05+29) T TGT TTT CTT TTG AAC ATC TTC TCT ID NO:8 SEQ H2.SA.(+08+32) T GAA TGT TTT CTT TTG AAC ATC TTC ID NO:9 SEQ H2.SA.(+11+35) T TGT GAA TGT TTT CTT TTG AAC ATC ID NO:10 SEQ H2.SA.(+14+38) A TTT TGT GAA TGT TTT CTT TTG AAC ID NO:11 SEQ H2.SA.(+17+41) A CCA TTT TGT GAA TGT TTT CTT TTG ID NO:12 SEQ H2.SA.(+20+44) T TAC CCA TTT TGT GAA TGT TTT CTT ID NO:13 SEQ H2.SA.(+23+47) C ATT TAC CCA TTT TGT GAA TGT TTT ID NO:14 SEQ H2.SA.(+26+50) T TGC ATT TAC CCA TTT TGT GAA TGT ID NO:15 SEQ H2.SA.(+29+53) T TTG TGC ATT TAC CCA TTT TGT GAA ID NO:16 SEQ H2.SA.(+32+56) G AAA TTG TGC ATT TAC CCA TTT TGT ID NO:17 SEQ H2.SA.(+35+59) T AGA AAA TTG TGC ATT TAC CCA TTT ID NO:18 SEQ H2.SD.(+22-03) C TAC CTT AGA AAA TTG TGC ATT TAC ID NO:20 SEQ H2.SD.(+19-06) T TCT TAC CTT AGA AAA TTG TGC ATT ID NO:21 SEQ H2.SD.(+16-09) A CAT TCT TAC CTT AGA AAA TTG TGC ID NO:22 SEQ. Petition 870260074072, de 24 / 07 / 2026, pág. 37 / 448 30 / 207 H2.SD.(+13-12) T AAC CAT TCT TAC CTT AGA AAA TTG SEQ ID NO:23 H2.SD.(+10-15) T ACA AAC CAT TCT TAC CTT AGA AAA SEQ ID NO:24 H2A(+06+30) T ATG TTT TCT TTT GAA CAT CTT CTC SEQ ID NO:25 H2A(+07+31) C AAT GTT TTC TTT TGA ACA TCT TCT SEQ ID NO:26 H2A(+09+33) C TGA ATG TTT TCT TTT GAA CAT CTT SEQ ID NO:27 H2A(+10+34) T GTG AAT GTT TTC TTT TGA ACA TCT SEQ ID NO:28 H2A(-23+02) A ATC TAA AAT GCA AAA TAA AAA AAT SEQ ID NO:29 H2A(-26-02) A TAA AAT GCA AAA TAA AAA AAT AAA SEQ ID NO:30 H2A(-29-05) T AAT GCA AAA TAA AAA AAT AAA AGT SEQ ID NO:31 H2A(-32-08) G GCA AAA TAA AAA AAT AAA AGT TAG SEQ ID NO:32 H2A(-35-11) G AAA TAA AAA AAT AAA AGT TAG GAA SEQ ID NO:33 H2A(-38-14) A TAA AAA AAT AAA AGT TAG GAA GCA SEQ ID NO:34 H2A(-41-17) T AAA AAT AAA AGT TAG GAA GCA ACT SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36 H2A(+46+62) CTT AGA AAA TTG TGC AT SEQ ID NO:38 H2D(+08-09) CAT TCT TAC CTT AGA AA SEQ ID NO:39

[081] where A is adenine, C is cytosine, G is guanine and T is thymine or uracil. In certain modalities, T is thymine.

[082] In some Formula (III) modalities, each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Annealing site Base sequence [5' to 3'] ID NO: SEQ H2.SA.(-20+05) A TTC ATC TAA AAT GCA AAA TAA AAA ID NO:1 SEQ H2.SA.(-14+11) T TTC TCT TTC ATC TAA AAT GCA AAA ID NO:2 SEQ H2.SA.(-11+14) A ATC TTC TCT TTC ATC TAA AAT GCA ID NO:3 SEQ H2.SA.(-08+17) G AAC ATC TTC TCT TTC ATC TAA AAT ID NO:4 SEQ H2.SA.(-05+20) A TTG AAC ATC TTC TCT TTC ATC TAA ID NO:5 SEQ H2.SA.(-02+23) T CTT TTG AAC ATC TTC TCT TTC ATC ID NO:6 SEQ H2.SA.(+02+26) TTT CTT TTG AAC ATC TTC TCT TTC A ID NO:7 SEQ Petition 870260074072, dated 07 / 24 / 2026, p. 38 / 448 31 / 207 H2.SA.(+05+29) T TGT TTT CTT TTG AAC ATC TTC TCT SEQ ID NO:8 H2.SA.(+08+32) T GAA TGT TTT CTT TTG AAC ATC TTC SEQ ID NO:9 H2.SA.(+11+35) T TGT GAA TGT TTT CTT TTG AAC ATC SEQ ID NO:10 H2.SA.(+14+38) A TTT TGT GAA TGT TTT CTT TTG AAC SEQ ID NO:11 H2.SA.(+17+41) A CCA TTT TGT GAA TGT TTT CTT TTG SEQ ID NO:12 H2.SA.(+20+44) T TAC CCA TTT TGT GAA TGT TTT CTT SEQ ID NO:13 H2.SA.(+38+62) T CTT AGA AAA TTG TGC ATT TAC CCA SEQ ID NO:19 H2.SD.(+22-03) C TAC CTT AGA AAA TTG TGC ATT TAC SEQ ID NO:20 H2.SD.(+19-06) T TCT TAC CTT AGA AAA TTG TGC ATT SEQ ID NO:21 H2A(+06+30) T ATG TTT TCT TTT GAA CAT CTT CTC SEQ ID NO:25 H2A(+07+31) C AAT GTT TTC TTT TGA ACA TCT TCT SEQ ID NO:26 H2A(+09+33) C TGA ATG TTT TCT TTT GAA CAT CTT SEQ ID NO:27 H2A(+10+34) T GTG AAT GTT TTC TTT TGA ACA TCT SEQ ID NO:28 H2A(-38-14) A TAA AAA AAT AAA AGT TAG GAA GCA SEQ ID NO:34 H2A(-41-17) T AAA AAT AAA AGT TAG GAA GCA ACT SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36

[083] where A is adenine, C is cytosine, G is guanine and T is thymine or uracil. In certain modalities, T is thymine.

[084] In some Formula (III) modalities, each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Annealing site Base sequence [5' to 3'] ID NO: SEQ H2.SA.(-20+05) A TTC ATC TAA AAT GCA AAA TAA AAA ID NO:1 SEQ H2.SA.(-14+11) T TTC TCT TTC ATC TAA AAT GCA AAA ID NO:2 SEQ H2.SA.(-11+14) A ATC TTC TCT TTC ATC TAA AAT GCA ID NO:3 SEQ H2.SA.(-08+17) G AAC ATC TTC TCT TTC ATC TAA AAT ID NO:4 SEQ H2.SA.(-05+20) A TTG AAC ATC TTC TCT TTC ATC TAA ID NO:5 SEQ H2.SA.(-02+23) T CTT TTG AAC ATC TTC TCT TTC ATC ID NO:6 SEQ H2.SA.(+02+26) TTT CTT TTG AAC ATC TTC TCT TTC A ID NO:7 SEQ Petition 870260074072, dated 07 / 24 / 2026, p. 39 / 448 32 / 207 H2.SA.(+05+29) T TGT TTT CTT TTG AAC ATC TTC TCT SEQ ID NO:8 H2.SA.(+08+32) T GAA TGT TTT CTT TTG AAC ATC TTC SEQ ID NO:9 H2.SA.(+11+35) T TGT GAA TGT TTT CTT TTG AAC ATC SEQ ID NO:10 H2.SA.(+14+38) A TTT TGT GAA TGT TTT CTT TTG AAC SEQ ID NO:11 H2.SA.(+17+41) A CCA TTT TGT GAA TGT TTT CTT TTG SEQ ID NO:12 H2.SA.(+20+44) T TAC CCA TTT TGT GAA TGT TTT CTT SEQ ID NO:13 H2.SD.(+22-03) C TAC CTT AGA AAA TTG TGC ATT TAC SEQ ID NO:20 H2.SD.(+19-06) T TCT TAC CTT AGA AAA TTG TGC ATT SEQ ID NO:21 H2A(+06+30) T ATG TTT TCT TTT GAA CAT CTT CTC SEQ ID NO:25 H2A(+07+31) C AAT GTT TTC TTT TGA ACA TCT TCT SEQ ID NO:26 H2A(+09+33) C TGA ATG TTT TCT TTT GAA CAT CTT SEQ ID NO:27 H2A(+10+34) T GTG AAT GTT TTC TTT TGA ACA TCT SEQ ID NO:28 H2A(-38-14) A TAA AAA AAT AAA AGT TAG GAA GCA SEQ ID NO:34 H2A(-41-17) T AAA AAT AAA AGT TAG GAA GCA ACT SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36

[085] em que A é adenina, C é citosina, G é guanina e T é timina ou uracila. In certain modalities, T is thymine.

[086] In some embodiments, each Nu from 1 to (n+1) and 5' to 3' of Formula (III) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, or SEQ ID NO:35. In some forms, each Nu from 1 to (n+1) and 5' to 3' of Formula (III) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27 or SEQ ID NO:28. In some forms, each Nu from 1 to (n+1) and 5' to 3' of Formula (III) corresponds to one of the following: SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:25 or SEQ ID NO:28. Petition 870260074072, dated 07 / 24 / 2026, p. 40 / 448 33 / 207

[087] In some embodiments, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (III) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, or SEQ ID NO:35. In some modalities, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (III) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27 or SEQ ID NO:28. In some modalities, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (III) corresponds to one of the following: SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:25 or SEQ ID NO:28. In some forms, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (III) corresponds to SEQ ID NO:19.In some forms, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (III) corresponds to SEQ ID NO:37.

[088] In another aspect, disclosure provides antisense oligomers of Formula (IV): (IV)

[089] where each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Annealing site Baseline sequence [5' to 3'] ID NO: SEQ H2.SA.(-20+05) A TTC ATC TAA AAT GCA AAA TAA AAA ID NO:1 SEQ H2.SA.(-14+11) T TTC TCT TTC ATC TAA AAT GCA AAA ID NO:2 SEQ Petition 870260074072, dated 07 / 24 / 2026, p. 41 / 448 34 / 207 H2.SA.(-11+14) A ATC TTC TCT TTC ATC TAA AAT GCA SEQ ID NO:3 H2.SA.(-08+17) G AAC ATC TTC TCT TTC ATC TAA AAT SEQ ID NO:4 H2.SA.(-05+20) A TTG AAC ATC TTC TCT TTC ATC TAA SEQ ID NO:5 H2.SA.(-02+23) T CTT TTG AAC ATC TTC TCT TTC ATC SEQ ID NO:6 H2.SA.(+02+26) TTT CTT TTG AAC ATC TTC TCT TTC A SEQ ID NO:7 H2.SA.(+05+29) T TGT TTT CTT TTG AAC ATC TTC TCT SEQ ID NO:8 H2.SA.(+08+32) T GAA TGT TTT CTT TTG AAC ATC TTC SEQ ID NO:9 H2.SA.(+11+35) T TGT GAA TGT TTT CTT TTG AAC ATC SEQ ID NO:10 H2.SA.(+14+38) A TTT TGT GAA TGT TTT CTT TTG AAC SEQ ID NO:11 H2.SA.(+17+41) A CCA TTT TGT GAA TGT TTT CTT TTG SEQ ID NO:12 H2.SA.(+20+44) T TAC CCA TTT TGT GAA TGT TTT CTT SEQ ID NO:13 H2.SA.(+23+47) C ATT TAC CCA TTT TGT GAA TGT TTT SEQ ID NO:14 H2.SA.(+26+50) T TGC ATT TAC CCA TTT TGT GAA TGT SEQ ID NO:15 H2.SA.(+29+53) T TTG TGC ATT TAC CCA TTT TGT GAA SEQ ID NO:16 H2.SA.(+32+56) G AAA TTG TGC ATT TAC CCA TTT TGT SEQ ID NO:17 H2.SA.(+35+59) T AGA AAA TTG TGC ATT TAC CCA TTT SEQ ID NO:18 H2.SA.(+38+62) T CTT AGA AAA TTG TGC ATT TAC CCA SEQ ID NO:19 H2.SD.(+22-03) C TAC CTT AGA AAA TTG TGC ATT TAC SEQ ID NO:20 H2.SD.(+19-06) T TCT TAC CTT AGA AAA TTG TGC ATT SEQ ID NO:21 H2.SD.(+16-09) A CAT TCT TAC CTT AGA AAA TTG TGC SEQ ID NO:22 H2.SD.(+13-12) T AAC CAT TCT TAC CTT AGA AAA TTG SEQ ID NO:23 H2.SD.(+10-15) T ACA AAC CAT TCT TAC CTT AGA AAA SEQ ID NO:24 H2A(+06+30) T ATG TTT TCT TTT GAA CAT CTT CTC SEQ ID NO:25 H2A(+07+31) C AAT GTT TTC TTT TGA ACA TCT TCT SEQ ID NO:26 H2A(+09+33) C TGA ATG TTT TCT TTT GAA CAT CTT SEQ ID NO:27 H2A(+10+34) T GTG AAT GTT TTC TTT TGA ACA TCT SEQ ID NO:28 H2A(-23+02) A ATC TAA AAT GCA AAA TAA AAA AAT SEQ ID NO:29 H2A(-26-02) A TAA AAT GCA AAA TAA AAA AAT AAA SEQ ID NO:30. Petição 870260074072, de 24 / 07 / 2026, pág. 42 / 448 35 / 207 H2A(-29-05) T AAT GCA AAA TAA AAA AAT AAA AGT SEQ ID NO:31 H2A(-32-08) G GCA AAA TAA AAA AAT AAA AGT TAG SEQ ID NO:32 H2A(-35-11) G AAA TAA AAA AAT AAA AGT TAG GAA SEQ ID NO:33 H2A(-38-14) A TAA AAA AAT AAA AGT TAG GAA GCA SEQ ID NO:34 H2A(-41-17) T AAA AAT AAA AGT TAG GAA GCA ACT SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36 H2D(+15-08) ATT CTT ACC TTA GAA AAT TGT GC SEQ ID NO:37 H2A(+46+62) CTT AGA AAA TTG TGC AT SEQ ID NO:38 H2D(+08-09) CAT TCT TAC CTT AGA AA SEQ ID NO:39

[090] where A is adenine, C is cytosine, G is guanine and T is thymine or uracil. In certain modalities, T is thymine.

[091] In some Formula (IV) modalities, each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Sítio de anelamento Sequência base [5' a 3'] ID NO: SEQ H2.SA.(-20+05) A TTC ATC TAA AAT GCA AAA TAA AAA ID NO:1 SEQ H2.SA.(-14+11) T TTC TCT TTC ATC TAA AAT GCA AAA ID NO:2 SEQ H2.SA.(-11+14) A ATC TTC TCT TTC ATC TAA AAT GCA ID NO:3 SEQ H2.SA.(-08+17) G AAC ATC TTC TCT TTC ATC TAA AAT ID NO:4 SEQ H2.SA.(-05+20) A TTG AAC ATC TTC TCT TTC ATC TAA ID NO:5 SEQ H2.SA.(-02+23) T CTT TTG AAC ATC TTC TCT TTC ATC ID NO:6 SEQ H2.SA.(+02+26) TTT CTT TTG AAC ATC TTC TCT TTC A ID NO:7 SEQ H2.SA.(+05+29) T TGT TTT CTT TTG AAC ATC TTC TCT ID NO:8 SEQ H2.SA.(+08+32) T GAA TGT TTT CTT TTG AAC ATC TTC ID NO:9 SEQ H2.SA.(+11+35) T TGT GAA TGT TTT CTT TTG AAC ATC ID NO:10 SEQ H2.SA.(+14+38) A TTT TGT GAA TGT TTT CTT TTG AAC ID NO:11 SEQ H2.SA.(+17+41) A CCA TTT TGT GAA TGT TTT CTT TTG ID NO:12 SEQ H2.SA.(+20+44) T TAC CCA TTT TGT GAA TGT TTT CTT ID NO:13 SEQ H2.SA.(+23+47) C ATT TAC CCA TTT TGT GAA TGT TTT ID NO:14 SEQ H2.SA.(+26+50) T TGC ATT TAC CCA TTT TGT GAA TGT ID NO:15 SEQ Petition 870260074072, dated 07 / 24 / 2026, pp. 43 / 448 36 / 207 H2.SA.(+29+53) T TTG TGC ATT TAC CCA TTT TGT GAA SEQ ID NO:16 H2.SA.(+32+56) G AAA TTG TGC ATT TAC CCA TTT TGT SEQ ID NO:17 H2.SA.(+35+59) T AGA AAA TTG TGC ATT TAC CCA TTT SEQ ID NO:18 H2.SD.(+22-03) C TAC CTT AGA AAA TTG TGC ATT TAC SEQ ID NO:20 H2.SD.(+19-06) T TCT TAC CTT AGA AAA TTG TGC ATT SEQ ID NO:21 H2.SD.(+16-09) A CAT TCT TAC CTT AGA AAA TTG TGC SEQ ID NO:22 H2.SD.(+13-12) T AAC CAT TCT TAC CTT AGA AAA TTG SEQ ID NO:23 H2.SD.(+10-15) T ACA AAC CAT TCT TAC CTT AGA AAA SEQ ID NO:24 H2A(+06+30) T ATG TTT TCT TTT GAA CAT CTT CTC SEQ ID NO:25 H2A(+07+31) C AAT GTT TTC TTT TGA ACA TCT TCT SEQ ID NO:26 H2A(+09+33) C TGA ATG TTT TCT TTT GAA CAT CTT SEQ ID NO:27 H2A(+10+34) T GTG AAT GTT TTC TTT TGA ACA TCT SEQ ID NO:28 H2A(-23+02) A ATC TAA AAT GCA AAA TAA AAA AAT SEQ ID NO:29 H2A(-26-02) A TAA AAT GCA AAA TAA AAA AAT AAA SEQ ID NO:30 H2A(-29-05) T AAT GCA AAA TAA AAA AAT AAA AGT SEQ ID NO:31 H2A(-32-08) G GCA AAA TAA AAA AAT AAA AGT TAG SEQ ID NO:32 H2A(-35-11) G AAA TAA AAA AAT AAA AGT TAG GAA SEQ ID NO:33 H2A(-38-14) A TAA AAA AAT AAA AGT TAG GAA GCA SEQ ID NO:34 H2A(-41-17) T AAA AAT AAA AGT TAG GAA GCA ACT SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36 H2A(+46+62) CTT AGA AAA TTG TGC AT SEQ ID NO:38 H2D(+08-09) CAT TCT TAC CTT AGA AA SEQ ID NO:39.

[092] em que A é adenina, C é citosina, G é guanina e T é timina ou uracila. Em certas modalidades, T é timina.

[093] In some Formula (IV) modalities, each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Annealing site Baseline sequence [5' to 3'] ID NO: SEQ H2.SA.(-20+05) A TTC ATC TAA AAT GCA AAA TAA AAA ID NO:1 SEQ H2.SA.(-14+11) T TTC TCT TTC ATC TAA AAT GCA AAA ID NO:2 SEQ Petition 870260074072, dated 07 / 24 / 2026, pp. 44 / 448 37 / 207 H2.SA.(-11+14) A ATC TTC TCT TTC ATC TAA AAT GCA SEQ ID NO:3 H2.SA.(-08+17) G AAC ATC TTC TCT TTC ATC TAA AAT SEQ ID NO:4 H2.SA.(-05+20) A TTG AAC ATC TTC TCT TTC ATC TAA SEQ ID NO:5 H2.SA.(-02+23) T CTT TTG AAC ATC TTC TCT TTC ATC SEQ ID NO:6 H2.SA.(+02+26) A TTT CTT TTG AAC ATC TTC TCT TTC SEQ ID NO:7 H2.SA.(+05+29) T TGT TTT CTT TTG AAC ATC TTC TCT SEQ ID NO:8 H2.SA.(+08+32) T GAA TGT TTT CTT TTG AAC ATC TTC SEQ ID NO:9 H2.SA.(+11+35) T TGT GAA TGT TTT CTT TTG AAC ATC SEQ ID NO:10 H2.SA.(+14+38) A TTT TGT GAA TGT TTT CTT TTG AAC SEQ ID NO:11 H2.SA.(+17+41) A CCA TTT TGT GAA TGT TTT CTT TTG SEQ ID NO:12 H2.SA.(+20+44) T TAC CCA TTT TGT GAA TGT TTT CTT SEQ ID NO:13 H2.SA.(+38+62) CCA T CTT AGA AAA TTG TGC ATT TAC SEQ ID NO:19 H2.SD.(+22-03) C TAC CTT AGA AAA TTG TGC ATT TAC SEQ ID NO:20 H2.SD.(+19-06) T TCT TAC CTT AGA AAA TTG TGC ATT SEQ ID NO:21 H2A(+06+30) T ATG TTT TCT TTT GAA CAT CTT CTC SEQ ID NO:25 H2A(+07+31) C AAT GTT TTC TTT TGA ACA TCT TCT SEQ ID NO:26 H2A(+09+33) C TGA ATG TTT TCT TTT GAA CAT CTT SEQ ID NO:27 H2A(+10+34) T GTG AAT GTT TTC TTT TGA ACA TCT SEQ ID NO:28 H2A(-38-14) GCA A TAA AAA AAT AAA AGT TAG GAA SEQ ID NO:34 H2A(-41-17) ACT T AAA AAT AAA AGT TAG GAA GCA SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36.

[094] where A is adenine, C is cytosine, G is guanine and T is thymine or uracil. In certain modalities, T is thymine.

[095] In some Formula (IV) modalities, each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Annealing site Baseline sequence [5' to 3'] NO: SEQ ID H2.SA.(-20+05) AAA A TTC ATC TAA AAT GCA AAA TAA NO:1 SEQ ID H2.SA.(-14+11) AAA T TTC TCT TTC ATC TAA AAT GCA NO:2 SEQ ID Petition 870260074072, dated 07 / 24 / 2026, pp. 45 / 448 38 / 207 H2.SA.(-11+14) ATC TTC TCT TTC ATC TAA AAT GCA A SEQ ID NO:3 H2.SA.(-08+17) AAC ATC TTC TCT TTC ATC TAA AAT G SEQ ID NO:4 H2.SA.(-05+20) TTG AAC ATC TTC TCT TTC ATC TAA A SEQ ID NO:5 H2.SA.(-02+23) CTT TTG AAC ATC TTC TCT TTC ATC T SEQ ID NO:6 H2.SA.(+02+26) TTT CTT TTG AAC ATC TTC TCT TTC A SEQ ID NO:7 H2.SA.(+05+29) TGT TTT CTT TTG AAC ATC TTC TCT T SEQ ID NO:8 H2.SA.(+08+32) GAA TGT TTT CTT TTG AAC ATC TTC T SEQ ID NO:9 H2.SA.(+11+35) TGT GAA TGT TTT CTT TTG AAC ATC T SEQ ID NO:10 H2.SA.(+14+38) TTT TGT GAA TGT TTT CTT TTG AAC A SEQ ID NO:11 H2.SA.(+17+41) CCA TTT TGT GAA TGT TTT CTT TTG A SEQ ID NO:12 H2.SA.(+20+44) TAC CCA TTT TGT GAA TGT TTT CTT T SEQ ID NO:13 H2.SD.(+22-03) TAC CTT AGA AAA TTG TGC ATT TAC C SEQ ID NO:20 H2.SD.(+19-06) TCT TAC CTT AGA AAA TTG TGC ATT T SEQ ID NO:21 H2A(+06+30) ATG TTT TCT TTT GAA CAT CTC T SEQ ID NO:25 H2A(+07+31) AAT GTT TTC TTT TGA ACA TCT CCT: SEQ TTC TTC TGA TGA ACA TCT C620 TGA+ IDA+3 ATG TTT TCT TTT GAA CAT CTT C SEQ ID NO:27 H2A(+10+34) GTG AAT GTT TTC TTT TGA ACA TCT T SEQ ID NO:28 H2A(-38-14) TAA AAA AAT AAA AGT TAG GAA GCA A SEQ ID NO:34 H2A-11 AAG AGT GAA AGT-41 AGT AAA GCA ACT T SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36.

[096] wherein A is adenine, C is cytosine, G is guanine and T is thymine or uracil. In some modalities, T is thymine.

[097] In some forms, each Nu from 1 to (n+1) and 5' to 3' of Formula (IV) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, or SEQ ID NO:35. In some forms, each Nu from 1 to (n+1) and 5' to 3' of Formula (IV) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:5, Petition 870260074072, dated 07 / 24 / 2026, pp. 46 / 448 39 / 207 SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27 or SEQ ID NO:28. In some embodiments, each Nu from 1 to (n+1) and 5' to 3' of Formula (IV) corresponds to one of the following: SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:25 or SEQ ID NO:28.

[098] In some embodiments, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (IV) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, or SEQ ID NO:35. In some modalities, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (IV) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27 or SEQ ID NO:28. In some modalities, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (IV) corresponds to one of the following: SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:25 or SEQ ID NO:28. In some forms, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (IV) corresponds to SEQ ID NO:19.In some forms, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (IV) corresponds to SEQ ID NO:37.

[099] In another aspect, the disclosure provides antisense oligomers of Formula (V): Petition 870260074072, dated 07 / 24 / 2026, pp. 47 / 448 40 / 207 (V)

[0100] or a pharmaceutically acceptable salt thereof,

[0101] R200 is hydrogen or a cell-penetrating peptide and where each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Sítio de anelamento Sequência base [5' a 3'] NO: SEQ ID H2.SA.(-20+05) AAA A TTC ATC TAA AAT GCA AAA TAA NO:1 SEQ ID H2.SA.(-14+11) AAA T TTC TCT TTC ATC TAA AAT GCA NO:2 SEQ ID H2.SA.(-11+14) GCA A ATC TTC TCT TTC ATC TAA AAT NO:3 SEQ ID H2.SA.(-08+17) AAT G AAC ATC TTC TCT TTC ATC TAA NO:4 SEQ ID H2.SA.(-05+20) TAA A TTG AAC ATC TTC TCT TTC ATC NO:5 SEQ ID H2.SA.(-02+23) ATC T CTT TTG AAC ATC TTC TCT TTC NO:6 SEQ ID H2.SA.(+02+26) TTC A TTT CTT TTG AAC ATC TTC TCT NO:7 SEQ ID H2.SA.(+05+29) TCT T TGT TTT CTT TTG AAC ATC TTC NO:8 SEQ ID H2.SA.(+08+32) TTC T GAA TGT TTT CTT TTG AAC ATC NO:9 SEQ ID H2.SA.(+11+35) ATC T TGT GAA TGT TTT CTT TTG AAC NO:10 SEQ ID H2.SA.(+14+38) AAC A TTT TGT GAA TGT TTT CTT TTG NO:11 SEQ ID H2.SA.(+17+41) TTG A CCA TTT TGT GAA TGT TTT CTT NO:12 SEQ ID H2.SA.(+20+44) CTT T TAC CCA TTT TGT GAA TGT TTT NO:13 SEQ ID H2.SA.(+23+47) TTT C ATT TAC CCA TTT TGT GAA TGT NO:14 SEQ ID H2.SA.(+26+50) TGT T TGC ATT TAC CCA TTT TGT GAA NO:15 SEQ ID H2.SA.(+29+53) GAA T TTG TGC ATT TAC CCA TTT TGT NO:16 SEQ ID H2.SA.(+32+56) TGT G AAA TTG TGC ATT TAC CCA TTT NO:17 SEQ ID. Petition 870260074072, of 24 / 07 / 2026, p. 48 / 448 41 / 207 H2.SA.(+35+59) TTT T AGA AAA TTG TGC ATT TAC CCA NO:18 SEQ ID H2.SA.(+38+62) CCA T CTT AGA AAA TTG TGC ATT TAC NO:19 SEQ ID H2.SD.(+22-03) TAC C TAC CTT AGA AAA TTG TGC ATT NO:20 SEQ ID H2.SD.(+19-06) ATT T TCT TAC CTT AGA AAA TTG TGC NO:21 SEQ ID H2.SD.(+16-09) TGC A CAT TCT TAC CTT AGA AAA TTG NO:22 SEQ ID H2.SD.(+13-12) TTG T AAC CAT TCT TAC CTT AGA AAA NO:23 SEQ ID H2.SD.(+10-15) AAA T ACA AAC CAT TCT TAC CTT AGA NO:24 SEQ ID H2A(+06+30) CTC T ATG TTT TCT TTT GAA CAT CTT NO:25 SEQ ID H2A(+07+31) TCT C AAT GTT TTC TTT TGA ACA TCT NO:26 SEQ ID H2A(+09+33) CTT C TGA ATG TTT TCT TTT GAA CAT NO:27 SEQ ID H2A(+10+34) TCT T GTG AAT GTT TTC TTT TGA ACA NO:28 SEQ ID H2A(-23+02) AAT A ATC TAA AAT GCA AAA TAA AAA NO:29 SEQ ID H2A(-26-02) AAA A TAA AAT GCA AAA TAA AAA AAT NO:30 SEQ ID H2A(-29-05) AGT T AAT GCA AAA TAA AAA AAT AAA NO:31 SEQ ID H2A(-32-08) TAG G GCA AAA TAA AAA AAT AAA AGT NO:32 SEQ ID H2A(-35-11) GAA G AAA TAA AAA AAT AAA AGT TAG NO:33 SEQ ID H2A(-38-14) GCA A TAA AAA AAT AAA AGT TAG GAA NO:34 SEQ ID H2A(-41-17) ACT T AAA AAT AAA AGT TAG GAA GCA NO:35 SEQ ID H2A(+11+29) TGT TTT CTT TTG AAC ATC T NO:36 SEQ ID H2D(+15-08) GC ATT CTT ACC TTA GAA AAT TGT NO:37 SEQ ID H2A(+46+62) CTT AGA AAA TTG TGC AT NO:38 SEQ ID H2D(+08-09) CAT TCT TAC CTT AGA AA NO:39 SEQ ID.

[0102] em que A é adenina, C é citosina, G é guanina e T é timina ou uracila. In certain modalities, T is thymine.

[0103] In some Formula (V) modalities, each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Annealing site of base sequence [5' to 3'] ID NO: SEQ H2.SA.(-20+05) A TTC ATC TAA AAT GCA AAA TAA AAA ID NO:1 SEQ Petition 870260074072, dated 07 / 24 / 2026, pp. 49 / 448 42 / 207 H2.SA.(-14+11) T TTC TCT TTC ATC TAA AAT GCA AAA SEQ ID NO:2 H2.SA.(-11+14) A ATC TTC TCT TTC ATC TAA AAT GCA SEQ ID NO:3 H2.SA.(-08+17) G AAC ATC TTC TCT TTC ATC TAA AAT SEQ ID NO:4 H2.SA.(-05+20) A TTG AAC ATC TTC TCT TTC ATC TAA SEQ ID NO:5 H2.SA.(-02+23) T CTT TTG AAC ATC TTC TCT TTC ATC SEQ ID NO:6 H2.SA.(+02+26) TTT CTT TTG AAC ATC TTC TCT TTC A SEQ ID NO:7 H2.SA.(+05+29) T TGT TTT CTT TTG AAC ATC TTC TCT SEQ ID NO:8 H2.SA.(+08+32) T GAA TGT TTT CTT TTG AAC ATC TTC SEQ ID NO:9 H2.SA.(+11+35) T TGT GAA TGT TTT CTT TTG AAC ATC SEQ ID NO:10 H2.SA.(+14+38) A TTT TGT GAA TGT TTT CTT TTG AAC SEQ ID NO:11 H2.SA.(+17+41) A CCA TTT TGT GAA TGT TTT CTT TTG SEQ ID NO:12 H2.SA.(+20+44) T TAC CCA TTT TGT GAA TGT TTT CTT SEQ ID NO:13 H2.SA.(+23+47) C ATT TAC CCA TTT TGT GAA TGT TTT SEQ ID NO:14 H2.SA.(+26+50) T TGC ATT TAC CCA TTT TGT GAA TGT SEQ ID NO:15 H2.SA.(+29+53) T TTG TGC ATT TAC CCA TTT TGT GAA SEQ ID NO:16 H2.SA.(+32+56) G AAA TTG TGC ATT TAC CCA TTT TGT SEQ ID NO:17 H2.SA.(+35+59) T AGA AAA TTG TGC ATT TAC CCA TTT SEQ ID NO:18 H2.SD.(+22-03) C TAC CTT AGA AAA TTG TGC ATT TAC SEQ ID NO:20 H2.SD.(+19-06) T TCT TAC CTT AGA AAA TTG TGC ATT SEQ ID NO:21 H2.SD.(+16-09) A CAT TCT TAC CTT AGA AAA TTG TGC SEQ ID NO:22 H2.SD.(+13-12) T AAC CAT TCT TAC CTT AGA AAA TTG SEQ ID NO:23 H2.SD.(+10-15) T ACA AAC CAT TCT TAC CTT AGA AAA SEQ ID NO:24 H2A(+06+30) T ATG TTT TCT TTT GAA CAT CTT CTC SEQ ID NO:25 H2A(+07+31) C AAT GTT TTC TTT TGA ACA TCT TCT SEQ ID NO:26 H2A(+09+33) C TGA ATG TTT TCT TTT GAA CAT CTT SEQ ID NO:27 H2A(+10+34) T GTG AAT GTT TTC TTT TGA ACA TCT SEQ ID NO:28 H2A(-23+02) A ATC TAA AAT GCA AAA TAA AAA AAT SEQ ID NO:29 H2A(-26-02) A TAA AAT GCA AAA TAA AAA AAT AAA SEQ ID NO:30. Petição 870260074072, de 24 / 07 / 2026, pág. 50 / 448 43 / 207 H2A(-29-05) T AAT GCA AAA TAA AAA AAT AAA AGT SEQ ID NO:31 H2A(-32-08) G GCA AAA TAA AAA AAT AAA AGT TAG SEQ ID NO:32 H2A(-35-11) G AAA TAA AAA AAT AAA AGT TAG GAA SEQ ID NO:33 H2A(-38-14) A TAA AAA AAT AAA AGT TAG GAA GCA SEQ ID NO:34 H2A(-41-17) T AAA AAT AAA AGT TAG GAA GCA ACT SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36 H2A(+46+62) CTT AGA AAA TTG TGC AT SEQ ID NO:38 H2D(+08-09) CAT TCT TAC CTT AGA AA SEQ ID NO:39

[0104] where A is adenine, C is cytosine, G is guanine and T is thymine or uracil. In certain modalities, T is thymine.

[0105] In some Formula (V) modalities, each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Sítio de anelamento Sequência base [5' a 3'] ID NO: SEQ H2.SA.(-20+05) A TTC ATC TAA AAT GCA AAA TAA AAA ID NO:1 SEQ H2.SA.(-14+11) T TTC TCT TTC ATC TAA AAT GCA AAA ID NO:2 SEQ H2.SA.(-11+14) A ATC TTC TCT TTC ATC TAA AAT GCA ID NO:3 SEQ H2.SA.(-08+17) G AAC ATC TTC TCT TTC ATC TAA AAT ID NO:4 SEQ H2.SA.(-05+20) A TTG AAC ATC TTC TCT TTC ATC TAA ID NO:5 SEQ H2.SA.(-02+23) T CTT TTG AAC ATC TTC TCT TTC ATC ID NO:6 SEQ H2.SA.(+02+26) TTT CTT TTG AAC ATC TTC TCT TTC A ID NO:7 SEQ H2.SA.(+05+29) T TGT TTT CTT TTG AAC ATC TTC TCT ID NO:8 SEQ H2.SA.(+08+32) T GAA TGT TTT CTT TTG AAC ATC TTC ID NO:9 SEQ H2.SA.(+11+35) T TGT GAA TGT TTT CTT TTG AAC ATC ID NO:10 SEQ H2.SA.(+14+38) A TTT TGT GAA TGT TTT CTT TTG AAC ID NO:11 SEQ H2.SA.(+17+41) A CCA TTT TGT GAA TGT TTT CTT TTG ID NO:12 SEQ H2.SA.(+20+44) T TAC CCA TTT TGT GAA TGT TTT CTT ID NO:13 SEQ H2.SA.(+38+62) T CTT AGA AAA TTG TGC ATT TAC CCA ID NO:19 SEQ H2.SD.(+22-03) C TAC CTT AGA AAA TTG TGC ATT TAC ID NO:20 SEQ Petition 870260074072, dated 07 / 24 / 2026, p. 51 / 448 44 / 207 H2.SD.(+19-06) T TCT TAC CTT AGA AAA TTG TGC ATT SEQ ID NO:21 H2A(+06+30) T ATG TTT TCT TTT GAA CAT CTT CTC SEQ ID NO:25 H2A(+07+31) C AAT GTT TTC TTT TGA ACA TCT TCT SEQ ID NO:26 H2A(+09+33) C TGA ATG TTT TCT TTT GAA CAT CTT SEQ ID NO:27 H2A(+10+34) T GTG AAT GTT TTC TTT TGA ACA TCT SEQ ID NO:28 H2A(-38-14) A TAA AAA AAT AAA AGT TAG GAA GCA SEQ ID NO:34 H2A(-41-17) T AAA AAT AAA AGT TAG GAA GCA ACT SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36

[0106] where A is adenine, C is cytosine, G is guanine and T is thymine or uracil. In certain modalities, T is thymine.

[0107] In some Formula (V) modalities, each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Sítio de anelamento Sequência base [5' a 3'] ID NO: SEQ H2.SA.(-20+05) A TTC ATC TAA AAT GCA AAA TAA AAA ID NO:1 SEQ H2.SA.(-14+11) T TTC TCT TTC ATC TAA AAT GCA AAA ID NO:2 SEQ H2.SA.(-11+14) A ATC TTC TCT TTC ATC TAA AAT GCA ID NO:3 SEQ H2.SA.(-08+17) G AAC ATC TTC TCT TTC ATC TAA AAT ID NO:4 SEQ H2.SA.(-05+20) A TTG AAC ATC TTC TCT TTC ATC TAA ID NO:5 SEQ H2.SA.(-02+23) T CTT TTG AAC ATC TTC TCT TTC ATC ID NO:6 SEQ H2.SA.(+02+26) A TTT CTT TTG AAC ATC TTC TCT TTC ID NO:7 SEQ H2.SA.(+05+29) T TGT TTT CTT TTG AAC ATC TTC TCT ID NO:8 SEQ H2.SA.(+08+32) T GAA TGT TTT CTT TTG AAC ATC TTC ID NO:9 SEQ H2.SA.(+11+35) T TGT GAA TGT TTT CTT TTG AAC ATC ID NO:10 SEQ H2.SA.(+14+38) A TTT TGT GAA TGT TTT CTT TTG AAC ID NO:11 SEQ H2.SA.(+17+41) A CCA TTT TGT GAA TGT TTT CTT TTG ID NO:12 SEQ H2.SA.(+20+44) T TAC CCA TTT TGT GAA TGT TTT CTT ID NO:13 SEQ H2.SD.(+22-03) C TAC CTT AGA AAA TTG TGC ATT TAC ID NO:20 SEQ H2.SD.(+19-06) T TCT TAC CTT AGA AAA TTG TGC ATT ID NO:21 SEQ Petition 870260074072, dated 07 / 24 / 2026, p. 52 / 448 45 / 207 H2A(+06+30) T ATG TTT TCT TTT GAA CAT CTT CTC SEQ ID NO:25 H2A(+07+31) C AAT GTT TTC TTT TGA ACA TCT TCT SEQ ID NO:26 H2A(+09+33) C TGA ATG TTT TCT TTT GAA CAT CTT SEQ ID NO:27 H2A(+10+34) T GTG AAT GTT TTC TTT TGA ACA TCT SEQ ID NO:28 H2A(-38-14) GCA A TAA AAA AAT AAA AGT TAG GAA SEQ ID NO:34 H2A(-41-17) ACT T AAA AAT AAA AGT TAG GAA GCA SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36

[0108] where A is adenine, C is cytosine, G is guanine and T is thymine or uracil. In certain modalities, T is thymine.

[0109] In some embodiments, each Nu from 1 to (n+1) and 5' to 3' of Formula (V) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, or SEQ ID NO:35. In some embodiments, each Nu from 1 to (n+1) and 5' to 3' of Formula (V) corresponds to the nucleobases in one of the following: SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, or SEQ ID NO:28. In some embodiments, each Nu from 1 to (n+1) and 5' to 3' of Formula (V) corresponds to the nucleobases in one of the following: SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:25, or SEQ ID NO:28.

[0110] In some forms, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (V) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, or SEQ ID NO:35. In some embodiments, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (V) corresponds to the nucleobases in one of the following: SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, Petition 870260074072, dated 07 / 24 / 2026, p. 53 / 448 46 / 207 SEQ ID NO:27 or SEQ ID NO:28. In some embodiments, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (V) corresponds to the nucleobases in one of the following: SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:25 or SEQ ID NO:28. In some embodiments, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (V) corresponds to the nucleobases in SEQ ID NO:19. In some embodiments, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (V) corresponds to the nucleobases in SEQ ID NO:37.

[0111] In another aspect, the disclosure provides antisense oligomers of Formula (VI): 5HCI (VI)

[0112] where each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Sítio de anelamento Sequência base [5' a 3'] ID NO: SEQ H2.SA.(-20+05) A TTC ATC TAA AAT GCA AAA TAA AAA ID NO:1 SEQ H2.SA.(-14+11) T TTC TCT TTC ATC TAA AAT GCA AAA ID NO:2 SEQ H2.SA.(-11+14) A ATC TTC TCT TTC ATC TAA AAT GCA ID NO:3 SEQ H2.SA.(-08+17) G AAC ATC TTC TCT TTC ATC TAA AAT ID NO:4 SEQ H2.SA.(-05+20) A TTG AAC ATC TTC TCT TTC ATC TAA ID NO:5 SEQ H2.SA.(-02+23) T CTT TTG AAC ATC TTC TCT TTC ATC ID NO:6 SEQ H2.SA.(+02+26) A TTT CTT TTG AAC ATC TTC TCT TTC ID NO:7 SEQ H2.SA.(+05+29) T TGT TTT CTT TTG AAC ATC TTC TCT ID NO:8 SEQ H2.SA.(+08+32) T GAA TGT TTT CTT TTG AAC ATC TTC ID NO:9 SEQ H2.SA.(+11+35) TGT GAA TGT TTT CTT TTG AAC ATC SEQ T ID NO:10 Petição 870260074072, de 24 / 07 / 2026, pág. 54 / 448 47 / 207 H2.SA.(+14+38) A TTT TGT GAA TGT TTT CTT TTG AAC SEQ ID NO:11 H2.SA.(+17+41) A CCA TTT TGT GAA TGT TTT CTT TTG SEQ ID NO:12 H2.SA.(+20+44) T TAC CCA TTT TGT GAA TGT TTT CTT SEQ ID NO:13 H2.SA.(+23+47) C ATT TAC CCA TTT TGT GAA TGT TTT SEQ ID NO:14 H2.SA.(+26+50) T TGC ATT TAC CCA TTT TGT GAA TGT SEQ ID NO:15 H2.SA.(+29+53) T TTG TGC ATT TAC CCA TTT TGT GAA SEQ ID NO:16 H2.SA.(+32+56) G AAA TTG TGC ATT TAC CCA TTT TGT SEQ ID NO:17 H2.SA.(+35+59) T AGA AAA TTG TGC ATT TAC CCA TTT SEQ ID NO:18 H2.SA.(+38+62) CCA T CTT AGA AAA TTG TGC ATT TAC SEQ ID NO:19 H2.SD.(+22-03) C TAC CTT AGA AAA TTG TGC ATT TAC SEQ ID NO:20 H2.SD.(+19-06) T TCT TAC CTT AGA AAA TTG TGC ATT SEQ ID NO:21 H2.SD.(+16-09) TGC A CAT TCT TAC CTT AGA AAA TTG SEQ ID NO:22 H2.SD.(+13-12) T AAC CAT TCT TAC CTT AGA AAA TTG SEQ ID NO:23 H2.SD.(+10-15) AAA T ACA AAC CAT TCT TAC CTT AGA SEQ ID NO:24 H2A(+06+30) T ATG TTT TCT TTT GAA CAT CTT CTC SEQ ID NO:25 H2A(+07+31) C AAT GTT TTC TTT TGA ACA TCT TCT SEQ ID NO:26 H2A(+09+33) C TGA ATG TTT TCT TTT GAA CAT CTT SEQ ID NO:27 H2A(+10+34) T GTG AAT GTT TTC TTT TGA ACA TCT SEQ ID NO:28 H2A(-23+02) A ATC TAA AAT GCA AAA TAA AAA AAT SEQ ID NO:29 H2A(-26-02) A TAA AAT GCA AAA TAA AAA AAT AAA SEQ ID NO:30 H2A(-29-05) AGT T AAT GCA AAA TAA AAA AAT AAA SEQ ID NO:31 H2A(-32-08) TAG G GCA AAA TAA AAA AAT AAA AGT SEQ ID NO:32 H2A(-35-11) GAA G AAA TAA AAA AAT AAA AGT TAG SEQ ID NO:33 H2A(-38-14) GCA A TAA AAA AAT AAA AGT TAG GAA SEQ ID NO:34 H2A(-41-17) ACT T AAA AAT AAA AGT TAG GAA GCA SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36 H2D(+15-08) ATT CTT ACC TTA GAA AAT TGT GC SEQ ID NO:37 H2A(+46+62) CTT AGA AAA TTG TGC AT SEQ ID NO:38. Petição 870260074072, de 24 / 07 / 2026, pág. 55 / 448 48 / 207 H2D(+08-09) CAT TCT TAC CTT AGA AA SEQ ID NO:39

[0113] where A is adenine, C is cytosine, G is guanine and T is thymine or uracil. In certain modalities, T is thymine.

[0114] In some Formula (VI) modalities, each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Sítio de anelamento Sequência base [5' a 3'] NO: SEQ ID H2.SA.(-20+05) AAA A TTC ATC TAA AAT GCA AAA TAA NO:1 SEQ ID H2.SA.(-14+11) AAA T TTC TCT TTC ATC TAA AAT GCA NO:2 SEQ ID H2.SA.(-11+14) GCA A ATC TTC TCT TTC ATC TAA AAT NO:3 SEQ ID H2.SA.(-08+17) AAT G AAC ATC TTC TCT TTC ATC TAA NO:4 SEQ ID H2.SA.(-05+20) TAA A TTG AAC ATC TTC TCT TTC ATC NO:5 SEQ ID H2.SA.(-02+23) ATC T CTT TTG AAC ATC TTC TCT TTC NO:6 SEQ ID H2.SA.(+02+26) TTC A TTT CTT TTG AAC ATC TTC TCT NO:7 SEQ ID H2.SA.(+05+29) TCT T TGT TTT CTT TTG AAC ATC TTC NO:8 SEQ ID H2.SA.(+08+32) TTC T GAA TGT TTT CTT TTG AAC ATC NO:9 SEQ ID H2.SA.(+11+35) ATC T TGT GAA TGT TTT CTT TTG AAC NO:10 SEQ ID H2.SA.(+14+38) AAC A TTT TGT GAA TGT TTT CTT TTG NO:11 SEQ ID H2.SA.(+17+41) TTG A CCA TTT TGT GAA TGT TTT CTT NO:12 SEQ ID H2.SA.(+20+44) CTT T TAC CCA TTT TGT GAA TGT TTT NO:13 SEQ ID H2.SA.(+23+47) TTT C ATT TAC CCA TTT TGT GAA TGT NO:14 SEQ ID H2.SA.(+26+50) TGT T TGC ATT TAC CCA TTT TGT GAA NO:15 SEQ ID H2.SA.(+29+53) GAA T TTG TGC ATT TAC CCA TTT TGT NO:16 SEQ ID H2.SA.(+32+56) TGT G AAA TTG TGC ATT TAC CCA TTT NO:17 SEQ ID H2.SA.(+35+59) TTT T AGA AAA TTG TGC ATT TAC CCA NO:18 SEQ ID H2.SD.(+22-03) TAC C TAC CTT AGA AAA TTG TGC ATT NO:20 SEQ ID H2.SD.(+19-06) ATT T TCT TAC CTT AGA AAA TTG TGC NO:21 SEQ ID H2.SD.(+16-09) TGC A CAT TCT TAC CTT AGA AAA TTG NO:22 SEQ ID H2.SD.(+13-12) TTG T AAC CAT TCT TAC CTT AGA AAA NO:23 SEQ ID. Petition 870260074072, de 24 / 07 / 2026, pág. 56 / 448 49 / 207 H2.SD.(+10-15) AAA T ACA AAC CAT TCT TAC CTT AGA NO:24 SEQ ID H2A(+06+30) CTC T ATG TTT TCT TTT GAA CAT CTT NO:25 SEQ ID H2A(+07+31) TCT C AAT GTT TTC TTT TGA ACA TCT NO:26 SEQ ID H2A(+09+33) CTT C TGA ATG TTT TCT TTT GAA CAT NO:27 SEQ ID H2A(+10+34) TCT T GTG AAT GTT TTC TTT TGA ACA NO:28 SEQ ID H2A(-23+02) AAT A ATC TAA AAT GCA AAA TAA AAA NO:29 SEQ ID H2A(-26-02) AAA A TAA AAT GCA AAA TAA AAA AAT NO:30 SEQ ID H2A(-29-05) AGT T AAT GCA AAA TAA AAA AAT AAA NO:31 SEQ ID H2A(-32-08) TAG G GCA AAA TAA AAA AAT AAA AGT NO:32 SEQ ID H2A(-35-11) GAA G AAA TAA AAA AAT AAA AGT TAG NO:33 SEQ ID H2A(-38-14) GCA A TAA AAA AAT AAA AGT TAG GAA NO:34 SEQ ID H2A(-41-17) ACT T AAA AAT AAA AGT TAG GAA GCA NO:35 SEQ ID H2A(+11+29) TGT TTT CTT TTG AAC ATC T NO:36 SEQ ID H2A(+46+62) CTT AGA AAA TTG TGC AT NO:38 SEQ ID H2D(+08-09) CAT TCT TAC CTT AGA AA NO:39 SEQ ID

[0115] em que A é adenina, C é citosina, G é guanina e T é timina ou uracila. Em certas modalidades, T é timina.

[0116] In some Formula (VI) modalities, each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Annealing site Base sequence [5' to 3'] NO: SEQ ID H2.SA.(-20+05) AAA A TTC ATC TAA AAT GCA AAA TAA NO:1 SEQ ID H2.SA.(-14+11) AAA T TTC TCT TTC ATC TAA AAT GCA NO:2 SEQ ID H2.SA.(-11+14) GCA A ATC TTC TCT TTC ATC TAA AAT NO:3 SEQ ID H2.SA.(-08+17) AAT G AAC ATC TTC TCT TTC ATC TAA NO:4 SEQ ID H2.SA.(-05+20) TAA A TTG AAC ATC TTC TCT TTC ATC NO:5 SEQ ID H2.SA.(-02+23) ATC T CTT TTG AAC ATC TTC TCT TTC NO:6 SEQ ID H2.SA.(+02+26) TTC A TTT CTT TTG AAC ATC TTC TCT NO:7 SEQ ID H2.SA.(+05+29) TCT T TGT TTT CTT TTG AAC ATC TTC NO:8 SEQ ID Petition 870260074072, dated 07 / 24 / 2026, p. 57 / 448 50 / 207 H2.SA.(+08+32) GAA TGT TTT CTT TTG AAC ATC TTC T SEQ ID NO:9 H2.SA.(+11+35) TGT GAA TGT TTT CTT TTG AAC ATC T SEQ ID NO:10 H2.SA.(+14+38) TTT TGT GAA TGT TTT CTT TTG AAC A SEQ ID NO:11 H2.SA.(+17+41) CCA TTT TGT GAA TGT TTT CTT TTG A SEQ ID NO:12 H2.SA.(+20+44) TAC CCA TTT TGT GAA TGT TTT CTT T SEQ ID NO:13 H2.SA.(+38+62) CTT AGA AAA TTG TGC ATT TAC CCA T SEQ ID NO:19 H2.SD.(+22-03) TAC CTT AGA AAA TTG TGC ATT TAC C SEQ ID NO:20 H2.SD.(+19-06) TCT TAC CTT AGA AAA TTG TGC ATT T SEQ ID NO:21 H2A(+06+30) ATG TTT TCT TTT GAA CAT CTT CTC T SEQ ID NO:25 H2A(+07+31) AAT GTT TTC TTT TGA ACA TCT TCT C SEQ ID NO:26 H2A(+09+33) TGA ATG TTT TCT TTT GAA CAT CTT C SEQ ID NO:27 H2A(+10+34) GTG AAT GTT TTC TTT TGA ACA TCT T SEQ ID NO:28 H2A(-38-14) TAA AAA AAT AAA AGT TAG GAA GCA A SEQ ID NO:34 H2A(-41-17) AAA AAT AAA AGT TAG GAA GCA ACT T SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36

[0117] em que A é adenina, C é citosina, G é guanina e T é timina ou uracila. In certain modalities, T is thymine.

[0118] In some Formula (VI) modalities, each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Annealing site Base sequence [5' to 3'] NO: SEQ ID H2.SA.(-20+05) AAA A TTC ATC TAA AAT GCA AAA TAA NO:1 SEQ ID H2.SA.(-14+11) AAA T TTC TCT TTC ATC TAA AAT GCA NO:2 SEQ ID H2.SA.(-11+14) GCA A ATC TTC TCT TTC ATC TAA AAT NO:3 SEQ ID H2.SA.(-08+17) AAT G AAC ATC TTC TCT TTC ATC TAA NO:4 SEQ ID H2.SA.(-05+20) TAA A TTG AAC ATC TTC TCT TTC ATC NO:5 SEQ ID H2.SA.(-02+23) ATC T CTT TTG AAC ATC TTC TCT TTC NO:6 SEQ ID H2.SA.(+02+26) TTC A TTT CTT TTG AAC ATC TTC TCT NO:7 SEQ ID H2.SA.(+05+29) TCT T TGT TTT CTT TTG AAC ATC TTC NO:8 SEQ ID Petition 870260074072, dated 07 / 24 / 2026, p. 58 / 448 51 / 207 H2.SA.(+08+32) TTC T GAA TGT TTT CTT TTG AAC ATC NO:9 SEQ ID H2.SA.(+11+35) ATC T TGT GAA TGT TTT CTT TTG AAC NO:10 SEQ ID H2.SA.(+14+38) AAC A TTT TGT GAA TGT TTT CTT TTG NO:11 SEQ ID H2.SA.(+17+41) TTG A CCA TTT TGT GAA TGT TTT CTT NO:12 SEQ ID H2.SA.(+20+44) CTT T TAC CCA TTT TGT GAA TGT TTT NO:13 SEQ ID H2.SD.(+22-03) TAC C TAC CTT AGA AAA TTG TGC ATT NO:20 SEQ ID H2.SD.(+19-06) ATT T TCT TAC CTT AGA AAA TTG TGC NO:21 SEQ ID H2A(+06+30) CTC T ATG TTT TCT TTT GAA CAT CTT NO:25 SEQ ID H2A(+07+31) TCT C AAT GTT TTC TTT TGA ACA TCT NO:26 SEQ ID H2A(+09+33) CTT C TGA ATG TTT TCT TTT GAA CAT NO:27 SEQ ID H2A(+10+34) TCT T GTG AAT GTT TTC TTT TGA ACA NO:28 SEQ ID H2A(-38-14) GCA A TAA AAA AAT AAA AGT TAG GAA NO:34 SEQ ID H2A(-41-17) ACT T AAA AAT AAA AGT TAG GAA GCA NO:35 SEQ ID H2A(+11+29) TGT TTT CTT TTG AAC ATC T NO:36 SEQ ID

[0119] em que A é adenina, C é citosina, G é guanina e T é timina ou uracila. Em certas modalidades, T é timina.

[0120] In some embodiments, each Nu from 1 to (n+1) and 5' to 3' of Formula (VI) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, or SEQ ID NO:35. In some embodiments, each Nu from 1 to (n+1) and 5' to 3' of Formula (VI) corresponds to the nucleobases in one of the following: SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27 or SEQ ID NO:28. In some embodiments, each Nu from 1 to (n+1) and 5' to 3' of Formula (VI) corresponds to the nucleobases in one of the following: SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:25 or SEQ ID NO:28. Petition 870260074072, dated 07 / 24 / 2026, p. 59 / 448 52 / 207

[0121] In some forms, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (VI) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, or SEQ ID NO:35. In some embodiments, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (VI) corresponds to the nucleobases in one of the following: SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27 or SEQ ID NO:28. In some embodiments, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (VI) corresponds to the nucleobases in one of the following: SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:25 or SEQ ID NO:28. In some forms, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (VI) corresponds to the nucleobases in SEQ ID NO:19.In some forms, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (VI) corresponds to the nucleobases in SEQ ID NO:37.

[0122] In some embodiments, an antisense oligomer of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI) is in free base form. In some embodiments, an antisense oligomer of Formula (I), Formula (II), Formula (III), or Formula (V) is a pharmaceutically acceptable salt thereof. In some embodiments, an antisense oligomer of Formula (I), Formula (II), Formula (III), or Formula (V) is a salt of HCl (hydrochloric acid) thereof. In certain embodiments of Formula (I), Formula (II), Formula (III), or Formula (V), the HCl salt is a salt of 1HCl, 2HCl, 3HCl, 4HCl, 5HCl, or 6HCl. In certain embodiments of Formula (I), Formula (II), or Formula (III), the HCl salt is a 6HCl salt. In certain embodiments of Formula (I), Formula (II) or Formula (V), the salt HCl is a 5HCl salt.

[0123] In several embodiments, the antisense oligomer, or its pharmaceutically acceptable salt, exhibits exon skipping in RD cells. In certain embodiments, the antisense oligomer, or its pharmaceutically acceptable salt, Petition 870260074072, dated 07 / 24 / 2026, page 60 / 448 53 / 207 exhibits <19.9% ​​exon skipping in RD cells at a concentration of 10 μM. In certain embodiments, the antisense oligomer, or its pharmaceutically acceptable salt, exhibits >20.0% exon skipping in RD cells at a concentration of 10 μM. In certain embodiments, the antisense oligomer, or its pharmaceutically acceptable salt, exhibits >30.0% exon skipping in RD cells at a concentration of 10 μM. In certain embodiments, the antisense oligomer, or its pharmaceutically acceptable salt, exhibits >40.0% exon skipping in RD cells at a concentration of 10 μM.

[0124] In another aspect, the disclosure provides a method for treating Duchenne muscular dystrophy (DMD) in an individual in need, wherein the individual has a dystrophin gene mutation that is capable of exon 2 skipping, the method comprising administering to the individual an antisense oligomer, or a pharmaceutically acceptable salt thereof of the disclosure. The disclosure also addresses the use of antisense oligomers, or their pharmaceutically acceptable salts, of the disclosure for the manufacture of a medicament for the treatment of Duchenne muscular dystrophy (DMD) in an individual in need thereof, wherein the individual has a dystrophin gene mutation that is capable of exon 2 skipping.

[0125] In another aspect, the disclosure provides a method for restoring an mRNA reading frame to induce dystrophin production in an individual with a dystrophin gene mutation that is susceptible to exon 2 skipping, the method comprising administering to the individual an antisense oligomer or pharmaceutically acceptable salt thereof, of the disclosure. In another aspect, the disclosure provides a method for deleting exon 2 from dystrophin pre-mRNA during mRNA processing in an individual with a dystrophin gene mutation that is susceptible to exon 2 skipping, the method comprising administering to the individual an antisense oligomer, or its pharmaceutically acceptable salt, of the disclosure. In another aspect, the disclosure provides a method for ligating exon 2, intron 1 or intron 2 of dystrophin pre-mRNA into Petition 870260074072, dated 07 / 24 / 2026, page 61 / 448 54 / 207 an individual with a dystrophin gene mutation that is capable of exon 2 skipping, the method comprising administering to the individual an antisense oligomer, or a pharmaceutically acceptable salt thereof, of the disclosure.

[0126] In another aspect, the disclosure provides an antisense oligomer, or pharmaceutically acceptable salt thereof, of the disclosure in this document for use in therapy. In certain embodiments, the disclosure provides an antisense oligomer, or pharmaceutically acceptable salt thereof, of the disclosure for use in the treatment of Duchenne muscular dystrophy. In certain embodiments, the disclosure provides an antisense oligomer, or pharmaceutically acceptable salt thereof, of the disclosure for use in the manufacture of a medicament for use in therapy. In certain embodiments, the disclosure provides an antisense oligomer, or pharmaceutically acceptable salt thereof, of the disclosure for use in the manufacture of a medicament for the treatment of Duchenne muscular dystrophy.

[0127] In another aspect, the disclosure also provides kits for the treatment of Duchenne muscular dystrophy (DMD) in an individual in need thereof, wherein the individual has a mutation of the dystrophin gene that is capable of exon 2 skipping, which kits comprise at least one antisense oligomer, or its pharmaceutically acceptable salt, of the present disclosure, packaged in a suitable container and instructions for its use. DETAILED DESCRIPTION OF THE DISCLOSURE

[0128] The embodiments of this disclosure generally relate to enhanced antisense oligomers and methods of use thereof, which are specifically designed to induce exon skipping in the human dystrophin gene. Dystrophin plays a vital role in muscle function, and several muscle-related diseases are characterized by mutant forms of this gene. Therefore, in certain embodiments, the enhanced antisense oligomers described herein induce exon skipping in mutated forms of the human dystrophin gene. Petition 870260074072, dated 07 / 24 / 2026, page 62 / 448 55 / 207 as the mutated dystrophin genes found in Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD).

[0129] Due to aberrant mRNA splicing events caused by mutations, these mutant human dystrophin genes either express defective dystrophin protein or do not express any measurable dystrophin, a condition that leads to various forms of muscular dystrophy. To remedy this condition, the antisense oligomers of the present disclosure hybridize with selected regions of a pre-processed mRNA from a mutated human dystrophin gene, induce exon skipping and differential splicing of otherwise aberrantly spliced ​​dystrophin mRNA, and thus allow muscle cells to produce an mRNA transcript encoding a functional dystrophin protein. In certain embodiments, the resulting dystrophin protein is not necessarily the wild-type dystrophin form, but is instead a truncated, yet still functional, form of dystrophin.

[0130] By increasing levels of functional dystrophin protein in muscle cells, these and related modalities are useful in the prophylaxis and treatment of muscular dystrophy, especially those forms of muscular dystrophy, such as DMD and BMD, that are characterized by the expression of defective dystrophin proteins due to aberrant mRNA splicing. The specific antisense oligomers described in this document provide even better specific targeting of the dystrophin exon compared to other oligomers and thus offer significant and practical advantages over alternative methods of treating relevant forms of muscular dystrophy.

[0131] Thus, the disclosure refers to antisense oligomers, or their pharmaceutically acceptable salts, comprising a base sequence with 8 to 50 morpholino subunits that hybridize with a target region of exon 2, intron 1 or intron 2 of human dystrophin pre-mRNA that is a region within exon 2, intron 1 or intron 2, or a pharmaceutically acceptable salt thereof. In a Petition 870260074072, dated 07 / 24 / 2026, p. 63 / 448 56 / 207 aspect, the antisense oligomer, or a pharmaceutically acceptable salt thereof, induces exon skipping in the human dystrophin gene. In one aspect, the antisense oligomer contains 16 to 32 morpholino subunits. In another aspect, the antisense oligomer, or its pharmaceutically acceptable salt, contains 19 to 25 morpholino subunits.

[0132] In certain embodiments, the antisense oligomer is conjugated to one or more cell-penetrating peptides (referred to in this document as CPPs). In certain embodiments, one or more CPPs are attached to a terminal of the antisense oligomer. In certain embodiments, at least one CPP is attached to the 5' terminus of the antisense oligomer. In certain embodiments, at least one CPP is attached to the 3' terminus of the antisense oligomer. In certain embodiments, a first CPP is attached to the 5' terminus and a second CPP is attached to the 3' terminus of the antisense oligomer.

[0133] In some embodiments, CPP is an arginine-rich peptide. The term arginine-rich refers to a CPP with at least 2, and preferably 2, 3, 4, 5, 6, 7, or 8 arginine residues, each optionally separated by one or more uncharged hydrophobic residues and optionally containing about 6-14 amino acid residues. As explained below, a CPP is preferably linked at its carboxy terminus to the 3' and / or 5' end of an antisense oligonucleotide via a linker, which may also be one or more amino acids, and is preferably also limited at its amino terminus by a Racom Raselecionado substituent of H, acyl, acetyl, benzoyl, or stearoyl. In some embodiments, Ra is acetyl.

[0134] As can be seen in the table below, non-limiting examples of CPP's for use in this document include -(RXR)4-Ra(SEQ ID NO: 40), R-(FFR)3-Ra(SEQ ID NO: 41), -BX-(RXR)4-Ra(SEQ ID NO: 42), -BXR-(FFR)3-Ra(SEQ ID NO: 43), -GLY-R-(FFR)3-Ra(SEQ ID NO: 44), -GLY-R5-Ra(SEQ ID NO: 45), -R5-Ra(SEQ ID NO: 46), -GLY-R6-Ra(SEQ ID NO: 47) and -R6-Ra(SEQ ID NO: 48), where Raé Petition 870260074072, dated 07 / 24 / 2026, p. 64 / 448 57 / 207 selected from H, acyl, benzoyl and stearoyl, wherein R is arginine, X is 6-aminohexanoic acid, B is β-alanine, F is phenylalanine and GLY (or G) is glycine. CPP R5 (SEQ ID NO: 46) is intended to indicate a peptide of five (5) arginine residues linked together by amide bonds (and not a single substituent, for example, R5(SEQ ID NO: 46)). CPP R6 (SEQ ID NO: 48) is intended to indicate a peptide of six (6) arginine residues linked together by amide bonds (and not a single substituent, for example, R6(SEQ ID NO: 48)). In some embodiments, Ra is acetyl.

[0135] Exemplary CPPs are provided in Table 1 (SEQ ID NOS. 40-46). Table 1: Exemplary Cell Penetrating Peptides Name Sequence SEQ ID NO: (RXR)4 RXRRXRRXRRXR 40 (RFF)3R RFFRFFRFFR 41 (RXR)4XB RXRRXRRXRRXRXB 42 (RFF)3RXB RFFRFFRFFRXB 43 (RFF)3RG RFFRFFRFFRG 44 R5G RRRRRG 45 R5 RRRRR 46 R6G RRRRRRG 47 R6 RRRRRR 48 R is arginine; X is 6-aminohexanoic acid; B is β-alanine; F is phenylalanine; G is glycine.

[0136] CPPs, their synthesis and methods of conjugation to an oligomer are further described in U.S. Patent Publication 2012 / 0289457 and International Patent Publication Nos. WO 2004 / 097017, WO 2009 / 005793 and WO 2012 / 150960, disclosures of which are incorporated herein by reference in their entirety.

[0137] In some embodiments, an antisense oligonucleotide comprises a Z substituent, defined as the combination of a CPP and a linker. The linker links the CPP at its carboxy terminus to the 3' and / or 5' end of the oligonucleotide. In several embodiments, an antisense oligonucleotide may comprise only a CPP linked to the 3' end of the oligomer. In other embodiments, an antisense oligonucleotide may comprise only a CPP linked to the 5' end of the oligomer. Petition 870260074072, dated 07 / 24 / 2026, p. 65 / 448 58 / 207

[0138] The linker within Z may comprise, for example, 1, 2, 3, 4 or 5 amino acids.

[0139] In particular modalities, Z is selected from:

[0140] -C(O)(CH2)5NH-CPP;

[0141] -C(O)(CH2)2NH-CPP;

[0142] -C(O)(CH2)2NHC(O)(CH2)5NH-CPP;

[0143] -C(O)CH2NH-CPP and the formula:

[0144] in which the CPP is linked to the linking portion by an amide linkage at the carboxy terminus of the CPP.

[0145] In several embodiments, CPP is an arginine-rich peptide, as described herein and seen in Table 1. In certain embodiments, the arginine-rich CPP is -R5-Ra, (i.e., five arginine residues; SEQ ID NO:46), wherein Ra is selected from H, acyl, acetyl, benzoyl, and stearoyl. In certain embodiments, Ra is acetyl. In several embodiments, CPP is selected from SEQ ID NOS. 40, 41, or 46, and the linker is selected from the group consisting of -C(O)(CH2)5NH-, -C(O)(CH2)2NH-, -C(O)(CH2)2NHC(O)(CH2)5NH-, -C(O)CH2NH-,0CPP and '. In some embodiments, the linker comprises 1, 2, 3, 4, or 5 amino acids.

[0146] In some embodiments, the CPP is SEQ ID NO:46 and the binder is Gly. In some embodiments, the CPP is SEQ ID NO:45.

[0147] In certain embodiments, the arginine-rich CPP is -R6-Ra, (i.e., six arginine residues; SEQ ID NO:48), where Ra is selected from H, acyl, Petition 870260074072, dated 07 / 24 / 2026, p. 66 / 448 59 / 207 acetyl, benzoyl and stearoyl. In certain embodiments, Raé acetyl. In several embodiments, the CPP is selected from SEQ ID NOS. 40, 41 or 48, and the linker is selected from the group consisting of -C(O)(CH2)5NH-, -C(O)(CH2)2NH-, -C(O)(CH2)2NHC(O)(CH2)5NH-, -C(O)CH2NH-, amino acids. In some forms, the linker comprises 1, 2, 3, 4 or 5

[0148] In some embodiments, the CPP is SEQ ID NO:48 and the linker is Gly. In some embodiments, the CPP is SEQ ID NO:47.

[0149] In certain embodiments, Z is -C(O)CH2NH-R6-Ra (Re disclosed as SEQ ID NO: 48) covalently linked to an antisense oligomer of disclosure at the 5' and / or 3' end of the oligomer, wherein Ra is H, acyl, acetyl, benzoyl, or stearoyl to cover the amino terminus of Re (SEQ ID NO: 48). In certain embodiments, Ra is acetyl. In these non-limiting examples, the CPP is -Re-Ra (SEQ ID NO: 48) and the linker is -C(O)CH2NH- (i.e., GLY). This particular example of Z = -C(O)CH2NH-Re-Ra (Re disclosed as SEQ ID NO: 48) is also exemplified by the following structure: Frog

[0150] in which Raé selected from H, acyl, acetyl, benzoyl and stearoyl.

[0151] In several modalities, the CPP is -Re-Ra(SEQ ID NO: 48), also exemplified as the following formula: Petition 870260074072, dated 07 / 24 / 2026, p. 67 / 448 60 / 207

[0152] in which Raé selected from H, acyl, acetyl, benzoyl and stearoyl. In certain modalities, CPP is SEQ ID NO:47. In some modalities, Raé acetil.

[0153] In some modalities, the CPP is -(RXR)4-Ra(SEQ ID NO: 40), also exemplified as the following formula:

[0154] In several modalities, the CPP is -R-(FFR)s-Ra (SEQ ID NO: 41), also exemplified as the following formula:

[0155] In several embodiments, Z is selected from: -C(O)(CH2)5NH-CPP; Petition 870260074072, dated 07 / 24 / 2026, p. 68 / 448 61 / 207 -C(O)(CH2)2NH-CPP; -C(O)(CH2)2NHC(O)(CH2)5NH-CPP; -C(O)CH2NH-CPP; and the formula:

[0156] wherein the CPP is linked to the ligand moiety by an amide linkage at the carboxy terminus of the CPP and wherein the CPP is selected from: Petition 870260074072, dated 07 / 24 / 2026, p. 69 / 448 62 / 207 , or (-Re-Ra(SEQ ID NO: 48)). In some modes, Raé acetil.

[0157] In one aspect, the disclosure provides a modified antisense oligomer capable of binding to a selected target to induce exon skipping in the human dystrophin gene, wherein the modified antisense oligomer comprises a base sequence that is complementary to an exon 2, intron 1, or intron 2 target region of the dystrophin pre-mRNA designated as an annealing site; wherein the base sequence and / or annealing site are selected from one of the following: Sítio de anelamento Sequência base [5' a 3'] NO: SEQ ID H2.SA.(-20+05) A TTC ATC TAA AAT GCA AAA TAA AAA NO:1 SEQ ID H2.SA.(-14+11) T TTC TCT TTC ATC TAA AAT GCA AAA NO:2 SEQ ID H2.SA.(-11+14) A ATC TTC TCT TTC ATC TAA AAT GCA NO:3 SEQ ID H2.SA.(-08+17) G AAC ATC TTC TCT TTC ATC TAA AAT NO:4 SEQ ID H2.SA.(-05+20) A TTG AAC ATC TTC TCT TTC ATC TAA NO:5 SEQ ID H2.SA.(-02+23) T CTT TTG AAC ATC TTC TCT TTC ATC NO:6 SEQ ID H2.SA.(+02+26) A TTT CTT TTG AAC ATC TTC TCT TTC NO:7 SEQ ID H2.SA.(+05+29) T TGT TTT CTT TTG AAC ATC TTC TCT NO:8 SEQ ID H2.SA.(+08+32) T GAA TGT TTT CTT TTG AAC ATC TTC NO:9 SEQ ID H2.SA.(+11+35) T TGT GAA TGT TTT CTT TTG AAC ATC NQ:10 SEQ ID H2.SA.(+14+38) A TTT TGT GAA TGT TTT CTT TTG AAC NO:11 SEQ ID H2.SA.(+17+41) A CCA TTT TGT GAA TGT TTT CTT TTG NO:12 SEQ ID H2.SA.(+20+44) T TAC CCA TTT TGT GAA TGT TTT CTT NO:13 SEQ ID Petição 870260074072, de 24 / 07 / 2026, pág. 70 / 448 63 / 207 H2.SA.(+23+47) C ATT TAC CCA TTT TGT GAA TGT TTT NO:14 SEQ ID H2.SA.(+26+50) T TGC ATT TAC CCA TTT TGT GAA TGT NO:15 SEQ ID H2.SA.(+29+53) T TTG TGC ATT TAC CCA TTT TGT GAA NO:16 SEQ ID H2.SA.(+32+56) G AAA TTG TGC ATT TAC CCA TTT TGT NO:17 SEQ ID H2.SA.(+35+59) T AGA AAA TTG TGC ATT TAC CCA TTT NO:18 SEQ ID H2.SA.(+38+62) CCA T CTT AGA AAA TTG TGC ATT TAC NO:19 SEQ ID H2.SD.(+22-03) C TAC CTT AGA AAA TTG TGC ATT TAC NO:20 SEQ ID H2.SD.(+19-06) T TCT TAC CTT AGA AAA TTG TGC ATT NO:21 SEQ ID H2.SD.(+16-09) TGC A CAT TCT TAC CTT AGA AAA TTG NO:22 SEQ ID H2.SD.(+13-12) T AAC CAT TCT TAC CTT AGA AAA TTG NO:23 SEQ ID H2.SD.(+10-15) AAA T ACA AAC CAT TCT TAC CTT AGA NO:24 SEQ ID H2A(+06+30) T ATG TTT TCT TTT GAA CAT CTT CTC NO:25 SEQ ID H2A(+07+31) C AAT GTT TTC TTT TGA ACA TCT TCT NO:26 SEQ ID H2A(+09+33) C TGA ATG TTT TCT TTT GAA CAT CTT NO:27 SEQ ID H2A(+10+34) T GTG AAT GTT TTC TTT TGA ACA TCT NO:28 SEQ ID H2A(-23+02) A ATC TAA AAT GCA AAA TAA AAA AAT NO:29 SEQ ID H2A(-26-02) A TAA AAT GCA AAA TAA AAA AAT AAA NO:30 SEQ ID H2A(-29-05) AGT T AAT GCA AAA TAA AAA AAT AAA NO:31 SEQ ID H2A(-32-08) TAG G GCA AAA TAA AAA AAT AAA AGT NO:32 SEQ ID H2A(-35-11) GAA G AAA TAA AAA AAT AAA AGT TAG NO:33 SEQ ID H2A(-38-14) GCA A TAA AAA AAT AAA AGT TAG GAA NO:34 SEQ ID H2A(-41-17) ACT T AAA AAT AAA AGT TAG GAA GCA NO:35 SEQ ID H2A(+11+29) TGT TTT CTT TTG AAC ATC T NO:36 SEQ ID H2D(+15-08) ATT CTT ACC TTA GAA AAT TGT GC NO:37 SEQ ID H2A(+46+62) CTT AGA AAA TTG TGC AT NO:38 SEQ ID H2D(+08-09) CAT TCT TAC CTT AGA AA NO:39 SEQ ID.

[0158] em que A é adenina, C é citosina, G é guanina e T é timina ou uracila. In certain modalities, T is thymine. Petition 870260074072, dated 07 / 24 / 2026, p. 71 / 448 64 / 207

[0159] In certain embodiments, the modified antisense oligomer is capable of binding to a selected target to induce exon skipping in the human dystrophin gene, wherein the modified antisense oligomer comprises a base sequence that is complementary to a target region of exon 2, intron 1, or intron 2 of the dystrophin premRNA designated as an annealing site; wherein the base sequence and / or annealing site are selected from one of the following: Sítio de anelamento Sequência base [5' a 3'] NO: SEQ ID H2.SA.(-20+05) AAA A TTC ATC TAA AAT GCA AAA TAA NO:1 SEQ ID H2.SA.(-14+11) AAA T TTC TCT TTC ATC TAA AAT GCA NO:2 SEQ ID H2.SA.(-11+14) GCA A ATC TTC TCT TTC ATC TAA AAT NO:3 SEQ ID H2.SA.(-08+17) AAT G AAC ATC TTC TCT TTC ATC TAA NO:4 SEQ ID H2.SA.(-05+20) TAA A TTG AAC ATC TTC TCT TTC ATC NO:5 SEQ ID H2.SA.(-02+23) ATC T CTT TTG AAC ATC TTC TCT TTC NO:6 SEQ ID H2.SA.(+02+26) TTC A TTT CTT TTG AAC ATC TTC TCT NO:7 SEQ ID H2.SA.(+05+29) TCT T TGT TTT CTT TTG AAC ATC TTC NO:8 SEQ ID H2.SA.(+08+32) TTC T GAA TGT TTT CTT TTG AAC ATC NO:9 SEQ ID H2.SA.(+11+35) ATC T TGT GAA TGT TTT CTT TTG AAC NO:10 SEQ ID H2.SA.(+14+38) AAC A TTT TGT GAA TGT TTT CTT TTG NO:11 SEQ ID H2.SA.(+17+41) TTG A CCA TTT TGT GAA TGT TTT CTT NO:12 SEQ ID H2.SA.(+20+44) CTT T TAC CCA TTT TGT GAA TGT TTT NO:13 SEQ ID H2.SA.(+23+47) TTT C ATT TAC CCA TTT TGT GAA TGT NO:14 SEQ ID H2.SA.(+26+50) TGT T TGC ATT TAC CCA TTT TGT GAA NO:15 SEQ ID H2.SA.(+29+53) GAA T TTG TGC ATT TAC CCA TTT TGT NO:16 SEQ ID H2.SA.(+32+56) TGT G AAA TTG TGC ATT TAC CCA TTT NO:17 SEQ ID H2.SA.(+35+59) TTT T AGA AAA TTG TGC ATT TAC CCA NO:18 SEQ ID H2.SD.(+22-03) TAC C TAC CTT AGA AAA TTG TGC ATT NO:20 SEQ ID H2.SD.(+19-06) ATT T TCT TAC CTT AGA AAA TTG TGC NO:21 SEQ ID H2.SD.(+16-09) TGC A CAT TCT TAC CTT AGA AAA TTG NO:22 SEQ ID. Petition 870260074072, de 24 / 07 / 2026, pág. 72 / 448 65 / 207 H2.SD.(+13-12) TTG T AAC CAT TCT TAC CTT AGA AAA NO:23 SEQ ID H2.SD.(+10-15) AAA T ACA AAC CAT TCT TAC CTT AGA NO:24 SEQ ID H2A(+06+30) CTC T ATG TTT TCT TTT GAA CAT CTT NO:25 SEQ ID H2A(+07+31) TCT C AAT GTT TTC TTT TGA ACA TCT NO:26 SEQ ID H2A(+09+33) CTT C TGA ATG TTT TCT TTT GAA CAT NO:27 SEQ ID H2A(+10+34) TCT T GTG AAT GTT TTC TTT TGA ACA NO:28 SEQ ID H2A(-23+02) AAT A ATC TAA AAT GCA AAA TAA AAA NO:29 SEQ ID H2A(-26-02) AAA A TAA AAT GCA AAA TAA AAA AAT NO:30 SEQ ID H2A(-29-05) AGT T AAT GCA AAA TAA AAA AAT AAA NO:31 SEQ ID H2A(-32-08) TAG G GCA AAA TAA AAA AAT AAA AGT NO:32 SEQ ID H2A(-35-11) GAA G AAA TAA AAA AAT AAA AGT TAG NO:33 SEQ ID H2A(-38-14) GCA A TAA AAA AAT AAA AGT TAG GAA NO:34 SEQ ID H2A(-41-17) ACT T AAA AAT AAA AGT TAG GAA GCA NO:35 SEQ ID H2A(+11+29) TGT TTT CTT TTG AAC ATC T NO:36 SEQ ID H2A(+46+62) CTT AGA AAA TTG TGC AT NO:38 SEQ ID H2D(+08-09) CAT TCT TAC CTT AGA AA NO:39 SEQ ID

[0160] where A is adenine, C is cytosine, G is guanine and T is thymine or uracil. In certain modalities, T is thymine.

[0161] In another aspect, the modified antisense oligomer is capable of binding to a selected target to induce exon skipping in the human dystrophin gene, wherein the modified antisense oligomer comprises a base sequence that is complementary to a target region of exon 2, intron 1, or intron 2 of the dystrophin pre-mRNA designated as an annealing site; wherein the base sequence and / or annealing site are selected from one of the following: Annealing site Baseline sequence [5' to 3'] SEQ ID NO: H2.SA.(-20+05) TTC ATC TAA AAT GCA AAA TAA AAA A SEQ ID NO:1 H2.SA.(-14+11) TTC TCT TTC ATC TAA AAT GCA AAA T SEQ ID NO:2 H2.SA.(-11 + 14) ATC TTC TCT TTC ATC TAA AAT GCA A SEQ ID NO:3 Petition 870260074072, dated 07 / 24 / 2026, p. 73 / 448 66 / 207 H2.SA.(-08+17) AAC ATC TTC TCT TTC ATC TAA AAT G SEQ ID NO:4 H2.SA.(-05+20) TTG AAC ATC TTC TCT TTC ATC TAA A SEQ ID NO:5 H2.SA.(-02+23) CTT TTG AAC ATC TTC TCT TTC ATC T SEQ ID NO:6 H2.SA.(+02+26) TTT CTT TTG AAC ATC TTC TCT TTC A SEQ ID NO:7 H2.SA.(+05+29) TGT TTT CTT TTG AAC ATC TTC TCT T SEQ ID NO:8 H2.SA.(+08+32) GAA TGT TTT CTT TTG AAC ATC TTC T SEQ ID NO:9 H2.SA.(+11+35) TGT GAA TGT TTT CTT TTG AAC ATC T SEQ ID NO:10 H2.SA.(+14+38) TTT TGT GAA TGT TTT CTT TTG AAC A SEQ ID NO:11 H2.SA.(+17+41) CCA TTT TGT GAA TGT TTT CTT TTG A SEQ ID NO:12 H2.SA.(+20+44) TAC CCA TTT TGT GAA TGT TTT CTT T SEQ ID NO:13 H2.SD.(+22-03) TAC CTT AGA AAA TTG TGC ATT TAC C SEQ ID NO:20 H2.SD.(+19-06) TCT TAC CTT AGA AAA TTG TGC ATT T SEQ ID NO:21 H2A(+06+30) ATG TTT TCT TTT GAA CAT CTC T SEQ ID NO:25 H2A(+07+31) AAT GTT TTC TTT TGA ACA TCT CCT: SEQ TTC TTC TGA TGA ACA TCT C620 TGA+ IDA+3 ATG TTT TCT TTT GAA CAT CTT C SEQ ID NO:27 H2A(+10+34) GTG AAT GTT TTC TTT TGA ACA TCT T SEQ ID NO:28 H2A(-38-14) TAA AAA AAT AAA AGT TAG GAA GCA A SEQ ID NO:34 H2A-11 AAG AGT GAA AGT-41 AGT AAA GCA ACT T SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36.

[0162] wherein A is adenine, C is cytosine, G is guanine and T is thymine or uracil. In some modalities, T is thymine.

[0163] In some forms, each Nu from 1 to (n+1) and 5' to 3' corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, or SEQ ID NO:35. In some modalities, each Nu from 1 to (n + 1) and 5' to 3' corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, Petition 870260074072, dated 07 / 24 / 2026, p. 74 / 448 67 / 207 SEQ ID NO:26, SEQ ID NO:27 or SEQ ID NO:28. In some forms, each Nu from 1 to (n+1) and 5' to 3' corresponds to one of the following: SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:25 or SEQ ID NO:28.

[0164] In some forms, T is thymine and each Nu from 1 to (n+1) and 5' to 3' corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, or SEQ ID NO:35. In some modalities, T is thymine and each Nu from 1 to (n + 1) and 5' to 3' corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27 or SEQ ID NO:28. In some modalities, T is thymine and each Nu from 1 to (n+1) and 5' to 3' corresponds to one of the following: SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:25 or SEQ ID NO:28. In some modalities, T is thymine and each Nu from 1 to (n+1) and 5' to 3' corresponds to SEQ ID NO:19 or SEQ ID NO:27.

[0165] In some embodiments, the antisense oligonucleotide or antisense oligonucleotide conjugate contains a T' portion attached to the end. 5' of the nucleic acid analog, wherein the T' portion is selected from: R200 C> ; and , where R200 is hydrogen or a cell-penetrating peptide and R1 is C1-C6 alkyl. In certain respects, R200 is hydrogen. Petition 870260074072, dated 07 / 24 / 2026, page 75 / 448 68 / 207

[0166] In some respects, the nucleobases of the modified antisense oligomer are linked to morpholino ring structures, wherein the morpholino ring structures are joined by phosphorus-containing intersubunit bonds that link a morpholino nitrogen of one ring structure to a 5' exocyclic carbon of an adjacent ring structure.

[0167] In some respects, the bases of the modified antisense oligomer are peptide nucleic acids (PNA), in which the sugar-phosphate polynucleotide structure is replaced by a flexible pseudo-peptide polymer to which the nucleobases are attached.

[0168] In some respects, the bases of the modified antisense oligomer are blocked nucleic acids (LNA), where the blocked nucleic acid structures are nucleotide analogs that are chemically modified where the ribose portion has an extra bridge connecting the 2' oxygen and the 4' carbon.

[0169] In some respects, the bases of the modified antisense oligomer are bridged nucleic acids (BNA), in which the sugar conformation is restricted or blocked by the introduction of an additional bridge structure into the furanose backbone. In some respects, the bases of the antisense oligomer are 2'-O,4'-C-ethylene (ENA) bridged nucleic acids.

[0170] Unless otherwise defined, all technical and scientific terms used in this document have the same meaning commonly understood by those skilled in the art to which the disclosure pertains. Although any methods and materials similar or equivalent to those described in this document may be used in the practice or testing of the present disclosure, preferred methods and materials are described. For the purposes of this disclosure, the following terms are defined below. Petition 870260074072, dated 07 / 24 / 2026, p. 76 / 448 69 / 207 1. Definitions

[0171] As used in this document, the term alkyl, unless otherwise specified, refers to a linear or branched saturated hydrocarbon. In certain embodiments, the alkyl group is a primary, secondary, or tertiary hydrocarbon. In certain embodiments, the alkyl group includes from one to ten carbon atoms, i.e., C1 to C10 alkyl. In certain embodiments, the alkyl group includes from one to six carbon atoms, i.e., C1 to C6 alkyl. The term includes substituted and unsubstituted alkyl groups, including halogenated alkyl groups. In certain embodiments, the alkyl group is a fluorinated alkyl group.Non-limiting examples of moieties with which the alkyl group may be substituted are selected from the group consisting of halogen (fluorine, chlorine, bromine, or iodine), hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, unprotected or protected, as necessary, as known to those skilled in the art, for example, as taught in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, hereby incorporated by reference. In certain embodiments, the alkyl group is selected from the group consisting of methyl, CF3, CCl3, CFCl2, CF2Cl, ethyl, CH2CF3, CF2CF3, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl. The term acyl refers to a C(O)R11 group (where R11 means H, alkyl or aryl as defined herein).Examples of acyl groups include formyl, acetyl, benzoyl, phenylacetyl, and similar groups.

[0172] Adaptable to exon 2 skip, as used here in relation to an individual or patient, is intended to include individuals and patients with one or more mutations or duplications in dystrophin which, in the absence of the dystrophin premRNA exon 2 skip, causes the reading frame to be out of frame, thus interrupting the translation of the premRNA or causing transcription of the duplicated exon, leading to an inability of the individual or patient to produce dystrophin. Petition 870260074072, dated 07 / 24 / 2026, page 77 / 448 70 / 207 functional or semi-functional. Determining whether a patient has a mutation in the dystrophin gene that is exon-skipping amenable is well within the scope of one skilled in the art (see, for example, Aartsma-Rus et al. (2009) Hum Mutat. 30: 293-299; Gurvich et al., Hum Mutat. 2009; 30 (4) 633-640; and Fletcher et al. (2010) Molecular Therapy 18 (6) 1218-1223.).

[0173] The term oligomer, as used herein, refers to a sequence of subunits connected by linkages between the subunits. In certain cases, the term oligomer is used in reference to an antisense oligomer. For antisense oligomers, each subunit consists of: (i) a ribose sugar or a derivative thereof; and (ii) a nucleobase attached to it, such that the order of the base-pairing moieties forms a base sequence that is complementary to a target sequence in a nucleic acid (typically an RNA) by Watson-Crick base pairing, to form an oligomer heteroduplex within the target sequence, provided that the subunit, the linkage between the subunits, or both do not occur naturally. In certain embodiments, the antisense oligomer is a morpholino phosphorodiamidate (PMO) oligomer. In other embodiments, the antisense oligomer is a 2'-O-methyl phosphorothioate.In other embodiments, the disclosure antisense oligomer is a peptide nucleic acid (PNA), a blocked nucleic acid (LNA), or a bridged nucleic acid (BNA), such as a 2'-O,4'-C-ethylene bridge nucleic acid (ENA). Additional exemplary embodiments are described in this document.

[0174] This antisense oligomer can be designed to block or inhibit mRNA translation or to inhibit the splicing processing of natural pre-mRNA and may be referred to as directed towards or directed against a target sequence with which it hybridizes. The target sequence is typically a region that includes an AUG start codon of an mRNA, a Translation Suppressor Oligomer, or a splice site of a pre-processed mRNA, a Splice Suppressor Oligomer (SSO). A Petition 870260074072, dated 07 / 24 / 2026, p. 78 / 448 71 / 207 A target sequence for a splice site may include an mRNA sequence with its 5' end 1 to about 25 base pairs downstream of a normal splice acceptor junction in a pre-processed mRNA. A preferred target sequence is any region of a pre-processed mRNA that includes a splice site or is contained entirely within an exon coding sequence or encompasses a splice acceptor or donor site. It is more generally said that an oligomer is targeted against a biologically relevant target, such as a protein, virus, or bacterium, when it is targeted against the target's nucleic acid in the manner described above.

[0175] The terms complementary and complementarity refer to two or more oligomers (i.e., each comprising a sequence of nucleobases) that are related to each other by the Watson-Crick base-pairing rules. For example, the nucleobase sequence TGA (5'^3') is complementary to the nucleobase sequence ACT (3'^5'). Complementarity can be partial, where less than all nucleobases of a given nucleobase sequence match the other nucleobase sequence according to the base-pairing rules. For example, in some embodiments, the complementarity between a given nucleobase sequence and another nucleobase sequence may be about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%. Or, there may be complete or perfect complementarity (100%) between a given sequence of nucleobases and another sequence of nucleobases, to continue the example.The degree of complementarity between nucleobase sequences has significant effects on the efficiency and resistance of hybridization between the sequences.

[0176] The term exon duplication refers to a genotype in which two or more copies of an exon are present and both are transcribed during the next generation. Petition 870260074072, dated 07 / 24 / 2026, p. 79 / 448 72 / 207 of the dystrophin pre-mRNA. Here, exon skipping is an intervention that would lead to the transcription of the correct number of exon copies in the mRNA transcript (i.e., one copy). A genotype with exon duplication leads to the transcription of an mRNA transcript that encodes a dystrophin gene with less activity than the wild-type dystrophin protein, and skipping one or more of the duplicated exons is an intervention that leads to the production of mRNA that encodes a highly active dystrophin.

[0177] The terms effective amount and therapeutically effective amount are used interchangeably herein and refer to an amount of a therapeutic compound, such as an antisense oligomer, administered to a mammalian individual, as a single dose or as part of a series of doses, that is effective in producing a desired therapeutic effect. For an antisense oligomer, this effect is typically caused by inhibiting translation or natural splice processing of a selected target sequence or by producing a clinically significant amount of dystrophin (statistical significance).

[0178] In some embodiments, an effective amount is about 1 mg / kg to about 200 mg / kg of a composition including an antisense oligomer for a period of time to treat the individual. In some embodiments, an effective amount is about 1 mg / kg to about 200 mg / kg of a composition including an antisense oligomer to increase the number of dystrophin-positive fibers in an individual. In certain embodiments, an effective amount is about 1 mg / kg to about 200 mg / kg of a composition including an antisense oligomer to stabilize, maintain, or improve walking distance, for example, at a 6 MWT, in a patient relative to a healthy peer.

[0179] “Improving or intensifying or increasing or enhancing or stimulating generally refers to the ability of one or more antisense oligomers or pharmaceutical compositions to produce or cause a Petition 870260074072, dated 07 / 24 / 2026, p. 80 / 448 73 / 207 greater physiological response (i.e., downstream effects) in a cell or an individual, compared with the response caused by no antisense oligomer or a control compound. A greater physiological response may include increased expression of a functional form of a dystrophin protein, or increased dystrophin-related biological activity in muscle tissue, among other responses evident from the understanding of the art and the description in this document.

[0180] As used in this document, the terms function and functional and similar terms refer to a biological, enzymatic or therapeutic function.

[0181] A functional dystrophin protein generally refers to a dystrophin protein with sufficient biological activity to reduce the progressive degradation of muscle tissue that is otherwise characteristic of muscular dystrophy, usually in comparison with the altered or defective form of dystrophin protein that is present in certain subjects with DMD or BMD. As an example, dystrophin-related activity in in vitro muscle cultures can be measured according to myotube size, myofibril organization (or disorganization), contractile activity, and spontaneous clustering of acetylcholine receptors (see, for example, Castanho et al., Journal of Cell Science, 112: 209-216, 1999). Animal models are also valuable resources for studying disease pathogenesis and provide a means to test dystrophin-related activity.Two of the most widely used animal models for DMD research are the mdx mouse and the golden retriever muscular dystrophy dog ​​(GRMD), both of which are dystrophin-negative (see, for example, Collins & Morgan, Int J Exp Pathol 84: 165-172, 2003). These and other animal models can be used to measure the functional activity of various dystrophin proteins. These include truncated forms of dystrophin, such as those forms that are produced after administration of some of the exon-jump antisense oligomers of this disclosure.

[0182] The terms incompatibility or mismatch refer to a Petition 870260074072, dated 07 / 24 / 2026, page 81 / 448 74 / 207 or more nucleobases (contiguous or separate) in an oligomer nucleobase sequence that do not match a target pre-mRNA according to base-pairing rules. While perfect complementarity is often desired, some embodiments may include one or more, but preferably 6, 5, 4, 3, 2, or 1 mismatches with respect to the target pre-mRNA. Variations at any location within the oligomer are included. In certain embodiments, antisense disclosure oligomers include variations in the nucleobase sequence near terminal variations within, and if present are typically within approximately 6, 5, 4, 3, 2, or 1 subunits of the 5' and / or 3' ends. In certain embodiments, one, two, or three nucleobases may be removed and still provide binding to the target.

[0183] The terms cell-penetrating peptide and CPP are used interchangeably and refer to cationic cell-penetrating peptides, also called transport peptides, carrier peptides, or peptide transduction domains. The peptides, as shown here, have the ability to induce cell penetration in 100% of the cells in a given cell culture population and allow macromolecular translocation into various tissues in vivo after systemic administration. A preferred embodiment of CPP is an arginine-rich peptide.

[0184] The terms morpholino, morpholino oligomer and PMO refer to a phosphorodiamidate morpholino oligomer with the following general structure: Petition 870260074072, dated 07 / 24 / 2026, page 82 / 448 75 / 207

[0185] and as described in Figure 2 of Summerton, J., et al., Antisense & Nucleic Acid Drug Development, 7: 187-195 (1997). Morpholinos, as described herein, include all stereoisomers and tautomers of the previous general structure. The syntheses, structures, and linkage characteristics of morpholino oligomers are detailed in U.S. Patents Nos. 5,698,685; 5,217,866; 5,142,047; 5,034,506; 5,166,315; 5,521,063; 5,506,337; 8,076,476; and 8,299,206, which are incorporated herein by reference.

[0186] In certain forms, a morpholino is conjugated at the 5' end or 3' of the oligomer with a tailing fraction to increase its stability and / or solubility. Exemplary tails include: H R200; and ΆτίΛτ, where R200 is hydrogen or a cell-penetrating peptide and R1 is C1-C6 alkyl.

[0187] In one embodiment, an exemplary portion of the tail, TEG or EG3 refers to the following portion of the tail: Petition 870260074072, dated 07 / 24 / 2026, p. 83 / 448 76 / 207

[0188] In one embodiment, an exemplary tail portion, GT refers to the following tail portion:

[0189] As used in this document, the terms -GR5 (SEQ ID NO: 45) and -GR5-Ac (SEQ ID NO: 45) are used interchangeably and refer to a peptide moiety conjugated to an antisense disclosure oligomer. In various embodiments, G represents a glycine residue conjugated to R5 (SEQ ID NO: 46) by an amide linkage, and each R represents an arginine residue conjugated by amide linkages such that R5 (SEQ ID NO: 46) means five (5) arginine residues conjugated by amide linkages. The arginine residues may have any stereo configuration, for example, the arginine residues may be L-arginine residues, D-arginine residues, or a mixture of D- and L-arginine residues. In certain embodiments, -GR5 (SEQ ID NO: 45) or -GR5-Ac (SEQ ID NO: 45) is attached to the distal -OH or NH2 of the tail portion.In certain embodiments, -GR5 (SEQ ID NO: 45) or -GR5-Ac (SEQ ID NO: 45) is conjugated with the morpholine ring nitrogen of the 3' plus morpholine subunit of a PMO antisense oligomer of disclosure. In some embodiments, -GR5 (SEQ ID NO: 45) or -GR5-Ac (SEQ ID. Petition 870260074072, dated 07 / 24 / 2026, page 84 / 448 77 / 207 NO: 45) is conjugated with the 3' end of an antisense oligomer of the disclosure or a pharmaceutically acceptable salt thereof, or ' 5HCI

[0190] As used in this document, the terms -GRe (SEQ ID NO: 47) and -GRe-Ac (SEQ ID NO: 47) are used interchangeably and refer to a peptide moiety conjugated to an antisense disclosure oligomer. In various embodiments, G represents a glycine residue conjugated with Re (SEQ ID NO: 48) by an amide linkage, and each R represents an arginine residue conjugated by amide linkages such that Re (SEQ ID NO: 48) means six (6) arginine residues conjugated by amide linkages. The arginine residues may have any stereo configuration, for example, the arginine residues may be L-arginine residues, D-arginine residues, or a mixture of D- and L-arginine residues. In certain embodiments, "-GR6(SEQ ID NO: 47) or -GR6-Ac (SEQ ID NO: 47) is attached to the -OH or NH2 distal of the tail portion. In certain embodiments, -GRe (SEQ Petition 870260074072, dated 07 / 24 / 2026, p. 85 / 448 78 / 207 In some embodiments, -GRe (SEQ ID NO: 47) or -GRe-Ac (SEQ ID NO: 47) is conjugated with the morpholine ring nitrogen of the 3' morpholine subunit of a PMO antisense disclosure oligomer. pharmaceutically acceptable of the same, or or urn salt •6HCI

[0191] The terms nucleobase (Nu), base-pairing fraction, or base are used interchangeably to refer to a purine or pyrimidine base found in naturally occurring or native DNA or RNA (e.g., uracil, thymine, adenine, cytosine, and guanine), as well as analogs of these naturally occurring purines and pyrimidines. These analogs may confer enhanced properties, such as binding affinity, to the oligomer. Exemplary analogs include hypoxanthine (the base component of inosine); 2,6-diaminopurine; 5-methylcytosine; C5-propynyl-modified pyrimidines; 10-(9-(aminoethoxy)phenoxazinyl) (G-clamp) and the like. Petition 870260074072, dated 07 / 24 / 2026, page 86 / 448 79 / 207

[0192] Other examples of base-pairing fractions include, among others, uracil, thymine, adenine, cytosine, guanine, and hypoxanthine (inosine) with their respective amino groups protected by acyl protecting groups, 2-fluorouracil, 2-fluorocytosine, 5-bromouracil, 5-iodouracil, 2,6-diaminopurine, azacytosine, pyrimidine analogs such as pseudoisocytosine and pseudouracil, and other modified nucleobases such as substituted 8-purines, xanthine, or hypoxanthine (where these two are products of natural degradation). Modified nucleobases disclosed in: Chiu and Rana, RNA, 2003, 9, 1034-1048; Limbach et al. Nucleic Acids Research, 1994, 22, 2183-2196; and Revankar and Rao, Comprehensive Natural Products Chemistry, vol. 7, 313 (1999); are also included, the contents of which are incorporated here by reference.

[0193] Other examples of base-pairing fractions include, among others, expanded-size nucleobases in which one or more benzene rings have been added. Nucleic acid base substitutions described in: the Glen Research catalog (www.glenresearch.com); Krueger AT et al., Acc. Chem. Res., 2007, 40, 141-150; Kool, ET, Acc. Chem. Res., 2002, 35, 936-943; Benner SA, et al., Nat. Rev. Genet., 2005, 6, 553-543; Romesberg, FE, et al., Curr. Opin. Chem. Biol., 2003, 7, 723-733; and Hirao, I., Curr. Opin. Chem. Biol., 2006, 10, 622-627; whose contents are incorporated herein by reference, are considered useful in the antisense oligomers described in this document. Examples of expanded-size nucleobases include those shown below, as well as their tautomeric forms. Petition 870260074072, dated 07 / 24 / 2026, p. 87 / 448 80 / 207

[0194] The terms parenteral administration and administered parenterally, as used in this document, refer to modes of administration other than enteral and topical administration, generally by injection, and include, among others, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0195] As used in this document, a set of square brackets used within a structural formula indicates that the structural characters between the brackets are repeated. In some embodiments, the square brackets used may be [ and ] and, in certain embodiments, the square brackets used to indicate repeated structural features may be ( and ). In some embodiments, the number of repeated iterations of the structural characters between square brackets is the number indicated outside the square brackets, such as 2, 3, 4, 5, 6, 7, and so on. In several embodiments, the number of repeated iterations of the structural feature between the square brackets is indicated Petition 870260074072, dated 07 / 24 / 2026, page 88 / 448 81 / 207 is replaced by a variable indicated outside the brackets, such as Z.

[0196] As used herein, a direct link or a wavy link drawn to a chiral carbon or phosphorus atom within a structural formula indicates that the stereochemistry of the chiral carbon or phosphorus is undefined and is intended to include all forms of the chiral center. Examples of such illustrations are shown below.

[0197] The phrase pharmaceutically acceptable means that the substance or composition must be compatible, chemically and / or toxicologically, with the other ingredients comprising a formulation and / or the subject being treated with it.

[0198] The term pharmaceutically acceptable carrier, as used in this document, refers to a non-toxic and inert solid, semi-solid or liquid excipient, diluent, encapsulation material or auxiliary formulation of any type. Some examples of materials that may serve as pharmaceutically acceptable carriers are: sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as coconut butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, oil Petition 870260074072, dated 07 / 24 / 2026, page 89 / 448 82 / 207 sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; compatible lubricants such as sodium lauryl sulfate and magnesium stearate; coloring agents; release agents; coating agents; sweetening agents; flavoring agents; fragrance agents; preservatives; and antioxidants; according to the formulator's criteria.

[0199] The term restoration with respect to dystrophin synthesis or production generally refers to the production of a dystrophin protein, including truncated forms of dystrophin, in a patient with muscular dystrophy after treatment with an antisense oligomer described herein. The percentage of dystrophin-positive fibers in a patient after treatment can be determined by a muscle biopsy using known techniques. For example, a muscle biopsy can be performed from a suitable muscle, such as the biceps brachii muscle in a patient.

[0200] Analysis of the percentage of dystrophin-positive fibers can be performed before and / or after treatment or at time points throughout the treatment. In some modalities, a post-treatment biopsy is performed on the muscle contralateral to the pre-treatment biopsy. Analysis of pre- and post-treatment dystrophin expression can be performed using any suitable dystrophin assay. In some modalities, immunohistochemical detection is performed on tissue sections from the muscle biopsy using an antibody that is a marker for dystrophin, such as a monoclonal or polyclonal antibody. For example, the antibody MANDYS106 can be used, which is a highly sensitive marker for dystrophin. Any suitable secondary antibody can be used.

[0201] In some modalities, the percentage of dystrophin-positive fibers is calculated by dividing the number of positive fibers by the total number of fibers counted. Normal muscle samples have 100% dystrophin-positive fibers. Therefore, the percentage of dystrophin-positive fibers can be expressed as a percentage of normal. To control for the presence of trace levels of dystrophin. Petition 870260074072, dated 07 / 24 / 2026, page 90 / 448 83 / 207 in muscle before treatment, as well as reversing fibers, an initial assessment can be adjusted using pre-treatment muscle sections of a patient to count dystrophin-positive fibers in post-treatment muscle. This can be used as a threshold for counting dystrophin-positive fibers in post-treatment muscle sections in that patient. In other modalities, antibody-stained tissue sections can also be used for dystrophin quantification using Bioquant image analysis software (Bioquant Image Analysis Corporation, Nashville, TN). The total dystrophin fluorescence signal intensity can be reported as a percentage of normal. Additionally, Western blot analysis with monoclonal or polyclonal anti-dystrophin antibodies can be used to determine the percentage of dystrophin-positive fibers. For example, the Leica Biosystems NCL-Dys1 anti-dystrophin antibody can be used.The percentage of dystrophin-positive fibers can also be analyzed by determining the expression of components of the sarcoglycan (β,γ) complex and / or neuronal NOS.

[0202] In some modalities, treatment with an antisense oligomer, or pharmaceutically acceptable salt thereof, of the disclosure delays or reduces progressive respiratory muscle dysfunction and / or failure in patients with DMD that would be expected without treatment. In some modalities, treatment with an antisense oligomer, or pharmaceutically acceptable salt thereof, of the disclosure may reduce or eliminate the need for ventilation assistance that would be expected without treatment. In some modalities, measurements of respiratory function to track the course of the disease, as well as the assessment of possible therapeutic interventions, include maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), and forced vital capacity (FVC). MIP and MEP measure the level of pressure a person can generate during inhalation and exhalation, respectively, and are sensitive measures of respiratory muscle strength.MIP is a measure of diaphragm muscle weakness.

[0203] In some modalities, MEP may decrease before changes in other pulmonary function tests, including MIP and FVC. In certain modalities, MEP may be an early indicator of respiratory dysfunction. In certain Petition 870260074072, dated 07 / 24 / 2026, p. 91 / 448 In 84 / 207 modalities, FVC can be used to measure the total volume of air expelled during forced exhalation after maximal inspiration. In patients with DMD, FVC increases concomitantly with physical growth until the onset of adolescence. However, as growth slows or is stunted by disease progression, and muscle weakness advances, vital capacity enters a declining phase and decreases at an average rate of about 8 to 8.5 percent per year after 10 to 12 years of age. In certain modalities, the percent of predicted MIP (weight-adjusted MIP), percent of predicted MEP (age-adjusted MEP), and percent of predicted FVC (age- and height-adjusted FVC) are supporting analyses.

[0204] The terms individual and patient, as used in this document, include any animal that exhibits a symptom, or is at risk of exhibiting a symptom, that can be treated with an antisense disclosure oligomer, such as an individual (or patient) who has or is at risk of having DMD or BMD, or any of the symptoms associated with these conditions (e.g., muscle fiber loss). Suitable subjects (or patients) include laboratory animals (such as mice, rats, rabbits, or guinea pigs), farm animals, and domestic animals or pets (such as a cat or dog). Non-human primates and, preferably, human patients (or subjects) are included. Also included are methods of producing dystrophin in an individual (or patient) with a dystrophin gene mutation or an exon 2 duplication that is amenable to exon 2 skipping.

[0205] The terms systemic administration, administered systemically, peripheral administration, and administered peripherally, as used in this document, refer to the administration of a compound, drug, or other material that is not directly to the central nervous system, so that it enters the patient's system and is thus subject to metabolism and other similar processes, for example, subcutaneous administration.

[0206] The targeting sequence phase refers to a nucleobase sequence of an oligomer that is complementary to a nucleotide sequence in a target pre-mRNA. In some disclosure embodiments, the nucleotide sequence in the target pre-mRNA is an exon 2, intron 1, or intron 2 annealing site in the dystrophin pre-mRNA. Representative annealing sites that are Petition 870260074072, dated 07 / 24 / 2026, p. 92 / 448 85 / 207 direcionados pelos oligonucleotides antissenso descritos neste documento include o seguito: H2.SA.(-20+05) H2.SA.(-14+11) H2.SA.(-11+14) H2.SA.(-08+17) H2.SA.(-05+20) H2.SA.(-02+23) H2.SA.(+02+26) H2.SA.(+05+29) H2.SA.(+08+32) H2.SA.(+11+35) H2.SA.(+14+38) H2.SA.(+17+41) H2.SA.(+20+44) H2.SA.(+23+47) H2.SA.(+26+50) H2.SA.(+29+53) H2.SA.(+32+56) H2.SA. (+35+59) H2.SA.(+38+62) H2.SD.(+22-03) H2.SD. (+19-06) H2.SD.(+16-09) H2.SD.(+13-12) H2.SD.(+10-15) H2A(+06+30) H2A(+07+31) H2A(+09+33) H2A(+10+34) H2A(-23+02) H2A(-26-02) H2A(-29-05) H2A(-32-08) H2A(-35-11) H2A(-38-14) H2A(-41-17) H2A(-03+28) H2A(+11+29) H2A(+46+62) H2D(+08-09) H2D(+15-08)

[0207] In some embodiments of the disclosure, the nucleotide sequence in the target pre-mRNA is an exon 2, intron 1, or intron 2 annealing site in the dystrophin pre-mRNA. Representative annealing sites that are targeted by the antisense oligonucleotides described in this document include the following: Petition 870260074072, dated 07 / 24 / 2026, page 93 / 448 86 / 207 H2.SA.(-20+05) H2.SA.(-14+11) H2.SA.(-11+14) H2.SA.(-08+17) H2. SA. (-05+20) H2. SA. (-02+23) H2. SA. (+02+26) H2.SA.(+05+29) H2.SA.(+08+32) H2.SA.(+11+35) H2.SA.(+14+38) H2.SA.(+17+41) H2. SA. (+20+44) H2.SA.(+23+47) H2.SA.(+26+50) H2.SA.(+29+53) H2.SA.(+32+56) H2.SA.(+35+59) H2.SD.(+22-03) H2.SD.(+19-06) H2.SD. (+16-09) H2.SD.(+13-12) H2.SD.(+10-15) H2A(+06+30) H2A(+07+31) H2A(+09+33) H2A(+10+34) H2A(-23+02) H2D(+08-09) H2A(-26-02) H2A(-29-05) H2A(-32-08) H2A(-35-ll) H2A(-38-14) H2A(-41-17) H2A(-03+28) H2A(+11+29) H2A(+46+62)

[0208] In some embodiments of the disclosure, the nucleotide sequence in the target premRNA is an exon 2, intron 1, or intron 2 annealing site in the dystrophin premRNA. Representative annealing sites that are targeted by the antisense oligonucleotides described in this document include the following: H2.SA.(-20+05) H2.SA.(-14+11) H2.SA.(-11+14) H2.SA.(-08+17) H2.SA.(-05+20) H2.SA.(-02+23) H2.SA.(+02+26) H2.SA.(+05+29) H2.SA.(+08+32) H2.SA.(+11+35) H2.SA.(+14+38) H2.SA.(+17+41) H2.SA.(+20+44) H2A(+ll+29) H2.SD.(+22-03) H2.SD. (+19-06) H2A(+06+30) H2A(+07+31) H2A(+09+33) H2A(+10+34) H2A(-38-14) H2A(-41-17)

[0209] Treatment of an individual (e.g., a mammal, such as a human) or a cell is any type of intervention used in an attempt to alter the natural course of the individual or cell. Treatment includes, among other things, administration of an oligomer or a pharmaceutical composition thereof, and may be performed prophylactically or after the onset of a pathological event or contact with an etiological agent. Treatment includes any desirable effect on the symptoms or pathology of a disease or condition associated with the dystrophin protein, such as in certain forms of muscular dystrophy, and may include, for example, minimal changes or improvements in a Petition 870260074072, dated 07 / 24 / 2026, page 94 / 448 87 / 207 or more measurable markers of the disease or condition being treated. Also included are prophylactic treatments, which may be aimed at reducing the rate of progression of the disease or condition being treated, delaying the onset of that disease or condition, or reducing the severity of its onset. Treatment or prophylaxis does not necessarily indicate complete eradication, cure, or prevention of the disease or condition or its associated symptoms.

[0210] In some modalities, treatment with an antisense oligomer, or pharmaceutically acceptable salt thereof, increases the production of new dystrophin, slows disease progression, delays or reduces loss of ambulation, reduces muscle inflammation, reduces muscle damage, improves muscle function, reduces loss of lung function, and / or increases muscle regeneration that would be expected without treatment. In some modalities, treatment maintains, postpones, or delays disease progression. In some modalities, treatment maintains ambulation or reduces loss of ambulation. In some modalities, treatment maintains lung function or reduces loss of lung function. In some modalities, treatment maintains or increases a stable walking distance in a patient, as measured, for example, by the 6-Minute Walk Test (6MWT).In some modalities, treatment maintains or reduces the time to walk / run 10 meters (i.e., the 10-meter walk / run test). In some modalities, treatment maintains or reduces the time to remain in the supine position (i.e., time to endure the test). In some modalities, treatment maintains or reduces the time to climb four standard steps (i.e., the four-step climb test). In some modalities, treatment maintains or reduces muscle inflammation in the patient, as measured by, for example, MRI (e.g., magnetic resonance imaging of the leg muscles). In some modalities, MRI measures T2 and / or fat fraction to identify muscle degeneration. MRI can identify changes in muscle structure and composition caused by inflammation, edema, muscle damage, and fat infiltration.

[0211] In some modalities, treatment with an antisense oligomer, or pharmaceutically acceptable salt thereof, of the dissemination increases new dystrophin production and delays or reduces the loss of ambulation that would be expected. Petition 870260074072, dated 07 / 24 / 2026, page 95 / 448 88 / 207 without treatment. For example, treatment may stabilize, maintain, improve, or increase walking ability (e.g., ambulation stabilization) in the individual. In some modalities, treatment maintains or increases a stable walking distance in a patient, as measured, for example, by the 6-Minute Walk Test (6MWT), described by McDonald, et al. Muscle Nerve, 2010; 42:966-74, incorporated here by reference. A change in 6-Minute Walk Distance (6MWD) can be expressed as an absolute value, a percentage change, or a change in % of predicted value. A DMD patient's performance on the 6MWT relative to typical performance of a healthy peer can be determined by calculating a % of predicted value. For example, the predicted % of 6MWD can be calculated using the following equation for men: 196.72 + (39.81 x age) - (1.36 x age²) + (132.28 x height in meters).For women, the predicted 6MWD can be calculated using the following equation: 188.61 + (51.50 x age) - (1.86 x age²) + (86.10 x height in meters) (Henricson et al. PLoS Curr., 2012, version 2, incorporated here by reference).

[0212] Muscle function loss in patients with DMD can occur relative to the history of normal growth and development in childhood. In fact, younger children with DMD may show an increase in walking distance during the 6MWT over about 1 year, despite progressive muscle impairment. In some modalities, the 6MWD of patients with DMD is compared to control subjects with typical development and to existing normative data from age- and sex-matched subjects. In some modalities, normal growth and development can be computed using an equation based on age and height adjusted to normative data. This equation can be used to convert 6MWD into a predicted percentile (% predicted) value in subjects with DMD. In certain modalities, analysis of predicted 6MWD% data represents a method for accounting for growth and development. Petition 870260074072, dated 07 / 24 / 2026, page 96 / 448 89 / 207 normal and may show that gains in function at early ages (e.g., less than or equal to 7 years) represent stable rather than improving abilities in patients with DMD (Henricson et al. PLoS Curr., 2012, version 2, incorporated here by reference).

[0213] An antisense molecule nomenclature system has been proposed and published to distinguish between different antisense molecules (see Mann et al., (2002) J Gen Med 4, 644-654). This nomenclature has become especially relevant when testing several slightly different antisense molecules, all targeting the same target region, as shown below: H#A / D(x:y).

[0214] The first letter designates the species (e.g., H: human, M: murine, C: canine). # designates the exon number of the target dystrophin. A / D and SA / SD indicate each acceptor or donor binding site at the beginning and end of the exon, respectively. (xy) represents the annealing coordinates where - or + indicate intronic or exonic sequences, respectively. For example, A(-6+18) would indicate the last 6 bases of the intron preceding the target exon and the first 18 bases of the target exon. The nearest splice site would be the acceptor, so these coordinates would be preceded by an A. The description of the annealing coordinates at the donor splice site could be D(+2-18) where the last 2 exonic bases and the first 18 intronic bases correspond to the annealing site of the antisense molecule. The fully exonic annealing coordinates would be represented by A(+65+85), which is the site between the 65th and 85th nucleotide from the beginning of that exon. II. Antisense oligomers or their pharmaceutically acceptable salts A. Antisense oligomers designed to induce exon 2 skipping.

[0215] In certain embodiments, the antisense disclosure oligomers are complementary to a target region of exon 2, intron 1, or intron 2 of the dystrophin gene and induce exon 2 skipping. In particular, disclosure refers to oligomers Petition 870260074072, dated 07 / 24 / 2026, p. 97 / 448 90 / 207 antisense complementary to urn exon 2, intron 1, or the target region of intron 2 of dystrophin premRNA designated as an annealing site. In some embodiments, the annealing site is any of the following: H2.SA.(-20+05) H2.SA.(-14+11) H2.SA.(-11+14) H2.SA.(-08+17) H2.SA.(-05+20) H2.SA.(-02+23) H2.SA.(+02+26) H2.SA.(+05+29) H2.SA.(+08+32) H2.SA.(+11+35) H2.SA.(+14+38) H2.SA.(+17+41) H2.SA.(+20+44) H2.SA.(+23+47) H2.SA.(+26+50) H2.SA.(+29+53) H2.SA.(+32+56) H2.SA.(+35+59) H2.SA.(+38+62) H2.SD. (+22-03) H2.SD.(+19-06) H2.SD.(+16-09) H2.SD.(+13-12) H2.SD.(+10-15) H2A(+06+30) H2A(+07+31) H2A(+09+33) H2A(+10+34) H2A(-23+02) H2A(-26-02) H2A(-29-05) H2A(-32-08) H2A(-35-ll) H2A(-38-14) H2A(-41-17) H2A(-03+28) H2A(+11+29) H2A(+46+62) H2D(+08-09) H2D(+15-08)

[0216] In some embodiments, the anchoring site is either following: H2.SA.(-20+05) H2.SD.(+22-03) H2.SA.(-14+11) H2.SD. (+19-06) H2.SA.(-11+14) H2.SD.(+16-09) H2.SA.(-08+17) H2.SD.(+13-12) H2.SA.(-05+20) H2.SD.(+10-15) H2.SA.(-02+2+3) H2.SD.(-02+3) H2.SA.(+02+26) H2.SA.(+07+31) H2.SA.(+05+29) H2A(+09+33) H2.SA.(+08+32) H2A(+10+34) H2.SA.(+11+35) H2A(-23+02) H1.SA.+4+33) H2D(+08-09) H2.SA.(+17+41) H2A(-26-02) H2.SA.(+20+44) H2A(-29-05) H2.SA.(+23+47) H2A(-32-08) H2.SA.(+26+50) H2.SA.(+26+50) H2.SA.(+23+47) H2A(-32-08) H2.SA.(+26+50) H2.SA.(+26+50) H2.SA.(+29+53) H2A(-38-14) H2.SA.(+32+56) H2A(-41-17) H2.SA.(+35+59) H2A(-03+28) H2A(+11+29) H2A(+46+62) Petition 870260074072, of 24 / 07 / 2026, p. 98 / 448 91 / 207

[0217] In some embodiments, ο anchoring site is any of the following: H2.SA.(-20+05) H2.SA.(+08+32) H2A(+06+30) H2.SA.(-14+11) H2.SA.(+11+35) H2A(+07+31) H2.SA.(-11+14) H2.SA.(+14+38) H2A(+09+33) H2.SA.(-08+17) H2.SA.(+17+41) H2A(+10+34) H2.SA.(-05+20) H2.SA.(+20+44) H2A(-38-14) H2.SA.(-02+23) H2.SA.(+38+62) H2A(-41-17) H2.SA.(+02+26) H2.SD.(+22-03) H2A(+11+29) H2.SA.(+05+29) H2.SD. (+19-06)

[0218] Em algumas modalidas, o sítio de anelamento é qualquer um dos seguentes: H2.SA.(-20+05) H2.SA.(-14+11) H2.SA.(-11+14) H2.SA.(-08+17) H2.SA.(-05+20) H2.SA.(-02+23) H2.SA.(+02+26) H2.SA.(+05+29) H2.SA.(+08+32) H2.SA.(+11+35) H2.SA.(+14+38) H2.SA.(+17+41) H2.SA.(+20+44) H2A(+ll+29) H2.SD.(+22-03) H2.SD.(+19-06) H2A(+06+30) H2A(+07+31) H2A(+09+33) H2A(+10+34) H2A(-38-14) H2A(-41-17)

[0219] In some embodiments, the annealing site is selected from the group consisting of H2.SA.(-11+14), H2.SA.(-08+17), H2.SA.(-05+20), H2.SA.(02+23), H2.SA.(+02+26), H2.SA.(+05+29), H2.SA.(+08+32), H2.SA.(+11+35), H2.SA.(+38+62), H2.SD.(+22-03), H2.SD.(+19-06), H2A(+06+30), H2A(+07+31), H2A(+09+33), H2A(+10+34), and H2A(-41-17). In some embodiments, the annealing site is selected from the group consisting of H2.SA.(-11+14), H2.SA.(05+20), H2.SA.(-02+23), H2.SA.(+02+26), H2.SA.(+05+29), H2.SA.(+08+32), H2.SA.(+11+35), H2.SD.(+22-03), H2.SD.(+19-06), H2A(+06+30), H2A(+07+31), H2A(+09+33), and H2A(+10+34). In some embodiments, the annealing site is selected from the group consisting of H2.SA.(-02+23), H2.SA.(+02+26), H2A(+06+30) and H2A(+10+34).

[0220] In some embodiments, the annealing site is selected from the group consisting of H2.SA.(-11+14), H2.SA.(-08+17), H2.SA.(-05+20), H2.SA.(02+23), H2.SA.(+02+26), H2.SA.(+05+29), H2.SA.(+08+32), H2.SA.(+11+35), Petition 870260074072, dated 07 / 24 / 2026, page 99 / 448 92 / 207 H2.SD.(+22-03), H2.SD.(+19-06), H2A(+06+30), H2A(+07+31), H2A(+09+33), H2A(+10+34), and H2A(-41-17). In some embodiments, the annealing site is selected from the group consisting of H2.SA.(-11+14), H2.SA.(-05+20), H2.SA.(02+23), H2.SA.(+02+26), H2.SA.(+05+29), H2.SA.(+08+32), H2.SA.(+11+35), H2.SD.(+22-03), H2.SD.(+19-06), H2A(+06+30), H2A(+07+31), H2A(+09+33), and H2A(+10+34). In some embodiments, the annealing site is selected from the group consisting of H2.SA.(-02+23), H2.SA.(+02+26), H2A(+06+30) and H2A(+10+34). In some modalities, the annealing site is H2.SA.(+38+62) or H2D(+15-08).

[0221] Disclosure antisense oligomers target dystrophin premRNA and induce exon 2 skipping, so that it is deleted or ignored from the mature processed mRNA transcript. By skipping exon 2, the interrupted reading frame is restored to a mutation in the frame. Although DMD is composed of several genetic subtypes, disclosure antisense oligomers, or their pharmaceutically acceptable salt, were specifically designed to ignore exon 2 of dystrophin premRNA.

[0222] The nucleobase sequence of an antisense oligomer that induces exon 2 skipping is designed to be complementary to a specific target sequence within exon 2, intron 1, or intron 2 of the dystrophin pre-mRNA. In some embodiments, an antisense oligomer is a PMO in which each morpholino ring of the PMO is linked to a nucleobase including, for example, nucleobases found in DNA (adenine, cytosine, guanine, and thymine).

[0223] In several embodiments, the antisense oligomer, or a pharmaceutically acceptable salt thereof, exhibits exon skipping in RD cells at a concentration of 10μM, wherein the antisense oligomer, or its pharmaceutically acceptable salt, exhibits <19.9% ​​exon skipping. In certain embodiments, the antisense oligomer, or its pharmaceutically acceptable salt, exhibits >20.0% exon skipping. Petition 870260074072, dated 07 / 24 / 2026, page 100 / 448 93 / 207 in RD cells. In certain embodiments, the antisense oligomer, or its pharmaceutically acceptable salt, exhibits >30.0% exon skipping in RD cells at a concentration of 10μM. In certain embodiments, the antisense oligomer, or its pharmaceutically acceptable salt, exhibits >40.0% exon skipping in RD cells at a concentration of 10μM. B. Chemical Characteristics of the Oligomer

[0224] Disclosure antisense oligomers may employ a variety of antisense oligomer chemistries. Examples of oligomer chemistries include, without limitation, morpholino oligomers, phosphorothioate-modified oligomers, 2'-O-methyl-modified nucleic acid (PNA) oligomers, peptide nucleic acid (LNA)-modified nucleic acid (LNA) oligomers, phosphorothioate oligomers, 2'-O-MOE-modified oligomers, 2'-fluoro-modified oligomers, 2'O, 4'C-ethylene-bridged nucleic acids (ENAs), tricyclo-DNAs, tricyclo-DNA phosphorothioate subunits, 2'-O-[2-(N-methylcarbamoyl)ethyl]-modified oligomers, including combinations of any of the foregoing. The chemistries modified with phosphorothioate and 2'-O-Me can be combined to generate a 2'-O-Me-phosphorothioate structure. See, for example, PCT Publications Nos. WO / 2013 / 112053 and WO / 2009 / 008725, which are incorporated herein by reference in their entirety.Exemplary forms of oligomer chemistry in disclosure are described in more detail below. 1. Peptide Nucleic Acids (PNAs)

[0225] Peptide nucleic acids (PNAs) are DNA analogues in which the backbone is structurally homomorphic to a deoxyribose backbone, consisting of N-(2-aminoethyl) glycine units to which pyrimidine or purine bases are attached. PNAs containing natural pyrimidine and purine bases hybridize with complementary oligomers obeying Watson-Crick base-pairing rules and mimic DNA in terms of base-pair recognition. The backbone of PNAs is formed by peptide bonds in Petition 870260074072, dated 07 / 24 / 2026, page 101 / 448 94 / 207 times the phosphodiester bonds, making them well-suited for antisense applications (see structure below). The main structure is unloaded, resulting in PNA / DNA or PNA / RNA duplexes that exhibit greater than normal thermal stability. PNAs are not recognized by nucleases or proteases. A non-limiting example of a PNA is shown below. HN PNA PNA

[0226] Despite a radical structural alteration in the natural structure, PNAs are capable of specific binding to sequences in a helical form to DNA or RNA. The characteristics of PNAs include a high binding affinity to complementary DNA or RNA, a destabilizing effect caused by single base mismatch, resistance to nucleases and proteases, hybridization to DNA or RNA independent of salt concentration, and triplex formation with homopurine DNA. PANAGENE™ has developed its proprietary Bts PNA monomers (Bts; benzothiazol-2-sulfonyl group) and proprietary oligomerization process. The PNA oligomerization using Bts PNA monomers consists of repetitive cycles of deprotection, coupling, and closure. PNAs can be produced synthetically using any technique known in the art. See, for example, U.S. Pat. Nos. 6,969,766; 7,211,668; 7,022,851; 7,125,994; 7,145,006; and Petition 870260074072, dated 07 / 24 / 2026, page 102 / 448 95 / 207 7,179,896. See also U.S. Pat. Nos. 5,539,082; 5,714,331; and 5,719,262 for the preparation of PNAs. Further teachings on PNA compounds may be found in Nielsen et al., Science, 254: 1497-1500, 1991. Each of the aforementioned documents is incorporated by reference in its entirety. 2. Locked Nucleic Acids (LNAs)

[0227] Antisense oligomers may also contain locked nucleic acid subunits (LNAs). LNAs are a member of a class of modifications called bridged nucleic acid (BNA). BNA is characterized by a covalent bond that locks the ribose ring conformation into a C30-endo (northern) sugar fold. For LNA, the bridge is composed of a methylene between the 2'-O and 4'-C positions. LNA enhances the core structure and base stacking to increase hybridization and thermal stability.

[0228] Structures of LNAs can be found, for example, in Wengel, et al., Chemical Communications (1998) 455; Koshkin et al., Tetrahedron (1998) 54:3607; Jesper Wengel, Accounts of Chem. Research (1999) 32:301; Obika, et al., Tetrahedron Letters (1997) 38:8735; Obika, et al., Tetrahedron Letters (1998) 39:5401; and Obika, et al., Bioorganic Medicinal Chemistry (2008) 16:9230, which are incorporated herein by reference in their entirety. A non-limiting example of an LNA is represented below. Petition 870260074072, dated 07 / 24 / 2026, p. 103 / 448 96 / 207 LNA

[0229] Disclosure antisense oligomers may incorporate one or more LNAs; in some cases, antisense oligomers may be entirely composed of LNAs. Methods for the synthesis of individual LNA nucleoside subunits and their incorporation into oligomers are described, for example, in US Pat. Nos. 7,572,582; 7,569,575; 7,084,125; 7,060,809; 7,053,207; 7,034,133; 6,794,499; and 6,670,461; each of which is incorporated by reference in its entirety. Typical intersubunit peptide linkers include phosphodiester and phosphorothioate moieties; alternatively, non-phosphorus-containing peptide linkers may be employed. Other embodiments include an antisense oligomer containing LNA, in which each LNA subunit is separated by a DNA subunit. Certain antisense oligomers are composed of alternating LNA and DNA subunits, where the intersubunit ligand is phosphorothioate.

[0230] 2'O,4'C-bridged nucleic acids (ENAs) are another member of the class of BNAs. A non-limiting example is shown below. Petition 870260074072, dated 07 / 24 / 2026, page 104 / 448 97 / 207 ENA

[0231] ENA oligomers and their preparation are described in Obika et al., Tetrahedron Lett (1997) 38 (50): 8735, which is incorporated here by reference in its entirety. Disclosure antisense oligomers may incorporate one or more ENA subunits. 3. Unblocked nucleic acid (UNA)

[0232] Antisense oligomers may also contain unlocked nucleic acid (UNA) subunits. UNA oligomers and UNAs are RNA analogs in which the C2'-C3' linkage of the subunit has been cleaved. While LNA is conformationally restricted (relative to DNA and RNA), UNA is very flexible. UNAs are disclosed, for example, in WO 2016 / 070166. A non-limiting example of a UNA is shown below. O. õ θH / - / P o S

[0233] Typical intersubunit peptide linkers include phosphodiester and phosphorothioate moieties; alternatively, non-phosphorus-containing peptide linkers may be employed. 4. Phosphorothioates Petition 870260074072, dated 07 / 24 / 2026, page 105 / 448 98 / 207

[0234] Phosphorothioates (or S-oligos) are a variant of normal DNA in which one of the non-bridge oxygens is replaced by a sulfur. A non-limiting example of a phosphorothioate is shown below. > Λ / oA The ^^Q^^Base Oh % ​

[0235] Sulfurization of the internucleotide bond reduces the action of endo- and exonucleases including 5' to 3' and 3' to 5' DNA POL 1 exonuclease, S1 and P1 nucleases, RNases, serum nucleases and snake venom phosphodiesterase. Phosphorothioates are produced by two main routes: by the action of a solution of elemental sulfur in carbon disulfide on a hydrogen phosphonate, or by the sulfurization method of phosphite triesters with tetraethylthiuram disulfide (TETD) or 3H-1,2-benzodithiol-3-one 1,1-dioxide (BDTD) (see, for example, Iyer et al., J. Org. Chem. 55, 4693-4699, 1990, which is incorporated herein by reference in its entirety). The latest methods avoid the problem of elemental sulfur insolubility in most organic solvents and the toxicity of carbon disulfide. The TETD and BDTD methods also produce phosphorothioates of higher purity. 5. Tricyclo-DNA and Tricyclo-Phosphorothioate Subunits

[0236] Tricyclo-DNAs (tc-DNAs) are a class of restricted DNA analogs in which each nucleotide is modified by the introduction of a cyclopropane ring to restrict the conformational flexibility of the backbone and to optimize the backbone geometry of the γ-twist angle. tc-DNAs Petition 870260074072, dated 07 / 24 / 2026, page 106 / 448 99 / 207 homobasic compounds containing adenine and thymine form extraordinarily stable AT base pairs with complementary RNAs. Tricyclo-DNAs and their synthesis are described in International Patent Application Publication No. WO 2010 / 115993, which is incorporated herein by reference in its entirety. The antisense oligomers of the disclosure may incorporate one or more tricyclo-DNA subunits; in some cases, the antisense oligomers may be entirely composed of tricyclo-DNA subunits.

[0237] Tricyclophosphorothioate subunits are tricyclo-DNA subunits with phosphorothioate intersubunit linkages. The tricyclophosphorothioate subunits and their synthesis are described in International Patent Application Publication No. WO 2013 / 053928, which is incorporated herein by reference in its entirety. The antisense oligomers of the disclosure may incorporate one or more tricyclo-DNA subunits; in some cases, the antisense oligomers may be entirely composed of tricyclo-DNA subunits. A non-limiting example of a tricyclo-DNA / tricyclophosphorothioate subunit is illustrated below. O=P-OI Base DNA Tricycle 6. 2'-O-Methyl, 2'-O-MOE and 2'-F Oligomers

[0238] 2'-O-Me oligomer molecules carry a methyl group at the 2'-OH residue of the ribose molecule. 2'-O-Me-RNAs exhibit the same (or similar) behavior as DNA, but are protected against nuclease degradation. 2'-O-Me-RNAs can also be combined with phosphorothioate (PTOs) oligomers for additional stabilization. 2'O-Me (phosphodiester or phosphorothioate) oligomers can be synthesized according to routine techniques in the art (see, for example, Petition 870260074072, dated 07 / 24 / 2026, page 107 / 448 100 / 207 Yoo et al., Nucleic Acids Res. 32: 2008-16, 2004, which is incorporated herein by reference in its entirety). A non-limiting example of a 2'-O-Me oligomer is described below. ? ° 2'-O-Me

[0239] 2'-O-methoxyethyl (2'-O-MOE) oligomers carry a methoxyethyl group at the 2'-OH residue of the ribose molecule and are discussed in Martin et al., Helv. Chim. Acta, 78, 486-504, 1995, which is incorporated here by reference in its entirety. A non-limiting example of a 2'-O-MOE subunit is illustrated below. Petition 870260074072, dated 07 / 24 / 2026, page 108 / 448 101 / 207

[0240] 2'-Fluoro (2'-F) oligomers have a fluorine radical in the 2' position instead of the 2'-OH. A non-limiting example of a 2'-F oligomer is described below. , B O=r —O ****** IO' 2'-F

[0241] 2'-fluoro oligomers are further described in WO 2004 / 043977, which is incorporated herein by reference in its entirety.

[0242] The 2'-O-Methyl, 2'-O-MOE and 2'-F oligomers may also comprise one or more phosphorothioate (PS) linkages as represented below. 2'-O-Methyl PS 2'-O-MOE PS 2'-F PS

[0243] In addition, 2'-O-Methyl, 2-O-MOE and 2'-F oligomers may comprise PS linkages between subunits throughout the oligomer, for example, as in the 2'-O-methyl PS oligomer drisapersen shown below. Petition 870260074072, dated 07 / 24 / 2026, p. 109 / 448 102 / 207

[0244] Alternatively, 2'-O-Methyl, 2-O-MOE and / or 2'-F oligomers may comprise PS linkages at the oligomer ends, as represented below. Petition 870260074072, dated 07 / 24 / 2026, p. 110 / 448 103 / 207 / ÓθΧsO

[0245] where:

[0246] R is CH2CH2OCH3 (methoxyethyl or MOE); and

[0247] X, Y and Z denote the number of nucleotides contained within each of the designated 5' wing, center gap and 3' wing regions, respectively.

[0248] Disclosure antisense oligomers may incorporate one or more 2'-O-Methyl, 2'-O-MOE, and 2'-F subunits and may utilize any of the interunit linkages described herein. In some cases, a disclosure antisense oligomer may be composed entirely of 2'-O-Methyl, 2'-O-MOE subunits. Petition 870260074072, dated 07 / 24 / 2026, page 111 / 448 104 / 207 or 2'-F. One embodiment of an antisense oligomer of disclosure is composed entirely of 2'-O-methyl subunits. 7. 2'-O-[2-(N-methylcarbamoyl)ethyl] oligomers (MCEs)

[0249] MCEs are another example of 2'-O modified ribonucleosides useful in antisense disclosure oligomers. Here, the 2'-OH is derived into a 2(N-methylcarbamoyl)ethyl moiety to increase nuclease resistance. A non-limiting example of an MCE oligomer is shown below.

[0250] MCEs and their synthesis are described in Yamada et al., J. Org. Chem. (2011) 76(9):3042-53, which is incorporated herein by reference in its entirety. Disclosure antisense oligomers may incorporate one or more MCE subunits. 8. Stereo Specific Oligomers

[0251] Specific stereo oligomers are those in which the stereochemistry of each phosphorus-containing bond is fixed by the synthesis method so that a substantially pure stereo oligomer is produced. A non-limiting example of a specific stereo oligomer is shown below. Petition 870260074072, dated 07 / 24 / 2026, page 112 / 448 105 / 207

[0252] In the example above, each phosphorus of the oligomer has the same stereo configuration. Additional examples include the oligomers described herein. For example, LNAs, ENAs, Tricyclo-DNAs, MCEs, 2'-O-Methyl, 2'-O-MOE, 2'-F and morpholino-based oligomers can be prepared with stereospecific phosphorus-containing internucleosidic linkages, such as, for example, phosphorothioate, phosphodiester, phosphoramidate, phosphorodiamidate or other phosphorus-containing internucleosidic linkages. Specific stereo oligomers, preparation methods, chiral-controlled synthesis, chiral design, and chiral auxiliaries for use in the preparation of such oligomers are detailed, for example, in WO2017192664, WO2017192679, WO2017062862, WO2017015575, WO2017015555, WO2015107425. WO2015108048, WO2015108046, WO2015108047, WO2012039448, WO2010064146, WO2011034072, WO2014010250, WO2014012081, WO20130127858 and WO2011005761, each of which is incorporated herein by reference in its entirety.

[0253] Specific stereo oligomers may have internucleosidic linkages containing phosphorus in an Rp or Sp configuration. Linkages containing chiral phosphorus in which the steric configuration of the linkages is controlled are referred to as stereopure, while linkages containing chiral phosphorus in which the steric configuration of the linkages is not controlled are referred to as stereorandom. In certain embodiments, Petition 870260074072, dated 07 / 24 / 2026, page 113 / 448 106 / 207 The oligomers of the disclosure comprise a plurality of stereopure and stereorandom linkages, such that the resulting oligomer has stereopure subunits at pre-specified positions of the oligomer. An example of the stereopure subunit site is provided in the publication of international patent application WO 2017 / 062862 A2 in Figures 7A and 7B. In one embodiment, all chiral phosphorus-containing linkages in an oligomer are stereorandom. In another embodiment, all chiral phosphorus-containing linkages in an oligomer are stereopure.

[0254] In an embodiment of an oligomer with n chiral phosphorus-containing bonds (where n is an integer 1 or greater), all n chiral phosphorus-containing bonds in the oligomer are stereorandom. In an embodiment of an oligomer with n chiral phosphorus-containing bonds (where n is an integer 1 or greater), all n chiral phosphorus-containing bonds in the oligomer are stereopure. In an embodiment of an oligomer with n chiral phosphorus-containing bonds (where n is an integer 1 or greater), at least 10% (to the nearest integer) of the n phosphorus-containing bonds in the oligomer are stereopure. In an embodiment of an oligomer with n chiral phosphorus-containing bonds (where n is an integer 1 or greater), at least 20% (to the nearest integer) of the n phosphorus-containing bonds in the oligomer are stereopure.In an embodiment of an oligomer with n chiral phosphorus-containing bonds (where n is an integer 1 or greater), at least 30% (to the nearest integer) of the n phosphorus-containing bonds in the oligomer are stereopure. In an embodiment of an oligomer with n chiral phosphorus-containing bonds (where n is an integer 1 or greater), at least 40% (to the nearest integer) of the n phosphorus-containing bonds in the oligomer are stereopure. In an embodiment of an oligomer with n chiral phosphorus-containing bonds (where n is an integer 1 or greater), at least 50% (to the nearest integer) of the n phosphorus-containing bonds in the oligomer are stereopure. Petition 870260074072, dated 07 / 24 / 2026, page 114 / 448 107 / 207 are stereopures. In an embodiment of an oligomer with n chiral phosphorus-containing bonds (where n is an integer 1 or greater), at least 60% (to the nearest integer) of the n phosphorus-containing bonds in the oligomer are stereopures. In an embodiment of an oligomer with n chiral phosphorus-containing bonds (where n is an integer 1 or greater), at least 70% (to the nearest integer) of the n phosphorus-containing bonds in the oligomer are stereopures. In an embodiment of an oligomer with n chiral phosphorus-containing bonds (where n is an integer 1 or greater), at least 80% (to the nearest integer) of the n phosphorus-containing bonds in the oligomer are stereopures. In an embodiment of an oligomer with n chiral phosphorus-containing bonds (where n is an integer 1 or greater), at least 90% (to the nearest integer) of the n phosphorus-containing bonds in the oligomer are stereopures.

[0255] In an embodiment of an oligomer with n chiral phosphorus-containing bonds (where n is an integer of 1 or more), the oligomer contains at least 2 contiguous stereopure phosphorus-containing bonds of the same stereophonic orientation (i.e., either Sp or Rp). In an embodiment of an oligomer with n chiral phosphorus-containing bonds (where n is an integer of 1 or more), the oligomer contains at least 3 contiguous stereopure phosphorus-containing bonds of the same stereophonic orientation (i.e., either Sp or Rp). In an embodiment of an oligomer with n chiral phosphorus-containing bonds (where n is an integer of 1 or more), the oligomer contains at least 4 contiguous stereopure phosphorus-containing bonds of the same stereophonic orientation (i.e., either Sp or Rp).In one embodiment of an oligomer with n chiral phosphorus-containing bonds (where n is an integer of 1 or more), the oligomer contains at least 5 contiguous stereopure phosphorus-containing bonds of the same stereo orientation (i.e., either Sp or Rp). In another embodiment of an oligomer with n chiral phosphorus-containing bonds (where n is an integer of 1 or more), the oligomer contains at least 6 contiguous phosphorus-containing bonds. Petition 870260074072, dated 07 / 24 / 2026, page 115 / 448 108 / 207 stereopure of the same stereo orientation (i.e., either Sp or Rp). In one embodiment of an oligomer with n chiral phosphorus-containing bonds (where n is an integer of 1 or more), the oligomer contains at least 7 contiguous stereopure phosphorus-containing bonds of the same stereophonic orientation (i.e., either Sp or Rp). In one embodiment of an oligomer with n chiral phosphorus-containing bonds (where n is an integer of 1 or more), the oligomer contains at least 8 contiguous stereopure phosphorus-containing bonds of the same stereophonic orientation (i.e., either Sp or Rp). In one embodiment of an oligomer with n chiral phosphorus-containing bonds (where n is an integer of 1 or more), the oligomer contains at least 9 contiguous stereopure phosphorus-containing bonds of the same stereo orientation (i.e., either Sp or Rp).In an embodiment of an oligomer with n chiral bonds containing phosphorus (where n is an integer of 1 or greater), the oligomer contains at least 10 contiguous bonds containing stereopure phosphorus of the same stereo orientation (i.e., either Sp or Rp). In an embodiment of an oligomer with n chiral bonds containing phosphorus (where n is an integer of 1 or more), the oligomer contains at least 11 contiguous bonds containing stereopure phosphorus of the same stereophonic orientation (i.e., either Sp or Rp). In an embodiment of an oligomer with n chiral bonds containing phosphorus (where n is an integer of 1 or more), the oligomer contains at least 12 contiguous bonds containing stereopure phosphorus of the same stereo orientation (i.e., either Sp or Rp).In one embodiment of an oligomer with n chiral bonds containing phosphorus (where n is an integer of 1 or more), the oligomer contains at least 13 contiguous bonds containing stereopure phosphorus of the same stereophonic orientation (i.e., either Sp or Rp). In one embodiment of an oligomer with n chiral bonds containing phosphorus (where n is an integer of 1 or more), the oligomer contains at least 14 contiguous bonds containing stereopure phosphorus of the same stereo orientation (i.e., either Sp or Rp). In one embodiment of an oligomer with n chiral bonds containing phosphorus (where n is an integer of 1 or more), the oligomer contains at least 14 contiguous bonds containing stereopure phosphorus of the same stereo orientation (i.e., either Sp or Rp). Petition 870260074072, dated 07 / 24 / 2026, page 116 / 448 109 / 207 n is an integer of 1 or more), the oligomer contains at least 15 contiguous bonds containing stereopure phosphorus of the same stereo orientation (i.e., either Sp or Rp). In an embodiment of an oligomer with n chiral bonds containing phosphorus (where n is an integer of 1 or more), the oligomer contains at least 16 contiguous bonds containing stereopure phosphorus of the same stereo orientation (i.e., either Sp or Rp). In an embodiment of an oligomer with n chiral bonds containing phosphorus (where n is an integer of 1 or more), the oligomer contains at least 17 contiguous bonds containing stereopure phosphorus of the same stereophonic orientation (i.e., either Sp or Rp). In one embodiment of an oligomer with n chiral phosphorus-containing linkages (where n is an integer of 1 or more), the oligomer contains at least 18 contiguous stereopure phosphorus-containing linkages of the same stereophonic orientation (i.e., either Sp or Rp).In one embodiment of an oligomer with n chiral phosphorus-containing bonds (where n is an integer of 1 or more), the oligomer contains at least 19 contiguous stereopure phosphorus-containing bonds of the same stereo orientation (i.e., either Sp or Rp). In another embodiment of an oligomer with n chiral phosphorus-containing bonds (where n is an integer of 1 or more), the oligomer contains at least 20 contiguous stereopure phosphorus-containing bonds of the same stereophonic orientation (i.e., either Sp or Rp). 9. Morpholino Oligomers

[0256] Exemplary forms of disclosure refer to oligomers of Petition 870260074072, dated 07 / 24 / 2026, page 117 / 448 110 / 207 morpholino phosphorodiamidate of the following general structure: Ίλ(Υ Νιι h3cxV NP=OH3Cό I

[0257] and as described in Figure 2 of Summerton, J., et al., Antisense & Nucleic Acid Drug Development, 7: 187-195 (1997). The morpholinos, as described in this document, are intended to cover all stereoisomers and tautomers of the general structure above. The syntheses, structures, and linkage characteristics of the morpholinos oligomers are detailed in US Patent Nos.: 5,698,685; 5,217,866; 5,142,047; 5,034,506; 5,166,315; 5,521,063; 5,506,337; 8,076,476; and 8,299,206, all of which are incorporated herein by reference.

[0258] In certain forms, a morpholino is conjugated at the 5' end or 3' of the oligomer with a tailing fraction to increase its stability and / or solubility. Exemplary tails include: R200

[0259] R200 is hydrogen or a cell-penetrating peptide and R1 is C1-C6 alkyl. Petition 870260074072, dated 07 / 24 / 2026, page 118 / 448 111 / 207

[0260] In several respects, the disclosure provides antisense oligomers according to Formula (I): O^=P---N(CH3)2 O^=P---N(CH3)2o (I)

[0261] or a pharmaceutically acceptable salt thereof, characterized in that:

[0262] each Nu is a nucleobase that, together, forms a targeting sequence; Petition 870260074072, dated 07 / 24 / 2026, p. 119 / 448 112 / 207

[0263] T' in Formula (I) is a fraction selected from:

[0264] R100 and R200 are each independently hydrogen or a cell-penetrating peptide and R1 is C1-C6 alkyl;

[0265] each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following:___________________________________________________________________ Sítio de anelamento Sequência base [5' a 3'] SEQ ID NO: H2.SA.(-20+05) TTC ATC TAA AAT GCA AAA TAA AAA A SEQ ID NO:1 H2.SA.(-14+11) TTC TCT TTC ATC TAA AAT GCA AAA T SEQ ID NO:2 H2.SA.(-11+14) ATC TTC TCT TTC ATC TAA AAT GCA A SEQ ID NO:3 H2.SA.(-08+17) AAC ATC TTC TCT TTC ATC TAA AAT G SEQ ID NO:4 H2.SA.(-05+20) TTG AAC ATC TTC TCT TTC ATC TAA A SEQ ID NO:5 H2.SA.(-02+23) CTT TTG AAC ATC TTC TCT TTC ATC T SEQ ID NO:6 H2.SA.(+02+26) TTT CTT TTG AAC ATC TTC TCT TTC A SEQ ID NO:7 H2.SA.(+05+29) TGT TTT CTT TTG AAC ATC TTC TCT T SEQ ID NO:8 H2.SA.(+08+32) GAA TGT TTT CTT TTG AAC ATC TTC T SEQ ID NO:9 H2.SA.(+11+35) TGT GAA TGT TTT CTT TTG AAC ATC T SEQ ID NO:10 H2.SA.(+14+38) TTT TGT GAA TGT TTT CTT TTG AAC A SEQ ID NO:11 H2.SA.(+17+41) CCA TTT TGT GAA TGT TTT CTT TTG A SEQ ID NO:12 H2.SA.(+20+44) TAC CCA TTT TGT GAA TGT TTT CTT T SEQ ID NO:13 H2.SA.(+23+47) ATT TAC CCA TTT TGT GAA TGT TTT C SEQ ID NO:14 H2.SA.(+26+50) TGC ATT TAC CCA TTT TGT GAA TGT T SEQ ID NO:15 H2.SA.(+29+53) TTG TGC ATT TAC CCA TTT TGT GAA T SEQ ID NO:16 H2.SA.(+32+56) AAA TTG TGC ATT TAC CCA TTT TGT G SEQ ID NO:17 H2.SA.(+35+59) AGA AAA TTG TGC ATT TAC CCA TTT T SEQ ID NO:18 H2.SA.(+38+62) CTT AGA AAA TTG TGC ATT TAC CCA T SEQ ID NO:19 H2.SD.(+22-03) TAC CTT AGA AAA TTG TGC ATT TAC C SEQ ID NO:20 H2.SD.(+19-06) TCT TAC CTT AGA AAA TTG TGC ATT T SEQ ID NO:21 H2.SD.(+16-09) CAT TCT TAC CTT AGA AAA TTG TGC ATT T SEQ ID NO:22 H2.SD.(+13-12) AAC CAT TCT TAC CTT AGA AAA TTG T SEQ ID NO:23 H2.SD.(+10-15) ACA AAC CAT TCT TAC CTT AGA AAA T SEQ ID NO:24 H2A(+06+30) ATG TTT TCT TTT GAA CAT CTT CTC T SEQ ID NO:25. Petition 870260074072, de 24 / 07 / 2026, pág. 120 / 448 113 / 207 H2A(+07+31) AAT GTT TTC TTT TGA ACA TCT TCT C SEQ ID NO:26 H2A(+09+33) TGA ATG TTT TCT TTT GAA CAT CTT C SEQ ID NO:27 H2A(+10+34) GTG AAT GTT TTC TTT TGA ACA TCT T SEQ ID NO:28 H2A(-23+02) ATC TAA AAT GCA AAA TAA AAA AAT A SEQ ID NO:29 H2A(-26-02) TAA AAT GCA AAA TAA AAA AAT AAA A SEQ ID NO:30 H2A(-29-05) AAT GCA AAA TAA AAA AAT AAA AGT T SEQ ID NO:31 H2A(-32-08) GCA AAA TAA AAA AAT AAA AGT TAG G SEQ ID NO:32 H2A(-35-11) AAA TAA AAA AAT AAA AGT TAG GAA G SEQ ID NO:33 H2A(-38-14) TAA AAA AAT AAA AGT TAG GAA GCA A SEQ ID NO:34 H2A(-41-17) AAA AAT AAA AGT TAG GAA GCA ACT T SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36 H2D(+15-08) ATT CTT ACC TTA GAA AAT TGT GC SEQ ID NO:37 H2A(+46+62) CTT AGA AAA TTG TGC AT SEQ ID NO:38 H2D(+08-09) CAT TCT TAC CTT AGA AA SEQ ID NO:39

[0266] em que A é adenina, C é citosina, G é guanina e T é timina ou uracila. Em certas modalidades, T é timina.

[0267] In some Formula (I) modalities, each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Sítio de anelamento Sequência base [5' a 3'] SEQ ID NO: H2.SA.(-20+05) TTC ATC TAA AAT GCA AAA TAA AAA A SEQ ID NO:1 H2.SA.(-14+11) TTC TCT TTC ATC TAA AAT GCA AAA T SEQ ID NO:2 H2.SA.(-11+14) ATC TTC TCT TTC ATC TAA AAT GCA A SEQ ID NO:3 H2.SA.(-08+17) AAC ATC TTC TCT TTC ATC TAA AAT G SEQ ID NO:4 H2.SA.(-05+20) TTG AAC ATC TTC TCT TTC ATC TAA A SEQ ID NO:5 H2.SA.(-02+23) CTT TTG AAC ATC TTC TCT TTC ATC T SEQ ID NO:6 H2.SA.(+02+26) TTT CTT TTG AAC ATC TTC TCT TTC A SEQ ID NO:7 H2.SA.(+05+29) TGT TTT CTT TTG AAC ATC TTC TCT T SEQ ID NO:8 H2.SA.(+08+32) GAA TGT TTT CTT TTG AAC ATC TTC T SEQ ID NO:9 H2.SA.(+11+35) TGT GAA TGT TTT CTT TTG AAC ATC T SEQ ID NO:10 H2.SA.(+14+38) TTT TGT GAA TGT TTT CTT TTG AAC A SEQ ID NO:11 H2.SA.(+17+41) CCA TTT TGT GAA TGT TTT CTT TTG A SEQ ID NO:12 H2.SA.(+20+44) TAC CCA TTT TGT GAA TGT TTT CTT T SEQ ID NO:13 H2.SA.(+23+47) ATT TAC CCA TTT TGT GAA TGT TTT C SEQ ID NO:14 H2.SA.(+26+50) TGC ATT TAC CCA TTT TGT GAA TGT T SEQ ID NO:15 H2.SA.(+29+53) TTG TGC ATT TAC CCA TTT TGT GAA T SEQ ID NO:16 H2.SA.(+32+56) AAA TTG TGC ATT TAC CCA TTT TGT G SEQ ID NO:17 H2.SA.(+35+59) AGA AAA TTG TGC ATT TAC CCA TTT T SEQ ID NO:18 H2.SD.(+22-03) TAC CTT AGA AAA TTG TGC ATT TAC C SEQ ID NO:20 H2.SD.(+19-06) TCT TAC CTT AGA AAA TTG TGC ATT T SEQ ID NO:21 H2.SD.(+16-09) CAT TCT TAC CTT AGA AAA TTG TGC A SEQ ID NO:22 H2.SD.(+13-12) AAC CAT TCT TAC CTT AGA AAA TTG TGC A SEQ ID NO:23 H2.SD.(+10-15) ACA AAC CAT TCT TAC CTT AGA AAA T SEQ ID NO:24 H2A(+06+30) ATG TTT TCT TTT GAA CAT CTT CTC T SEQ ID NO:25. Petition 870260074072, de 24 / 07 / 2026, pág. 121 / 448 114 / 207 H2A(+07+31) AAT GTT TTC TTT TGA ACA TCT TCT C SEQ ID NO:26 H2A(+09+33) TGA ATG TTT TCT TTT GAA CAT CTT C SEQ ID NO:27 H2A(+10+34) GTG AAT GTT TTC TTT TGA ACA TCT T SEQ ID NO:28 H2A(-23+02) ATC TAA AAT GCA AAA TAA AAA AAT A SEQ ID NO:29 H2A(-26-02) TAA AAT GCA AAA TAA AAA AAT AAA A SEQ ID NO:30 H2A(-29-05) AAT GCA AAA TAA AAA AAT AAA AGT T SEQ ID NO:31 H2A(-32-08) GCA AAA TAA AAA AAT AAA AGT TAG G SEQ ID NO:32 H2A(-35-11) AAA TAA AAA AAT AAA AGT TAG GAA G SEQ ID NO:33 H2A(-38-14) TAA AAA AAT AAA AGT TAG GAA GCA A SEQ ID NO:34 H2A(-41-17) AAA AAT AAA AGT TAG GAA GCA ACT T SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36 H2A(+46+62) CTT AGA AAA TTG TGC AT SEQ ID NO:38 H2D(+08-09) CAT TCT TAC CTT AGA AA SEQ ID NO:39

[0268] where A is adenine, C is cytosine, G is guanine and T is thymine or uracil. In certain modalities, T is thymine.

[0269] In some Formula (I) modalities, each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Sítio de anelamento Sequência base [5' a 3'] NO: SEQ ID H2.SA.(-20+05) A TTC ATC TAA AAT GCA AAA TAA AAA NO:1 SEQ ID H2.SA.(-14+11) T TTC TCT TTC ATC TAA AAT GCA AAA NO:2 SEQ ID H2.SA.(-11+14) A ATC TTC TCT TTC ATC TAA AAT GCA NO:3 SEQ ID H2.SA.(-08+17) G AAC ATC TTC TCT TTC ATC TAA AAT NO:4 SEQ ID H2.SA.(-05+20) A TTG AAC ATC TTC TCT TTC ATC TAA NO:5 SEQ ID H2.SA.(-02+23) T CTT TTG AAC ATC TTC TCT TTC ATC NO:6 SEQ ID H2.SA.(+02+26) TTT CTT TTG AAC ATC TTC TCT TTC A NO:7 SEQ ID H2.SA.(+05+29) T TGT TTT CTT TTG AAC ATC TTC TCT NO:8 SEQ ID H2.SA.(+08+32) T GAA TGT TTT CTT TTG AAC ATC TTC NO:9 SEQ ID H2.SA.(+11+35) T TGT GAA TGT TTT CTT TTG AAC ATC NO:10 SEQ ID H2.SA.(+14+38) A TTT TGT GAA TGT TTT CTT TTG AAC NO:11 SEQ ID H2.SA.(+17+41) A CCA TTT TGT GAA TGT TTT CTT TTG NO:12 SEQ ID H2.SA.(+20+44) T TAC CCA TTT TGT GAA TGT TTT CTT NO:13 SEQ ID H2.SD.(+22-03) C TAC CTT AGA AAA TTG TGC ATT TAC NO:20 SEQ ID H2.SD.(+19-06) T TCT TAC CTT AGA AAA TTG TGC ATT NO:21 SEQ ID Petition 870260074072, dated 07 / 24 / 2026, p. 122 / 448 115 / 207 H2A(+06+30) T ATG TTT TCT TTT GAA CAT CTT CTC NO:25 SEQ ID H2A(+07+31) C AAT GTT TTC TTT TGA ACA TCT TCT NO:26 SEQ ID H2A(+09+33) C TGA ATG TTT TCT TTT GAA CAT CTT NO:27 SEQ ID H2A(+10+34) T GTG AAT GTT TTC TTT TGA ACA TCT NO:28 SEQ ID H2A(-38-14) A TAA AAA AAT AAA AGT TAG GAA GCA NO:34 SEQ ID H2A(-41-17) T AAA AAT AAA AGT TAG GAA GCA ACT NO:35 SEQ ID H2A(+11+29) TGT TTT CTT TTG AAC ATC T NO:36 SEQ ID

[0270] where A is adenine, C is cytosine, G is guanine and T is thymine or uracil. In certain modalities, T is thymine.

[0271] In some embodiments, each Nu from 1 to (n+1) and 5' to 3' of Formula (I) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, or SEQ ID NO:35. In some modalities, each Nu from 1 to (n+1) and 5' to 3' of Formula (I) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27 or SEQ ID NO:28. In some modalities, each Nu from 1 to (n+1) and 5' to 3' of Formula (I) corresponds to one of the following: SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:25 or SEQ ID NO:28.

[0272] In some forms, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (I) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, or SEQ ID NO:35. In some modalities, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (I) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27 or SEQ ID NO:28. In some modalities, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Petition 870260074072, dated 07 / 24 / 2026, pp. 123 / 448 116 / 207 Formula (I) corresponds to one of the following: SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:25 or SEQ ID NO:28. In some embodiments, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (I) corresponds to SEQ ID NO:19. In some embodiments, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (I) corresponds to SEQ ID NO:37.

[0273] In several modalities, T' is hydrogen or a cell-penetrating peptide.

[0274] In several embodiments, R100 is hydrogen. In several other embodiments, R100 is a cell-penetrating peptide. In several embodiments, if R100 is a cell-penetrating peptide, R100 is -R5 (SEQ ID NO: 46). In several other embodiments, if R100 is a cell-penetrating peptide, R100 is -G-R5 (SEQ ID NO: 45). In several embodiments, if R100 is a cell-penetrating peptide, R100 is -R6 (SEQ ID NO: 48). In several other embodiments, if R100 is a cell-penetrating peptide, R100 is -G-R6 (SEQ ID NO: 47).

[0275] In some embodiments, an antisense oligomer of Formula (I) is in the free base form. In some embodiments, an antisense oligomer of Formula (I) is a pharmaceutically acceptable salt thereof. In some embodiments, an antisense oligomer of Formula (I) is a salt of HCl (hydrochloric acid) thereof. In certain embodiments, the HCl salt is a salt of 1HCl, 2HCl, 3HCl, 4HCl, 5HCl, or 6HCl. In certain embodiments, the HCl salt is a 6HCl salt. Petition 870260074072, dated 07 / 24 / 2026, pp. 124 / 448 117 / 207

[0276] In several modalities, T' is R200 is either hydrogen or a cell-penetrating peptide, and R100 is a cell-penetrating peptide.

[0277] In several modalities, T' is cell-penetrating peptide.

[0278] In several modalities, T' is and R100 is -G-R5 (SEQ ID NO: 45). Petition 870260074072, dated 07 / 24 / 2026, p. 125 / 448 118 / 207

[0279] In several modalities, T' is , and R100 is -G-R6 (SEQ ID NO: 47).

[0280] In some forms, including, for example, some forms of Formula (I), an antisense oligomer of disclosure is in accordance with Formula (II): [5'] [3'] r200 0 (II)

[0281] or a pharmaceutically acceptable salt thereof,

[0282] R200 is hydrogen or a cell-penetrating peptide; and where each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Sítio de anelamento Sequência base [5' a 3'] SEQ ID NO: H2.SA.(-20+05) TTC ATC TAA AAT GCA AAA TAA AAA A SEQ ID NO:1 H2.SA.(-14+11) TTC TCT TTC ATC TAA AAT GCA AAA T SEQ ID NO:2 H2.SA.(-11+14) ATC TTC TCT TTC ATC TAA AAT GCA A SEQ ID NO:3 H2.SA.(-08+17) AAC ATC TTC TCT TTC ATC TAA AAT G SEQ ID NO:4 H2.SA.(-05+20) TTG AAC ATC TTC TCT TTC ATC TAA A SEQ ID NO:5 H2.SA.(-02+23) CTT TTG AAC ATC TTC TCT TTC ATC T SEQ ID NO:6 H2.SA.(+02+26) TTT CTT TTG AAC ATC TTC TCT TTC A SEQ ID NO:7 H2.SA.(+05+29) TGT TTT CTT TTG AAC ATC TTC TCT T SEQ ID NO:8 H2.SA.(+08+32) GAA TGT TTT CTT TTG AAC ATC TTC T SEQ ID NO:9 H2.SA.(+11+35) TGT GAA TGT TTT CTT TTG AAC ATC T SEQ ID NO:10 H2.SA.(+14+38) TTT TGT GAA TGT TTT CTT TTG AAC A SEQ ID NO:11 H2.SA.(+17+41) CCA TTT TGT GAA TGT TTT CTT TTG A SEQ ID NO:12 Petição 870260074072, de 24 / 07 / 2026, pág. 126 / 448 119 / 207 H2.SA.(+20+44) TAC CCA TTT TGT GAA TGT TTT CTT T SEQ ID NO:13 H2.SA.(+23+47) ATT TAC CCA TTT TGT GAA TGT TTT C SEQ ID NO:14 H2.SA.(+26+50) TGC ATT TAC CCA TTT TGT GAA TGT T SEQ ID NO:15 H2.SA.(+29+53) TTG TGC ATT TAC CCA TTT TGT GAA T SEQ ID NO:16 H2.SA.(+32+56) AAA TTG TGC ATT TAC CCA TTT TGT G SEQ ID NO:17 H2.SA.(+35+59) AGA AAA TTG TGC ATT TAC CCA TTT T SEQ ID NO:18 H2.SA.(+38+62) CTT AGA AAA TTG TGC ATT TAC CCA TTT T SEQ ID NO:19 H2.SD.(+22-03) TAC CTT AGA AAA TTG TGC ATT TAC C SEQ ID NO:20 H2.SD.(+19-06) TCT TAC CTT AGA AAA TTG TGC ATT T SEQ ID NO:21 H2.SD.(+16-09) CAT TCT TAC CTT AGA AAA TTG TGC A SEQ ID NO:22 H2.SD.(+13-12) AAC CAT TCT TAC CTT AGA AAA TTG T SEQ ID NO:23 H2.SD.(+10-15) ACA AAC CAT TCT TAC CTT AGA AAA T SEQ ID NO:24 H2A(+06+30) ATG TTT TCT TTT GAA CAT CTT CTC T SEQ ID NO:25 H2A(+07+31) AAT GTT TTC TTT TGA ACA TCT TCT C SEQ ID NO:26 H2A(+09+33) TGA ATG TTT TCT TTT GAA CAT CTT C SEQ ID NO:27 H2A(+10+34) GTG AAT GTT TTC TTT TGA ACA TCT T SEQ ID NO:28 H2A(-23+02) ATC TAA AAT GCA AAA TAA AAA AAT A SEQ ID NO:29 H2A(-26-02) TAA AAT GCA AAA TAA AAA AAT AAA A SEQ ID NO:30 H2A(-29-05) AAT GCA AAA TAA AAA AAT AAA AGT T SEQ ID NO:31 H2A(-32-08) GCA AAA TAA AAA AAT AAA AGT TAG G SEQ ID NO:32 H2A(-35-11) AAA TAA AAA AAT AAA AGT TAG GAA G SEQ ID NO:33 H2A(-38-14) TAA AAA AAT AAA AGT TAG GAA GCA A SEQ ID NO:34 H2A(-41-17) AAA AAT AAA AGT TAG GAA GCA ACT T SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36 H2D(+15-08) ATT CTT ACC TTA GAA AAT TGT GC SEQ ID NO:37 H2A(+46+62) CTT AGA AAA TTG TGC AT SEQ ID NO:38 H2D(+08-09) CAT TCT TAC CTT AGA AA SEQ ID NO:39.

[0283] em que A é adenina, C é citosina, G é guanina e T é timina ou uracila. In certain modalities, T is thymine.

[0284] In some embodiments of Formula (II), each Nu from 1 to (n+1) and 5' to 3' corresponds to nucleobases in one of the following: Annealing site Base sequence [5' to 3'] SEQ ID NO: H2.SA.(-20+05) TTC ATC TAA AAT GCA AAA TAA AAA A SEQ ID NO:1 H2.SA.(-14+11) TTC TCT TTC ATC TAA AAT GCA AAA T SEQ ID NO:2 H2.SA.(-11+14) ATC TTC TCT TTC ATC TAA AAT GCA A SEQ ID NO:3 H2.EN.(-08+17) AAC ATC TTC TCT TTC ATC TAA AAT G SEQ ID NO:4 H2.EN.(-05+20) TTG AAC ATC TTC TCT TTC ATC TAA A SEQ ID NO:5 H2.EN.(-02+23) CTT TTG AAC ATC TTC TCT TTC ATC T SEQ ID NO:6 H2.EN.(+02+26) TTT CTT TTG AAC ATC TTC TCT TTC A SEQ ID NO:7 H2.EN.(+05+29) TGT TTT CTT TTG AAC ATC TTC TCT T SEQ ID NO:8 H2.EN.(+08+32) GAA TGT TTT CTT TTG AAC ATC TTC T SEQ ID NO:9 H2.EN.(+11+35) TGT GAA TGT TTT CTT TTG AAC ATC T SEQ ID NO:10 H2.EN.(+14+38) TTT TGT GAA TGT TTT CTT TTG AAC A SEQ ID NO:11 Petition 870260074072, 07 / 24 / 2026, p. 127 / 4 120 / 207 H2.SA.(+17+41) CCA TTT TGT GAA TGT TTT CTT TTG A SEQ ID NO:12 H2.SA.(+20+44) TAC CCA TTT TGT GAA TGT TTT CTT T SEQ ID NO:13 H2.SA.(+23+47) ATT TAC CCA TTT TGT GAA TGT TTT C SEQ ID NO:14 H2.SA.(+26+50) TGC ATT TAC CCA TTT TGT GAA TGT T SEQ ID NO:15 H2.SA.(+29+53) TTG TGC ATT TAC CCA TTT TGT GAA T SEQ ID NO:16 H2.SA.(+32+56) AAA TTG TGC ATT TAC CCA TTT TGT G SEQ ID NO:17 H2.SA.(+35+59) AGA AAA TTG TGC ATT TAC CCA TTT T SEQ ID NO:18 H2.SD.(+22-03) TAC CTT AGA AAA TTG TGC ATT TAC C SEQ ID NO:20 H2.SD.(+19-06) TCT TAC CTT AGA AAA TTG TGC ATT T SEQ ID NO:21 H2.SD.(+16-09) CAT TCT TAC CTT AGA AAA TTG TGC A SEQ ID NO:22 H2.SD.(+13-12) AAC CAT TCT TAC CTT AGA AAA TTG T SEQ ID NO:23 H2.SD.(+10-15) ACA AAC CAT TCT TAC CTT AGA AAA T SEQ ID NO:24 H2A(+06+30) ATG TTT TCT TTT GAA CAT CTT CTC T SEQ ID NO:25 H2A(+07+31) AAT GTT TTC TTT TGA ACA TCT TCT C SEQ ID NO:26 H2A(+09+33) TGA ATG TTT TCT TTT GAA CAT CTT C SEQ ID NO:27 H2A(+10+34) GTG AAT GTT TTC TTT TGA ACA TCT T SEQ ID NO:28 H2A(-23+02) ATC TAA AAT GCA AAA TAA AAA AAT A SEQ ID NO:29 H2A(-26-02) TAA AAT GCA AAA TAA AAA AAT AAA A SEQ ID NO:30 H2A(-29-05) AAT GCA AAA TAA AAA AAT AAA AGT T SEQ ID NO:31 H2A(-32-08) GCA AAA TAA AAA AAT AAA AGT TAG G SEQ ID NO:32 H2A(-35-11) AAA TAA AAA AAT AAA AGT TAG GAA G SEQ ID NO:33 H2A(-38-14) TAA AAA AAT AAA AGT TAG GAA GCA A SEQ ID NO:34 H2A(-41-17) AAA AAT AAA AGT TAG GAA GCA ACT T SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36 H2A(+46+62) CTT AGA AAA TTG TGC AT SEQ ID NO:38 H2D(+08-09) CAT TCT TAC CTT AGA AA SEQ ID NO:39.

[0285] em que A é adenina, C é citosina, G é guanina e T é timina ou uracila. Em certas modalidades, T é timina.

[0286] In some embodiment of Formula (II), each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Annealing site Base sequence [5' to 3'] NO: SEQ ID H2.SA.(-20+05) AAA A TTC ATC TAA AAT GCA AAA TAA NO:1 SEQ ID H2.SA.(-14+11) AAA T TTC TCT TTC ATC TAA AAT GCA NO:2 SEQ ID H2.SA.(-11+14) GCA A ATC TTC TCT TTC ATC TAA AAT NO:3 SEQ ID H2.SA.(-08+17) G AAC ATC TTC TCT TTC ATC TAA AAT NO:4 SEQ ID H2.SA.(-05+20) TAA A TTG AAC ATC TTC TCT TTC ATC NO:5 SEQ ID H2.SA.(-02+23) ATC T CTT TTG AAC ATC TTC TCT TTC NO:6 SEQ ID H2.SA.(+02+26) A TTT CTT TTG AAC ATC TTC TCT TTC NO:7 SEQ ID Petition 870260074072, dated 07 / 24 / 2026, pp. 128 / 448 121 / 207 H2.SA.(+05+29) T TGT TTT CTT TTG AAC ATC TTC TCT NO:8 SEQ ID H2.SA.(+08+32) TTC T GAA TGT TTT CTT TTG AAC ATC NO:9 SEQ ID H2.SA.(+11+35) ATC T TGT GAA TGT TTT CTT TTG AAC NO:10 SEQ ID H2.SA.(+14+38) A TTT TGT GAA TGT TTT CTT TTG AAC NO:11 SEQ ID H2.SA.(+17+41) TTG A CCA TTT TGT GAA TGT TTT CTT NO:12 SEQ ID H2.SA.(+20+44) CTT T TAC CCA TTT TGT GAA TGT TTT NO:13 SEQ ID H2.SD.(+22-03) TAC C TAC CTT AGA AAA TTG TGC ATT NO:20 SEQ ID H2.SD.(+19-06) ATT T TCT TAC CTT AGA AAA TTG TGC NO:21 SEQ ID H2A(+06+30) T ATG TTT TCT TTT GAA CAT CTT CTC NO:25 SEQ ID H2A(+07+31) C AAT GTT TTC TTT TGA ACA TCT TCT NO:26 SEQ ID H2A(+09+33) C TGA ATG TTT TCT TTT GAA CAT CTT NO:27 SEQ ID H2A(+10+34) TCT T GTG AAT GTT TTC TTT TGA ACA NO:28 SEQ ID H2A(-38-14) GCA A TAA AAA AAT AAA AGT TAG GAA NO:34 SEQ ID H2A(-41-17) ACT T AAA AAT AAA AGT TAG GAA GCA NO:35 SEQ ID H2A(+11+29) TGT TTT CTT TTG AAC ATC T NO:36 SEQ ID

[0287] em que A é adenina, C é citosina, G é guanina e T é timina ou uracila. In certain modalities, T is thymine.

[0288] In some embodiments, each Nu from 1 to (n+1) and 5' to 3' of Formula (II) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, or SEQ ID NO:35. In some forms, each Nu from 1 to (n+1) and 5' to 3' of Formula (II) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27 or SEQ ID NO:28. In Petition 870260074072, dated 07 / 24 / 2026, pp. 129 / 448 122 / 207 some modalities, each Nu from 1 to (n+1) and 5' to 3' of Formula (II) corresponds to one of the following: SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:25 or SEQ ID NO:28.

[0289] In some embodiments, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (II) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, or SEQ ID NO:35. In some modalities, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (II) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27 or SEQ ID NO:28. In some modalities, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (II) corresponds to one of the following: SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:25 or SEQ ID NO:28. In some forms, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (II) corresponds to SEQ ID NO:19.In some forms, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (II) corresponds to SEQ ID NO:37.

[0290] In some embodiments, an antisense oligomer of Formula (II) is in the free base form. In some embodiments, an antisense oligomer of Formula (II) is a pharmaceutically acceptable salt form thereof. In some embodiments, an antisense oligomer of Formula (II) is an HCl (hydrochloric acid) salt thereof. In certain embodiments, the HCl salt is a 1HCl, 2HCl, 3HCl, 4HCl, 5HCl, or 6HCl salt. In certain embodiments, the HCl salt is a 6HCl salt. Petition 870260074072, dated 07 / 24 / 2026, pp. 130 / 448 123 / 207

[0291] In some embodiments, including, for example, some embodiments of Formula (I), an antisense oligomer of disclosure conforms to Formula (III): (III)

[0292] or a pharmaceutically acceptable salt thereof,

[0293] R200 is hydrogen or a cell-penetrating peptide and each Nu from a (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Sítio de anelamento Sequência base [5' a 3'] SEQ ID NO: H2.SA.(-20+05) TTC ATC TAA AAT GCA AAA TAA AAA A SEQ ID NO:1 H2.SA.(-14+11) TTC TCT TTC ATC TAA AAT GCA AAA T SEQ ID NO:2 H2.SA.(-11+14) ATC TTC TCT TTC ATC TAA AAT GCA A SEQ ID NO:3 H2.SA.(-08+17) AAC ATC TTC TCT TTC ATC TAA AAT G SEQ ID NO:4 H2.SA.(-05+20) TTG AAC ATC TTC TCT TTC ATC TAA A SEQ ID NO:5 H2.SA.(-02+23) CTT TTG AAC ATC TTC TCT TTC ATC T SEQ ID NO:6 H2.SA.(+02+26) TTT CTT TTG AAC ATC TTC TCT TTC A SEQ ID NO:7 H2.SA.(+05+29) TGT TTT CTT TTG AAC ATC TTC TCT T SEQ ID NO:8 H2.SA.(+08+32) GAA TGT TTT CTT TTG AAC ATC TTC T SEQ ID NO:9 H2.SA.(+11+35) TGT GAA TGT TTT CTT TTG AAC ATC T SEQ ID NO:10 H2.SA.(+14+38) TTT TGT GAA TGT TTT CTT TTG AAC A SEQ ID NO:11 H2.SA.(+17+41) CCA TTT TGT GAA TGT TTT CTT TTG A SEQ ID NO:12 H2.SA.(+20+44) TAC CCA TTT TGT GAA TGT TTT CTT T SEQ ID NO:13 H2.SA.(+23+47) ATT TAC CCA TTT TGT GAA TGT TTT C SEQ ID NO:14 H2.SA.(+26+50) TGC ATT TAC CCA TTT TGT GAA TGT T SEQ ID NO:15 H2.SA.(+29+53) TTG TGC ATT TAC CCA TTT TGT GAA T SEQ ID NO:16 H2.SA.(+32+56) AAA TTG TGC ATT TAC CCA TTT TGT G SEQ ID NO:17 H2.SA.(+35+59) AGA AAA TTG TGC ATT TAC CCA TTT T SEQ ID NO:18 H2.SA.(+38+62) CTT AGA AAA TTG TGC ATT TAC CCA T SEQ ID NO:19 H2.SD.(+22-03) TAC CTT AGA AAA TTG TGC ATT TAC C SEQ ID NO:20 H2.SD.(+19-06) TCT TAC CTT AGA AAA TTG TGC ATT T SEQ ID NO:21. Petition 870260074072, de 24 / 07 / 2026, pág. 131 / 448 124 / 207 H2.SD.(+16-09) CAT TCT TAC CTT AGA AAA TTG TGC A SEQ ID NO:22 H2.SD.(+13-12) AAC CAT TCT TAC CTT AGA AAA TTG T SEQ ID NO:23 H2.SD.(+10-15) ACA AAC CAT TCT TAC CTT AGA AAA T SEQ ID NO:24 H2A(+06+30) ATG TTT TCT TTT GAA CAT CTT CTC T SEQ ID NO:25 H2A(+07+31) AAT GTT TTC TTT TGA ACA TCT TCT C SEQ ID NO:26 H2A(+09+33) TGA ATG TTT TCT TTT GAA CAT CTT C SEQ ID NO:27 H2A(+10+34) GTG AAT GTT TTC TTT TGA ACA TCT T SEQ ID NO:28 H2A(-23+02) ATC TAA AAT GCA AAA TAA AAA AAT A SEQ ID NO:29 H2A(-26-02) TAA AAT GCA AAA TAA AAA AAT AAA A SEQ ID NO:30 H2A(-29-05) AAT GCA AAA TAA AAA AAT AAA AGT T SEQ ID NO:31 H2A(-32-08) GCA AAA TAA AAA AAT AAA AGT TAG G SEQ ID NO:32 H2A(-35-11) AAA TAA AAA AAT AAA AGT TAG GAA G SEQ ID NO:33 H2A(-38-14) TAA AAA AAT AAA AGT TAG GAA GCA A SEQ ID NO:34 H2A(-41-17) AAA AAT AAA AGT TAG GAA GCA ACT T SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36 H2D(+15-08) ATT CTT ACC TTA GAA AAT TGT GC SEQ ID NO:37 H2A(+46+62) CTT AGA AAA TTG TGC AT SEQ ID NO:38 H2D(+08-09) CAT TCT TAC CTT AGA AA SEQ ID NO:39.

[0294] em que A é adenina, C é citosina, G é guanina e T é timina ou uracila. In certain modalities, T is thymine.

[0295] In some Formula (III) modalities, each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Sítio de anelamento Sequência base [5' a 3'] SEQ ID NO: H2.SA.(-20+05) TTC ATC TAA AAT GCA AAA TAA AAA A SEQ ID NO:1 H2.SA.(-14+11) TTC TCT TTC ATC TAA AAT GCA AAA T SEQ ID NO:2 H2.SA.(-11+14) ATC TTC TCT TTC ATC TAA AAT GCA A SEQ ID NO:3 H2.SA.(-08+17) AAC ATC TTC TCT TTC ATC TAA AAT G SEQ ID NO:4 H2.SA.(-05+20) TTG AAC ATC TTC TCT TTC ATC TAA A SEQ ID NO:5 H2.SA.(-02+23) CTT TTG AAC ATC TTC TCT TTC ATC T SEQ ID NO:6 H2.SA.(+02+26) TTT CTT TTG AAC ATC TTC TCT TTC A SEQ ID NO:7 H2.SA.(+05+29) TGT TTT CTT TTG AAC ATC TTC TCT T SEQ ID NO:8 H2.SA.(+08+32) GAA TGT TTT CTT TTG AAC ATC TTC T SEQ ID NO:9 H2.SA.(+11+35) TGT GAA TGT TTT CTT TTG AAC ATC T SEQ ID NO:10 H2.SA.(+14+38) TTT TGT GAA TGT TTT CTT TTG AAC A SEQ ID NO:11 H2.SA.(+17+41) CCA TTT TGT GAA TGT TTT CTT TTG A SEQ ID NO:12 H2.SA.(+20+44) TAC CCA TTT TGT GAA TGT TTT CTT T SEQ ID NO:13 H2.SA.(+23+47) ATT TAC CCA TTT TGT GAA TGT TTT C SEQ ID NO:14 H2.SA.(+26+50) TGC ATT TAC CCA TTT TGT GAA TGT T SEQ ID NO:15 H2.SA.(+29+53) TTG TGC ATT TAC CCA TTT TGT GAA T SEQ ID NO:16 H2.SA.(+32+56) AAA TTG TGC ATT TAC CCA TTT TGT G SEQ ID NO:17 H2.SA.(+35+59) AGA AAA TTG TGC ATT TAC CCA TTT T SEQ ID NO:18 H2.SD.(+22-03) TAC CTT AGA AAA TTG TGC ATT TAC C SEQ ID NO:20 H2.SD.(+19-06) TCT TAC CTT AGA AAA TTG TGC ATT T SEQ ID NO:21. Petition 870260074072, de 24 / 07 / 2026, pág. 132 / 448 125 / 207 H2.SD.(+16-09) CAT TCT TAC CTT AGA AAA TTG TGC A SEQ ID NO:22 H2.SD.(+13-12) AAC CAT TCT TAC CTT AGA AAA TTG T SEQ ID NO:23 H2.SD.(+10-15) ACA AAC CAT TCT TAC CTT AGA AAA T SEQ ID NO:24 H2A(+06+30) ATG TTT TCT TTT GAA CAT CTT CTC T SEQ ID NO:25 H2A(+07+31) AAT GTT TTC TTT TGA ACA TCT TCT C SEQ ID NO:26 H2A(+09+33) TGA ATG TTT TCT TTT GAA CAT CTT C SEQ ID NO:27 H2A(+10+34) GTG AAT GTT TTC TTT TGA ACA TCT T SEQ ID NO:28 H2A(-23+02) ATC TAA AAT GCA AAA TAA AAA AAT A SEQ ID NO:29 H2A(-26-02) TAA AAT GCA AAA TAA AAA AAT AAA A SEQ ID NO:30 H2A(-29-05) AAT GCA AAA TAA AAA AAT AAA AGT T SEQ ID NO:31 H2A(-32-08) GCA AAA TAA AAA AAT AAA AGT TAG G SEQ ID NO:32 H2A(-35-11) AAA TAA AAA AAT AAA AGT TAG GAA G SEQ ID NO:33 H2A(-38-14) TAA AAA AAT AAA AGT TAG GAA GCA A SEQ ID NO:34 H2A(-41-17) AAA AAT AAA AGT TAG GAA GCA ACT T SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36 H2A(+46+62) CTT AGA AAA TTG TGC AT SEQ ID NO:38 H2D(+08-09) CAT TCT TAC CTT AGA AA SEQ ID NO:39

[0296] where A is adenine, C is cytosine, G is guanine and T is thymine or uracil. In certain modalities, T is thymine.

[0297] In some Formula (III) modalities, each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Sítio de anelamento Sequência base [5' a 3'] ID NO: SEQ H2.SA.(-20+05) A TTC ATC TAA AAT GCA AAA TAA AAA ID NO:1 SEQ H2.SA.(-14+11) T TTC TCT TTC ATC TAA AAT GCA AAA ID NO:2 SEQ H2.SA.(-11+14) A ATC TTC TCT TTC ATC TAA AAT GCA ID NO:3 SEQ H2.SA.(-08+17) G AAC ATC TTC TCT TTC ATC TAA AAT ID NO:4 SEQ H2.SA.(-05+20) A TTG AAC ATC TTC TCT TTC ATC TAA ID NO:5 SEQ H2.SA.(-02+23) T CTT TTG AAC ATC TTC TCT TTC ATC ID NO:6 SEQ H2.SA.(+02+26) A TTT CTT TTG AAC ATC TTC TCT TTC ID NO:7 SEQ H2.SA.(+05+29) T TGT TTT CTT TTG AAC ATC TTC TCT ID NO:8 SEQ H2.SA.(+08+32) T GAA TGT TTT CTT TTG AAC ATC TTC ID NO:9 SEQ H2.SA.(+11+35) T TGT GAA TGT TTT CTT TTG AAC ATC ID NO:10 SEQ H2.SA.(+14+38) A TTT TGT GAA TGT TTT CTT TTG AAC ID NO:11 SEQ H2.SA.(+17+41) A CCA TTT TGT GAA TGT TTT CTT TTG ID NO:12 SEQ H2.SA.(+20+44) T TAC CCA TTT TGT GAA TGT TTT CTT ID NO:13 SEQ Petição 870260074072, de 24 / 07 / 2026, pág. 133 / 448 126 / 207 H2.SD.(+22-03) C TAC CTT AGA AAA TTG TGC ATT TAC SEQ ID NO:20 H2.SD.(+19-06) T TCT TAC CTT AGA AAA TTG TGC ATT SEQ ID NO:21 H2A(+06+30) T ATG TTT TCT TTT CTT CTT CTC SEQ ID NO:25 H2A(+07+31) C AAT GTT TTC TTT TGA ACA TCT TCT SEQ ID NO:26 H2A(+09+33) C TGA ATG TTT TCT TTT GAA CAT CTT SEQ ID NO:27 H2A(+10+34) T GTG AAT GTT TTC TTT SE TGA TCT TQA ID NO: 28-28 H2A(+09+33) GCA A TAA AAA AAT AAA AGT TAG GAA SEQ ID NO:34 H2A(-41-17) ACT T AAA AAT AAA AGT TAG GAA GCA SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36

[0298] wherein A is adenine, C is cytosine, G is guanine and T is thymine or uracil. In some modalities, T is thymine.

[0299] In some embodiments, each Nu from 1 to (n+1) and 5' to 3' of Formula (III) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, or SEQ ID NO:35. In some forms, each Nu from 1 to (n+1) and 5' to 3' of Formula (III) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27 or SEQ ID NO:28. In some forms, each Nu from 1 to (n+1) and 5' to 3' of Formula (III) corresponds to one of the following: SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:25 or SEQ ID NO:28.

[0300] In some embodiments, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (III) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, or SEQ ID NO:35. In some forms, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (III) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, Petition 870260074072, dated 07 / 24 / 2026, pp. 134 / 448 127 / 207 SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, or SEQ ID NO:28. In some embodiments, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (III) corresponds to one of the following: SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:25, or SEQ ID NO:28. In some embodiments, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (III) corresponds to SEQ ID NO:19. In some embodiments, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (III) corresponds to SEQ ID NO:37.

[0301] In some embodiments, an antisense oligomer of Formula (III) is in the free base form. In some embodiments, an antisense oligomer of Formula (III) is a pharmaceutically acceptable salt thereof. In some embodiments, an antisense oligomer of Formula (III) is an HCl (hydrochloric acid) salt thereof. In certain embodiments, the HCl salt is a 6HCl salt.

[0302] In some embodiments, including, for example, some embodiments of Formula (I), an antisense oligomer of disclosure conforms to Formula (IV): (IV)

[0303] where each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Annealing site Base sequence [5' to 3'] SEQ ID NO: H2.SA.(-20+05) TTC ATC TAA AAT GCA AAA TAA AAA A SEQ ID NO:1 H2.SA.(-14+11) TTC TCT TTC ATC TAA AAT GCA AAA T SEQ ID NO:2 H2.SA.(-11+14) ATC TTC TCT TTC ATC TAA AAT GCA A SEQ ID NO:3 H2.SA.(-08+17) AAC ATC TTC TCT TTC ATC TAA AAT G SEQ ID NO:4 H2.SA.(-05+20) TTG AAC ATC TTC TCT TTC ATC TAA A SEQ ID NO:5 Petition 870260074072, dated 07 / 24 / 2026, pp. 135 / 448 128 / 207 H2.SA.(-02+23) CTT TTG AAC ATC TTC TCT TTC ATC T SEQ ID NO:6 H2.SA.(+02+26) TTT CTT TTG AAC ATC TTC TCT TTC A SEQ ID NO:7 H2.SA.(+05+29) TGT TTT CTT TTG AAC ATC TTC TCT T SEQ ID NO:8 H2.SA.(+08+32) GAA TGT TTT CTT TTG AAC ATC TTC T SEQ ID NO:9 H2.SA.(+11+35) TGT GAA TGT TTT CTT TTG AAC ATC T SEQ ID NO:10 H2.SA.(+14+38) TTT TGT GAA TGT TTT CTT TTG AAC A SEQ ID NO:11 H2.SA.(+17+41) CCA TTT TGT GAA TGT TTT CTT TTG A SEQ ID NO:12 H2.SA.(+20+44) TAC CCA TTT TGT GAA TGT TTT CTT T SEQ ID NO:13 H2.SA.(+23+47) ATT TAC CCA TTT TGT GAA TGT TTT C SEQ ID NO:14 H2.SA.(+26+50) TGC ATT TAC CCA TTT TGT GAA TGT T SEQ ID NO:15 H2.SA.(+29+53) TTG TGC ATT TAC CCA TTT TGT GAA T SEQ ID NO:16 H2.SA.(+32+56) AAA TTG TGC ATT TAC CCA TTT TGT G SEQ ID NO:17 H2.SA.(+35+59) AGA AAA TTG TGC ATT TAC CCA TTT T SEQ ID NO:18 H2.SA.(+38+62) CTT AGA AAA TTG TGC ATT TAC CCA TTT T SEQ ID NO:19 H2.SD.(+22-03) TAC CTT AGA AAA TTG TGC ATT TAC C SEQ ID NO:20 H2.SD.(+19-06) TCT TAC CTT AGA AAA TTG TGC ATT T SEQ ID NO:21 H2.SD.(+16-09) CAT TCT TAC CTT AGA AAA TTG TGC A SEQ ID NO:22 H2.SD.(+13-12) AAC CAT TCT TAC CTT AGA AAA TTG T SEQ ID NO:23 H2.SD.(+10-15) ACA AAC CAT TCT TAC CTT AGA AAA T SEQ ID NO:24 H2A(+06+30) ATG TTT TCT TTT GAA CAT CTT CTC T SEQ ID NO:25 H2A(+07+31) AAT GTT TTC TTT TGA ACA TCT TCT C SEQ ID NO:26 H2A(+09+33) TGA ATG TTT TCT TTT GAA CAT CTT C SEQ ID NO:27 H2A(+10+34) GTG AAT GTT TTC TTT TGA ACA TCT T SEQ ID NO:28 H2A(-23+02) ATC TAA AAT GCA AAA TAA AAA AAT A SEQ ID NO:29 H2A(-26-02) TAA AAT GCA AAA TAA AAA AAT AAA A SEQ ID NO:30 H2A(-29-05) AAT GCA AAA TAA AAA AAT AAA AGT T SEQ ID NO:31 H2A(-32-08) GCA AAA TAA AAA AAT AAA AGT TAG G SEQ ID NO:32 H2A(-35-11) AAA TAA AAA AAT AAA AGT TAG GAA G SEQ ID NO:33 H2A(-38-14) TAA AAA AAT AAA AGT TAG GAA GCA A SEQ ID NO:34 H2A(-41-17) AAA AAT AAA AGT TAG GAA GCA ACT T SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36 H2D(+15-08) ATT CTT ACC TTA GAA AAT TGT GC SEQ ID NO:37 H2A(+46+62) CTT AGA AAA TTG TGC AT SEQ ID NO:38 H2D(+08-09) CAT TCT TAC CTT AGA AA SEQ ID NO:39.

[0304] em que A é adenina, C é citosina, G é guanina e T é timina ou uracila. In certain modalities, T is thymine.

[0305] In some Formula (IV) modalities, each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Annealing site Base sequence [5' to 3'] SEQ ID NO: H2.SA.(-20+05) TTC ATC TAA AAT GCA AAA TAA AAA A SEQ ID NO:1 H2.SA.(-14+11) TTC TCT TTC ATC TAA AAT GCA AAA T SEQ ID NO:2 H2.SA.(-11+14) ATC TTC TCT TTC ATC TAA AAT GCA A SEQ ID NO:3 H2.SA.(-08+17) AAC ATC TTC TCT TTC ATC TAA AAT G SEQ ID NO:4 Petition 870260074072, dated 07 / 24 / 2026, pp. 136 / 448 129 / 207 H2.SA.(-05+20) TTG AAC ATC TTC TCT TTC ATC TAA A SEQ ID NO:5 H2.SA.(-02+23) CTT TTG AAC ATC TTC TCT TTC ATC T SEQ ID NO:6 H2.SA.(+02+26) TTT CTT TTG AAC ATC TTC TCT TTC A SEQ ID NO:7 H2.SA.(+05+29) TGT TTT CTT TTG AAC ATC TTC TCT T SEQ ID NO:8 H2.SA.(+08+32) GAA TGT TTT CTT TTG AAC ATC TTC T SEQ ID NO:9 H2.SA.(+11+35) TGT GAA TGT TTT CTT TTG AAC ATC T SEQ ID NO:10 H2.SA.(+14+38) TTT TGT GAA TGT TTT CTT TTG AAC A SEQ ID NO:11 H2.SA.(+17+41) CCA TTT TGT GAA TGT TTT CTT TTG A SEQ ID NO:12 H2.SA.(+20+44) TAC CCA TTT TGT GAA TGT TTT CTT T SEQ ID NO:13 H2.SA.(+23+47) ATT TAC CCA TTT TGT GAA TGT TTT C SEQ ID NO:14 H2.SA.(+26+50) TGC ATT TAC CCA TTT TGT GAA TGT T SEQ ID NO:15 H2.SA.(+29+53) TTG TGC ATT TAC CCA TTT TGT GAA T SEQ ID NO:16 H2.SA.(+32+56) AAA TTG TGC ATT TAC CCA TTT TGT G SEQ ID NO:17 H2.SA.(+35+59) AGA AAA TTG TGC ATT TAC CCA TTT T SEQ ID NO:18 H2.SD.(+22-03) TAC CTT AGA AAA TTG TGC ATT TAC C SEQ ID NO:20 H2.SD.(+19-06) TCT TAC CTT AGA AAA TTG TGC ATT T SEQ ID NO:21 H2.SD.(+16-09) CAT TCT TAC CTT AGA AAA TTG TGC A SEQ ID NO:22 H2.SD.(+13-12) AAC CAT TCT TAC CTT AGA AAA TTG T SEQ ID NO:23 H2.SD.(+10-15) ACA AAC CAT TCT TAC CTT AGA AAA T SEQ ID NO:24 H2A(+06+30) ATG TTT TCT TTT GAA CAT CTT CTC T SEQ ID NO:25 H2A(+07+31) AAT GTT TTC TTT TGA ACA TCT TCT C SEQ ID NO:26 H2A(+09+33) TGA ATG TTT TCT TTT GAA CAT CTT C SEQ ID NO:27 H2A(+10+34) GTG AAT GTT TTC TTT TGA ACA TCT T SEQ ID NO:28 H2A(-23+02) ATC TAA AAT GCA AAA TAA AAA AAT A SEQ ID NO:29 H2A(-26-02) TAA AAT GCA AAA TAA AAA AAT AAA A SEQ ID NO:30 H2A(-29-05) AAT GCA AAA TAA AAA AAT AAA AGT T SEQ ID NO:31 H2A(-32-08) GCA AAA TAA AAA AAT AAA AGT TAG G SEQ ID NO:32 H2A(-35-11) AAA TAA AAA AAT AAA AGT TAG GAA G SEQ ID NO:33 H2A(-38-14) TAA AAA AAT AAA AGT TAG GAA GCA A SEQ ID NO:34 H2A(-41-17) AAA AAT AAA AGT TAG GAA GCA ACT T SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36 H2A(+46+62) CTT AGA AAA TTG TGC AT SEQ ID NO:38.

[0306] where A is adenine, C is cytosine, G is guanine and T is thymine or uracil. In certain modalities, T is thymine.

[0307] In some Formula (IV) modalities, each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Annealing site Base sequence [5' to 3'] SEQ ID NO: H2.SA.(-20+05) TTC ATC TAA AAT GCA AAA TAA AAA A SEQ ID NO:1 H2.SA.(-14+11) TTC TCT TTC ATC TAA AAT GCA AAA T SEQ ID NO:2 H2.SA.(-11+14) ATC TTC TCT TTC ATC TAA AAT GCA A SEQ ID NO:3 H2.SA.(-08+17) AAC ATC TTC TCT TTC ATC TAA AAT G SEQ ID NO:4 H2.SA.(-05+20) TTG AAC ATC TTC TCT TTC ATC TAA A SEQ ID NO:5 H2.SA.(-02+23) CTT TTG AAC ATC TTC TCT TTC ATC T SEQ ID NO:6 Petition 870260074072, dated 07 / 24 / 2026, pp. 137 / 448 130 / 207 H2.SA.(+02+26) TTT CTT TTG AAC ATC TTC TCT TTC A SEQ ID NO:7 H2.SA.(+05+29) TGT TTT CTT TTG AAC ATC TTC TCT T SEQ ID NO:8 H2.SA.(+08+32) GAA TGT TTT CTT TTG AAC ATC TTC T SEQ ID NO:9 H2.SA.(+11+35) TGT GAA TGT TTT CTT TTG AAC ATC T SEQ ID NO:10 H2.SA.(+14+38) TTT TGT GAA TGT TTT CTT TTG AAC A SEQ ID NO:11 H2.SA.(+17+41) CCA TTT TGT GAA TGT TTT CTT TTG A SEQ ID NO:12 H2.SA.(+20+44) TAC CCA TTT TGT GAA TGT TTT CTT T SEQ ID NO:13 H2.SD.(+22-03) TAC CTT AGA AAA TTG TGC ATT TAC C SEQ ID NO:20 H2.SD.(+19-06) TCT TAC CTT AGA AAA TTG TGC ATT T SEQ ID NO:21 H2A(+06+30) ATG TTT TCT TTT GAA CAT CTT CTC T SEQ ID NO:25 H2A(+07+31) AAT GTT TTC TTT TGA ACA TCT TCT C SEQ ID NO:26 H2A(+09+33) TGA ATG TTT TCT TTT GAA CAT CTT C SEQ ID NO:27 H2A(+10+34) GTG AAT GTT TTC TTT TGA ACA TCT T SEQ ID NO:28 H2A(-38-14) TAA AAA AAT AAA AGT TAG GAA GCA A SEQ ID NO:34 H2A(-41-17) AAA AAT AAA AGT TAG GAA GCA ACT T SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36

[0308] where A is adenine, C is cytosine, G is guanine and T is thymine or uracil. In certain modalities, T is thymine.

[0309] In some embodiments, each Nu from 1 to (n+1) and 5' to 3' of Formula (IV) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, or SEQ ID NO:35. In some modalities, each Nu from 1 to (n+1) and 5' to 3' of Formula (IV) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27 or SEQ ID NO:28. In some modalities, each Nu from 1 to (n+1) and 5' to 3' of Formula (IV) corresponds to one of the following: SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:25 or SEQ ID NO:28.

[0310] In some embodiments, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (IV) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, or SEQ ID NO:35. In some forms, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (IV) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27 or Petition 870260074072, dated 07 / 24 / 2026, pp. 138 / 448 131 / 207 SEQ ID NO:28. In some embodiments, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (IV) corresponds to one of the following: SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:25 or SEQ ID NO:28. In some embodiments, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (IV) corresponds to SEQ ID NO:19. In some embodiments, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (IV) corresponds to SEQ ID NO:37.

[0311] In some embodiments, including, for example, some embodiments of Formula (I), an antisense oligomer of disclosure is in accordance with Formula (V): (V)

[0312] or a pharmaceutically acceptable salt thereof,

[0313] R200 is hydrogen or a cell-penetrating peptide, each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Sítio de anelamento Sequência base [5' a 3'] SEQ ID NO: H2.SA.(-20+05) TTC ATC TAA AAT GCA AAA TAA AAA A SEQ ID NO:1 H2.SA.(-14+11) TTC TCT TTC ATC TAA AAT GCA AAA T SEQ ID NO:2 H2.SA.(-11+14) ATC TTC TCT TTC ATC TAA AAT GCA A SEQ ID NO:3 H2.SA.(-08+17) AAC ATC TTC TCT TTC ATC TAA AAT G SEQ ID NO:4 H2.SA.(-05+20) TTG AAC ATC TTC TCT TTC ATC TAA A SEQ ID NO:5 H2.SA.(-02+23) CTT TTG AAC ATC TTC TCT TTC ATC T SEQ ID NO:6 H2.SA.(+02+26) TTT CTT TTG AAC ATC TTC TCT TTC A SEQ ID NO:7 H2.SA.(+05+29) TGT TTT CTT TTG AAC ATC TTC TCT T SEQ ID NO:8 H2.SA.(+08+32) GAA TGT TTT CTT TTG AAC ATC TTC T SEQ ID NO:9 H2.SA.(+11+35) TGT GAA TGT TTT CTT TTG AAC ATC T SEQ ID NO:10 H2.SA.(+14+38) TTT TGT GAA TGT TTT CTT TTG AAC A SEQ ID NO:11 H2.SA.(+17+41) CCA TTT TGT GAA TGT TTT CTT TTG A SEQ ID NO:12 H2.SA.(+20+44) TAC CCA TTT TGT GAA TGT TTT CTT T SEQ ID NO:13 H2.SA.(+23+47) ATT TAC CCA TTT TGT GAA TGT TTT C SEQ ID NO:14 Petição 870260074072, de 24 / 07 / 2026, pág. 139 / 448 132 / 207H2.SA.(+26+50) TGC ATT TAC CCA TTT TGT GAA TGT T SEQ ID NO:15 H2.SA.(+29+53) TTG TGC ATT TAC CCA TTT TGT GAA T SEQ ID NO:16 H2.SA.(+32+56) AAA TTG TGC ATT TAC CCA TTT TGT G SEQ ID NO:17 H2.SA.(+35+59) AGA AAA TTG TGC ATT TAC CCA TTT T SEQ ID NO:18 H2.SA.(+38+62) CTT AGA AAA TTG TGC ATT TAC CCA T SEQ ID NO:19 H2.SD.(+22-03) TAC CTT AGA AAA TTG TGC ATT TAC C SEQ ID NO:20 H2.SD.(+19-06) TCT TAC CTT AGA AAA TTG TGC ATT T SEQ ID NO:21 H2.SD.(+16-09) CAT TCT TAC CTT AGA AAA TTG TGC A SEQ ID NO:22 H2.SD.(+13-12) AAC CAT TCT TAC CTT AGA AAA TTG T SEQ ID NO:23 H2.SD.(+10-15) ACA AAC CAT TCT TAC CTT AGA AAA T SEQ ID NO:24 H2A(+06+30) ATG TTT TCT TTT GAA CAT CTT CTC T SEQ ID NO:25 H2A(+07+31) AAT GTT TTC TTT TGA ACA TCT TCT C SEQ ID NO:26 H2A(+09+33) TGA ATG TTT TCT TTT GAA CAT CTT C SEQ ID NO:27 H2A(+10+34) GTG AAT GTT TTC TTT TGA ACA TCT T SEQ ID NO:28 H2A(-23+02) ATC TAA AAT GCA AAA TAA AAA AAT A SEQ ID NO:29 H2A(-26-02) TAA AAT GCA AAA TAA AAA AAT AAA A SEQ ID NO:30 H2A(-29-05) AAT GCA AAA TAA AAA AAT AAA AGT T SEQ ID NO:31 H2A(-32-08) GCA AAA TAA AAA AAT AAA AGT TAG G SEQ ID NO:32 H2A(-35-11) AAA TAA AAA AAT AAA AGT TAG GAA G SEQ ID NO:33 H2A(-38-14) TAA AAA AAT AAA AGT TAG GAA GCA A SEQ ID NO:34 H2A(-41-17) AAA AAT AAA AGT TAG GAA GCA ACT T SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36 H2D(+15-08) ATT CTT ACC TTA GAA AAT TGT GC SEQ ID NO:37 H2A(+46+62) CTT AGA AAA TTG TGC AT SEQ ID NO:38 H2D(+08-09) CAT TCT TAC CTT AGA AA SEQ ID NO:39.

[0314] em que A é adenina, C é citosina, G é guanina e T é timina ou uracila. In certain modalities, T is thymine.

[0315] In some Formula (V) modalities, each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Sítio de anelamento Sequência base [5' a 3'] SEQ ID NO: H2.SA.(-20+05) TTC ATC TAA AAT GCA AAA TAA AAA A SEQ ID NO:1 H2.SA.(-14+11) TTC TCT TTC ATC TAA AAT GCA AAA T SEQ ID NO:2 H2.SA.(-11+14) ATC TTC TCT TTC ATC TAA AAT GCA A SEQ ID NO:3 H2.SA.(-08+17) AAC ATC TTC TCT TTC ATC TAA AAT G SEQ ID NO:4 H2.SA.(-05+20) TTG AAC ATC TTC TCT TTC ATC TAA A SEQ ID NO:5 H2.SA.(-02+23) CTT TTG AAC ATC TTC TCT TTC ATC T SEQ ID NO:6 H2.SA.(+02+26) TTT CTT TTG AAC ATC TTC TCT TTC A SEQ ID NO:7 H2.SA.(+05+29) TGT TTT CTT TTG AAC ATC TTC TCT T SEQ ID NO:8 H2.SA.(+08+32) GAA TGT TTT CTT TTG AAC ATC TTC T SEQ ID NO:9 H2.SA.(+11+35) TGT GAA TGT TTT CTT TTG AAC ATC T SEQ ID NO:10 H2.SA.(+14+38) TTT TGT GAA TGT TTT CTT TTG AAC A SEQ ID NO:11 H2.SA.(+17+41) CCA TTT TGT GAA TGT TTT CTT TTG A SEQ ID NO:12 H2.SA.(+20+44) TAC CCA TTT TGT GAA TGT TTT CTT T SEQ ID NO:13 Petição 870260074072, de 24 / 07 / 2026, pág. 140 / 448 133 / 207 H2.SA.(+23+47) ATT TAC CCA TTT TGT GAA TGT TTT C SEQ ID NO:14 H2.SA.(+26+50) TGC ATT TAC CCA TTT TGT GAA TGT T SEQ ID NO:15 H2.SA.(+29+53) TTG TGC ATT TAC CCA TTT TGT GAA T SEQ ID NO:16 H2.SA.(+32+56) AAA TTG TGC ATT TAC CCA TTT TGT G SEQ ID NO:17 H2.SA.(+35+59) AGA AAA TTG TGC ATT TAC CCA TTT T SEQ ID NO:18 H2.SD.(+22-03) TAC CTT AGA AAA TTG TGC ATT TAC C SEQ ID NO:20 H2.SD.(+19-06) TCT TAC CTT AGA AAA TTG TGC ATT T SEQ ID NO:21 H2.SD.(+16-09) CAT TCT TAC CTT AGA AAA TTG TGC A SEQ ID NO:22 H2.SD.(+13-12) AAC CAT TCT TAC CTT AGA AAA TTG T SEQ ID NO:23 H2.SD.(+10-15) ACA AAC CAT TCT TAC CTT AGA AAA T SEQ ID NO:24 H2A(+06+30) ATG TTT TCT TTT GAA CAT CTT CTC T SEQ ID NO:25 H2A(+07+31) AAT GTT TTC TTT TGA ACA TCT TCT C SEQ ID NO:26 H2A(+09+33) TGA ATG TTT TCT TTT GAA CAT CTT C SEQ ID NO:27 H2A(+10+34) GTG AAT GTT TTC TTT TGA ACA TCT T SEQ ID NO:28 H2A(-23+02) ATC TAA AAT GCA AAA TAA AAA AAT A SEQ ID NO:29 H2A(-26-02) TAA AAT GCA AAA TAA AAA AAT AAA A SEQ ID NO:30 H2A(-29-05) AAT GCA AAA TAA AAA AAT AAA AGT T SEQ ID NO:31 H2A(-32-08) GCA AAA TAA AAA AAT AAA AGT TAG G SEQ ID NO:32 H2A(-35-11) AAA TAA AAA AAT AAA AGT TAG GAA G SEQ ID NO:33 H2A(-38-14) TAA AAA AAT AAA AGT TAG GAA GCA A SEQ ID NO:34 H2A(-41-17) AAA AAT AAA AGT TAG GAA GCA ACT T SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36 H2A(+46+62) CTT AGA AAA TTG TGC AT SEQ ID NO:38 H2D(+08-09) CAT TCT TAC CTT AGA AA SEQ ID NO:39.

[0316] em que A é adenina, C é citosina, G é guanina e T é timina ou uracila. Em certas modalidades, T é timina.

[0317] In some Formula (V) modalities, each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Sítio de anelamento Sequência base [5' a 3'] SEQ ID NO: H2.SA.(-20+05) TTC ATC TAA AAT GCA AAA TAA AAA A SEQ ID NO:1 H2.SA.(-14+11) TTC TCT TTC ATC TAA AAT GCA AAA T SEQ ID NO:2 H2.SA.(-11+14) ATC TTC TCT TTC ATC TAA AAT GCA A SEQ ID NO:3 H2.SA.(-08+17) AAC ATC TTC TCT TTC ATC TAA AAT G SEQ ID NO:4 H2.SA.(-05+20) TTG AAC ATC TTC TCT TTC ATC TAA A SEQ ID NO:5 H2.SA.(-02+23) CTT TTG AAC ATC TTC TCT TTC ATC T SEQ ID NO:6 H2.SA.(+02+26) TTT CTT TTG AAC ATC TTC TCT TTC A SEQ ID NO:7 H2.SA.(+05+29) TGT TTT CTT TTG AAC ATC TTC TCT T SEQ ID NO:8 H2.SA.(+08+32) GAA TGT TTT CTT TTG AAC ATC TTC T SEQ ID NO:9 H2.SA.(+11+35) TGT GAA TGT TTT CTT TTG AAC ATC T SEQ ID NO:10 H2.SA.(+14+38) TTT TGT GAA TGT TTT CTT TTG AAC A SEQ ID NO:11 H2.SA.(+17+41) CCA TTT TGT GAA TGT TTT CTT TTG A SEQ ID NO:12 H2.SA.(+20+44) TAC CCA TTT TGT GAA TGT TTT CTT T SEQ ID NO:13 H2.SD.(+22-03) TAC CTT AGA AAA TTG TGC ATT TAC C SEQ ID NO:20 Petição 870260074072, de 24 / 07 / 2026, pág. 141 / 448 134 / 207 H2.SD.(+19-06) TCT TAC CTT AGA AAA TTG TGC ATT T SEQ ID NO:21 H2A(+06+30) ATG TTT TCT TTT GAA CAT CTT CTC T SEQ ID NO:25 H2A(+07+31) AAT GTT TTC TTT TGA ACA TCT TCT SEQ ID NO:26: H2A(+09+33) TGA ATG TTT TCT TTT GAA CAT CTT C SEQ ID NO:27 H2A(+10+34) GTG AAT GTT TTC TTT TGA ACA TCT T SEQ ID NO:28 H2A(-38-14) TAA AAA AAT AAA AGT TAG GAA GAA AQA ID NO: 4-31 HCA-4 AAA AAT AAA AGT TAG GAA GCA ACT T SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36

[0318] wherein A is adenine, C is cytosine, G is guanine and T is thymine or uracil. In some modalities, T is thymine.

[0319] In some embodiments, each Nu from 1 to (n+1) and 5' to 3' of Formula (V) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, or SEQ ID NO:35. In some modalities, each Nu from 1 to (n+1) and 5' to 3' of Formula (V) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27 or SEQ ID NO:28. In some modalities, each Nu from 1 to (n+1) and 5' to 3' of Formula (V) corresponds to one of the following: SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:25 or SEQ ID NO:28.

[0320] In some forms, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (V) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, or SEQ ID NO:35. In some modalities, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (V) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27 or SEQ ID NO:28. In some modalities, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (V) corresponds to one of the following: SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:25 or SEQ ID NO:28. In some modalities, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (V) corresponds to SEQ ID NO:19.In some modalities, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (V) corresponds to SEQ ID NO:37. Petition 870260074072, dated 07 / 24 / 2026, pp. 142 / 448 135 / 207

[0321] In some embodiments, an antisense oligomer of Formula (V) is in the free base form. In some embodiments, an antisense oligomer of Formula (V) is a pharmaceutically acceptable salt thereof. In some embodiments, an antisense oligomer of Formula (IV) is a salt of HCl (hydrochloric acid) thereof. In certain embodiments, the HCl salt is a 5HCl salt.

[0322] In some embodiments, including, for example, some embodiments of Formula (I), an antisense oligomer of disclosure is in accordance with Formula (VI): (VI)

[0323] where each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Sítio de anelamento Sequência base [5' a 3'] SEQ ID NO: H2.SA.(-20+05) TTC ATC TAA AAT GCA AAA TAA AAA A SEQ ID NO:1 H2.SA.(-14+11) TTC TCT TTC ATC TAA AAT GCA AAA T SEQ ID NO:2 H2.SA.(-11+14) ATC TTC TCT TTC ATC TAA AAT GCA A SEQ ID NO:3 H2.SA.(-08+17) AAC ATC TTC TCT TTC ATC TAA AAT G SEQ ID NO:4 H2.SA.(-05+20) TTG AAC ATC TTC TCT TTC ATC TAA A SEQ ID NO:5 H2.SA.(-02+23) CTT TTG AAC ATC TTC TCT TTC ATC T SEQ ID NO:6 H2.SA.(+02+26) TTT CTT TTG AAC ATC TTC TCT TTC A SEQ ID NO:7 H2.SA.(+05+29) TGT TTT CTT TTG AAC ATC TTC TCT T SEQ ID NO:8 H2.SA.(+08+32) GAA TGT TTT CTT TTG AAC ATC TTC T SEQ ID NO:9 H2.SA.(+11+35) TGT GAA TGT TTT CTT TTG AAC ATC T SEQ ID NO:10 H2.SA.(+14+38) TTT TGT GAA TGT TTT CTT TTG AAC A SEQ ID NO:11 H2.SA.(+17+41) CCA TTT TGT GAA TGT TTT CTT TTG A SEQ ID NO:12 H2.SA.(+20+44) TAC CCA TTT TGT GAA TGT TTT CTT T SEQ ID NO:13 H2.SA.(+23+47) ATT TAC CCA TTT TGT GAA TGT TTT C SEQ ID NO:14 H2.SA.(+26+50) TGC ATT TAC CCA TTT TGT GAA TGT T SEQ ID NO:15 H2.SA.(+29+53) TTG TGC ATT TAC CCA TTT TGT GAA T SEQ ID NO:16 H2.SA.(+32+56) AAA TTG TGC ATT TAC CCA TTT TGT G SEQ ID NO:17 H2.SA.(+35+59) AGA AAA TTG TGC ATT TAC CCA TTT T SEQ ID NO:18 H2.SA.(+38+62) CTT AGA AAA TTG TGC ATT TAC CCA T SEQ ID NO:19. Petition 870260074072, de 24 / 07 / 2026, pág. 143 / 448 136 / 207 H2.SD.(+22-03) TAC CTT AGA AAA TTG TGC ATT TAC C SEQ ID NO:20 H2.SD.(+19-06) TCT TAC CTT AGA AAA TTG TGC ATT T SEQ ID NO:21 H2.SD.(+16-09) CAT TCT TAC CTT AGA AAA TTG TGC A SEQ ID NO:22 H2.SD.(+13-12) AAC CAT TCT TAC CTT AGA AAA TTG T SEQ ID NO:23 H2.SD.(+10-15) ACA AAC CAT TCT TAC CTT AGA AAA T SEQ ID NO:24 H2A(+06+30) ATG TTT TCT TTT GAA CAT CTT CTC T SEQ ID NO:25 H2A(+07+31) AAT GTT TTC TTT TGA ACA TCT TCT C SEQ ID NO:26 H2A(+09+33) TGA ATG TTT TCT TTT GAA CAT CTT C SEQ ID NO:27 H2A(+10+34) GTG AAT GTT TTC TTT TGA ACA TCT T SEQ ID NO:28 H2A(-23+02) ATC TAA AAT GCA AAA TAA AAA AAT A SEQ ID NO:29 H2A(-26-02) TAA AAT GCA AAA TAA AAA AAT AAA A SEQ ID NO:30 H2A(-29-05) AAT GCA AAA TAA AAA AAT AAA AGT T SEQ ID NO:31 H2A(-32-08) GCA AAA TAA AAA AAT AAA AGT TAG G SEQ ID NO:32 H2A(-35-11) AAA TAA AAA AAT AAA AGT TAG GAA G SEQ ID NO:33 H2A(-38-14) TAA AAA AAT AAA AGT TAG GAA GCA A SEQ ID NO:34 H2A(-41-17) AAA AAT AAA AGT TAG GAA GCA ACT T SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36 H2D(+15-08) ATT CTT ACC TTA GAA AAT TGT GC SEQ ID NO:37 H2A(+46+62) CTT AGA AAA TTG TGC AT SEQ ID NO:38 H2D(+08-09) CAT TCT TAC CTT AGA AA SEQ ID NO:39.

[0324] em que A é adenina, C é citosina, G é guanina e T é timina ou uracila. In certain modalities, T is thymine.

[0325] In some Formula (VI) modalities, each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Sítio de anelamento Sequência base [5' a 3'] SEQ ID NO: H2.SA.(-20+05) TTC ATC TAA AAT GCA AAA TAA AAA A SEQ ID NO:1 H2.SA.(-14+11) TTC TCT TTC ATC TAA AAT GCA AAA T SEQ ID NO:2 H2.SA.(-11+14) ATC TTC TCT TTC ATC TAA AAT GCA A SEQ ID NO:3 H2.SA.(-08+17) AAC ATC TTC TCT TTC ATC TAA AAT G SEQ ID NO:4 H2.SA.(-05+20) TTG AAC ATC TTC TCT TTC ATC TAA A SEQ ID NO:5 H2.SA.(-02+23) CTT TTG AAC ATC TTC TCT TTC ATC T SEQ ID NO:6 H2.SA.(+02+26) TTT CTT TTG AAC ATC TTC TCT TTC A SEQ ID NO:7 H2.SA.(+05+29) TGT TTT CTT TTG AAC ATC TTC TCT T SEQ ID NO:8 H2.SA.(+08+32) GAA TGT TTT CTT TTG AAC ATC TTC T SEQ ID NO:9 H2.SA.(+11+35) TGT GAA TGT TTT CTT TTG AAC ATC T SEQ ID NO:10 H2.SA.(+14+38) TTT TGT GAA TGT TTT CTT TTG AAC A SEQ ID NO:11 H2.SA.(+17+41) CCA TTT TGT GAA TGT TTT CTT TTG A SEQ ID NO:12 H2.SA.(+20+44) TAC CCA TTT TGT GAA TGT TTT CTT T SEQ ID NO:13 H2.SA.(+23+47) ATT TAC CCA TTT TGT GAA TGT TTT C SEQ ID NO:14 H2.SA.(+26+50) TGC ATT TAC CCA TTT TGT GAA TGT T SEQ ID NO:15 H2.SA.(+29+53) TTG TGC ATT TAC CCA TTT TGT GAA T SEQ ID NO:16 H2.SA.(+32+56) AAA TTG TGC ATT TAC CCA TTT TGT G SEQ ID NO:17 H2.SA.(+35+59) AGA AAA TTG TGC ATT TAC CCA SEQ ID NO:18. Petition 870260074072, of 24 / 07 / 2026, p. 144 / 448 137 / 207 H2.SD.(+22-03) TAC CTT AGA AAA TTG TGC ATT TAC C SEQ ID NO:20 H2.SD.(+19-06) TCT TAC CTT AGA AAA TTG TGC ATT T SEQ ID NO:21 H2.SD.(+16-09) CAT TCT TAC CTT AGA AAA TTG TGC A SEQ ID NO:22 H2.SD.(+13-12) AAC CAT TCT TAC CTT AGA AAA TTG T SEQ ID NO:23 H2.SD.(+10-15) ACA AAC CAT TCT TAC CTT AGA AAA T SEQ ID NO:24 H2A(+06+30) ATG TTT TCT TTT GAA CAT CTT CTC T SEQ ID NO:25 H2A(+07+31) AAT GTT TTC TTT TGA ACA TCT TCT C SEQ ID NO:26 H2A(+09+33) TGA ATG TTT TCT TTT GAA CAT CTT C SEQ ID NO:27 H2A(+10+34) GTG AAT GTT TTC TTT TGA ACA TCT T SEQ ID NO:28 H2A(-23+02) ATC TAA AAT GCA AAA TAA AAA AAT A SEQ ID NO:29 H2A(-26-02) TAA AAT GCA AAA TAA AAA AAT AAA A SEQ ID NO:30 H2A(-29-05) AAT GCA AAA TAA AAA AAT AAA AGT T SEQ ID NO:31 H2A(-32-08) GCA AAA TAA AAA AAT AAA AGT TAG G SEQ ID NO:32 H2A(-35-11) AAA TAA AAA AAT AAA AGT TAG GAA G SEQ ID NO:33 H2A(-38-14) TAA AAA AAT AAA AGT TAG GAA GCA A SEQ ID NO:34 H2A(-41-17) AAA AAT AAA AGT TAG GAA GCA ACT T SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36 H2A(+46+62) CTT AGA AAA TTG TGC AT SEQ ID NO:38.

[0326] em que A é adenina, C é citosina, G é guanina e T é timina ou uracila. Em certas modalidades, T é timina.

[0327] In some Formula (VI) modalities, each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases in one of the following: Sítio de anelamento Sequência base [5' a 3'] SEQ ID NO: H2.SA.(-20+05) TTC ATC TAA AAT GCA AAA TAA AAA A SEQ ID NO:1 H2.SA.(-14+11) TTC TCT TTC ATC TAA AAT GCA AAA T SEQ ID NO:2 H2.SA.(-11+14) ATC TTC TCT TTC ATC TAA AAT GCA A SEQ ID NO:3 H2.SA.(-08+17) AAC ATC TTC TCT TTC ATC TAA AAT G SEQ ID NO:4 H2.SA.(-05+20) TTG AAC ATC TTC TCT TTC ATC TAA A SEQ ID NO:5 H2.SA.(-02+23) CTT TTG AAC ATC TTC TCT TTC ATC T SEQ ID NO:6 H2.SA.(+02+26) TTT CTT TTG AAC ATC TTC TCT TTC A SEQ ID NO:7 H2.SA.(+05+29) TGT TTT CTT TTG AAC ATC TTC TCT T SEQ ID NO:8 H2.SA.(+08+32) GAA TGT TTT CTT TTG AAC ATC TTC T SEQ ID NO:9 H2.SA.(+11+35) TGT GAA TGT TTT CTT TTG AAC ATC T SEQ ID NO:10 H2.SA.(+14+38) TTT TGT GAA TGT TTT CTT TTG AAC A SEQ ID NO:11 H2.SA.(+17+41) CCA TTT TGT GAA TGT TTT CTT TTG A SEQ ID NO:12 H2.SA.(+20+44) TAC CCA TTT TGT GAA TGT TTT CTT T SEQ ID NO:13 H2.SD.(+22-03) TAC CTT AGA AAA TTG TGC ATT TAC C SEQ ID NO:20 H2.SD.(+19-06) TCT TAC CTT AGA AAA TTG TGC ATT T SEQ ID NO:21 H2A(+06+30) ATG TTT TCT TTT GAA CAT CTC T SEQ ID NO:25 H2A(+07+31) AAT GTT TTC TTT TGA ACA TCT CCT: SEQ TTC TTC TGA TGA ACA TCT C620 TGA+ IDA+3 ATG TTT TCT TTT GAA CAT CTT C SEQ ID NO:27 H2A(+10+34) GTG AAT GTT TTC TTT TGA ACA TCT T SEQ ID NO:28 H2A(-38-14) TAA AAA AAT AAA AGT TAG GAA GCA A SEQ ID NO:34. Petition 870260074072, of 24 / 07 / 2026, p. 145 / 448 138 / 207 H2A(-41-17) AAA AAT AAA AGT TAG GAA GCA ACT T SEQ ID NO:35 H2A(+11+29) TGT TTT CTT TTG AAC ATC T SEQ ID NO:36

[0328] wherein A is adenine, C is cytosine, G is guanine and T is thymine or uracil. In some modalities, T is thymine.

[0329] In some embodiments, each Nu from 1 to (n+1) and 5' to 3' of Formula (VI) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, or SEQ ID NO:35. In some modalities, each Nu from 1 to (n+1) and 5' to 3' of Formula (VI) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27 or SEQ ID NO:28. In some modalities, each Nu from 1 to (n+1) and 5' to 3' of Formula (VI) corresponds to one of the following: SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:25 or SEQ ID NO:28.

[0330] In some embodiments, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (VI) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, or SEQ ID NO:35. In some modalities, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (VI) corresponds to one of the following: SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27 or SEQ ID NO:28. In some modalities, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (VI) corresponds to one of the following: SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:25 or SEQ ID NO:28. In some modalities, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (VI) corresponds to SEQ ID NO:19. In some Petition 870260074072, dated 07 / 24 / 2026, pp. 146 / 448 139 / 207 modalities, T is thymine and each Nu from 1 to (n+1) and 5' to 3' of Formula (VI) corresponds to the nucleobases in SEQ ID NO:37. 10. Nucleobase Modifications and Replacements

[0331] In certain embodiments, disclosure antisense oligomers are composed of RNA nucleobases and DNA nucleobases (often referred to in the art simply as base). RNA bases are commonly known as adenine (A), uracil (U), cytosine (C), and guanine (G). DNA bases are commonly known as adenine (A), thymine (T), cytosine (C), and guanine (G). In several embodiments, disclosure antisense oligomers are composed of cytosine (C), guanine (G), thymine (T), adenine (A), 5-methylcytosine (5mC), uracil (U), and hypoxanthine (I).

[0332] In certain embodiments, one or more RNA or DNA bases in an oligomer may be modified or replaced by a base that is not an RNA or DNA base. Oligomers containing a modified or substituted base include oligomers in which one or more purine or pyrimidine bases most commonly found in nucleic acids are replaced by less common or unnatural bases.

[0333] Purine bases comprise a pyrimidine ring fused to an imidazole ring, as described by the following general formula. Purina

[0334] Adenine and guanine are the two most commonly found purine nucleobases in nucleic acids. Other naturally occurring purines include, but are not limited to, N6-methyladenine, N2-methylguanine, hypoxanthine, and 7-methylguanine. Petition 870260074072, dated 07 / 24 / 2026, pp. 147 / 448 140 / 207

[0335] Pyrimidine bases comprise a six-membered pyrimidine ring, as described by the following general formula. v-ns Pyrimidine Nucleus

[0336] Cytosine, uracil, and thymine are the most commonly found pyrimidine bases in nucleic acids. Other naturally occurring pyrimidines include, but are not limited to, 5-methylcytosine, 5-hydroxymethylcytosine, pseudouracil, and 4-thiouracil. In one embodiment, the oligomers described in this document contain thymine bases in place of uracil.

[0337] Other suitable bases include, but are not limited to: 2,6-diaminopurine, orotic acid, agmatidine, lysidine, 2-thiopyrimidines (e.g., 2-thiouracil, 2-thiothymine), G-clamp and its derivatives, 5-substituted pyrimidines (e.g., 5-halouracil, 5-propynyluracil, 5-propynylcytosine, 5-aminomethyluracil, 5-hydroxymethyluracil, 5-aminomethylcytosine, 5-hydroxymethylcytosine, Super T), 7-desazaguanine, 7-desazaadenine, 7-aza-2,6-diaminopurine, 8-aza-7-desazaguanine, 8-aza-7-desazaadenine, 8-aza-7-desaza-2,6-diaminopurine, Super G, Super A and N4-ethylcytosine or their derivatives. derivatives; N2-cyclopentylguanine (cPent-G), N2-cyclopentyl-2-aminopurine (cPent-AP), and N2-propyl-2-aminopurine (Pr-AP), pseudouracil or its derivatives; and degenerate or universal bases, such as 2,6-difluorotoluene or bases lacking as abasic sites (e.g., 1-deoxyribose, 1,2-dideoxyribose, 1-deoxy-2-O-methylribose; or pyrrolidine derivatives in which the ring oxygen has been replaced by nitrogen (azaribose)).Examples of derivatives of Super A, Super G, and Super T can be found in U.S. Patent 6,683,173 (Epoch Biosciences), which is incorporated herein by reference in its entirety. cPent-G, cPent-AP, and Pr-AP have been shown to reduce immunostimulatory effects when incorporated into siRNA (Peacock H. et al. Am. Chem. Soc. 2011, 133, 9200). Pseudouracil is one. Petition 870260074072, dated 07 / 24 / 2026, pages 148 / 448 141 / 207 isomerized natural version of uracil, with a C-glycoside instead of the regular N-glycoside as in uridine. Synthetic mRNA containing pseudouridine may have an improved safety profile compared to uridine-containing mPvNA (WO 2009127230, incorporated herein in its entirety by reference).

[0338] Certain nucleobases are particularly useful for increasing the binding affinity of antisense disclosure oligomers. These include pyrimidines substituted at the 5-position, 6-azapyrimidines, and purines substituted at the N-2, N-6, and O-6 positions, including 2-aminopropyladenine, 5-propynyluracil, and 5-propynylcytosine. 5-Methylcytosine substitutions have been shown to increase nucleic acid duplex stability by 0.6–1.2 °C and are currently preferred base substitutions, even more so when combined with 2'-O-methoxyethyl sugar modifications. Additional exemplary modified nucleobases include those in which at least one hydrogen atom of the nucleobase is replaced by fluorine. 11. Pharmaceutically Acceptable Salts of Antisense Oligomers

[0339] Certain embodiments of antisense oligomers described in this document may contain a basic functional group, such as amino or alkylamino, and are therefore capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids. The term pharmaceutically acceptable salts in this respect refers to the relatively non-toxic inorganic and organic acid addition salts of antisense oligomers of the present disclosure. These salts may be prepared in situ in the administration vehicle or in the manufacturing process of the dosage form, or by separate reaction of a purified antisense oligomer of the disclosure in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed during purification. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, tosylate, and citrate salts. Petition 870260074072, dated 07 / 24 / 2026, pp. 149 / 448 142 / 207 maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glycoheptonate, lactobionate, and lauryl sulfonate and the like. (See, for example, Berge et al. (1977) Pharmaceutical Salts, J. Pharm. Sci. 66:1-19).

[0340] Pharmaceutically acceptable salts of the antisense oligomers in question include conventional non-toxic salts or quaternary ammonium salts of antisense oligomers, for example, of non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include those derived from inorganic acids, such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isotonic, and the like.

[0341] In certain embodiments, the antisense oligomers of this disclosure may contain one or more acidic functional groups and thus are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term pharmaceutically acceptable salts in these cases refers to the relatively non-toxic, inorganic and organic base addition salts of antisense oligomers of this disclosure. These salts may also be prepared in situ in the administration vehicle or in the manufacturing process of the dosage form, or by separate reaction of the purified antisense oligomer in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia or with a pharmaceutically acceptable primary, secondary or tertiary organic amine. Representative alkaline or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like.Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, etc. Petition 870260074072, dated 07 / 24 / 2026, pp. 150 / 448 143 / 207 ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. (See, for example, Berge et al., supra). III. Formulations and Methods of Administration

[0342] In certain embodiments, this disclosure provides pharmaceutical formulations or compositions suitable for the therapeutic delivery of antisense oligomers, or pharmaceutically acceptable salts thereof, as described herein. Therefore, in certain embodiments, this disclosure provides pharmaceutically acceptable compositions comprising a therapeutically effective amount of one or more of the antisense oligomers, or their pharmaceutically acceptable salts, described herein, formulated together with one or more pharmaceutically acceptable carriers (additives) and / or diluents. While it is possible for an antisense oligomer, or a pharmaceutically acceptable salt thereof, from this disclosure to be administered alone, it is preferable to administer the antisense oligomer, or a pharmaceutically acceptable salt thereof, as a pharmaceutical formulation (composition).In one embodiment, the antisense oligomer, or its pharmaceutically acceptable salt, of the formulation conforms to Formula (III) or Formula (IV).

[0343] Methods for delivering nucleic acid molecules, which may be applicable to the antisense oligomers, or their pharmaceutically acceptable salts, of this disclosure, are described, for example, in: Akhtar et al., 1992, Trends Cell Bio., 2:139; Delivery strategies for antisense oligonucleotide therapy, ed. Akhtar, 1995, CRC Press; and Sullivan et al., PCT WO 94 / 02595. These and other protocols may be used for delivering virtually any nucleic acid molecule, including the antisense oligomers, or their pharmaceutically acceptable salts, of this disclosure.

[0344] The pharmaceutical compositions of this disclosure may be specially formulated for administration in solid or liquid form, including Petition 870260074072, dated 07 / 24 / 2026, pp. 151 / 448 144 / 207 those adapted for the following: (1) oral administration, for example, drains (aqueous or non-aqueous solutions or suspensions), tablets (intended for buccal, sublingual or systemic absorption), boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous, or epidural injection, as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginal or intrarectal, for example, as a pessary, cream or foam; (5) sublingual; (6) ocular; (7) transdermal; or (8) nasal.

[0345] Some examples of materials that may serve as pharmaceutically acceptable carriers include, without limitation: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline solution; (18) Ringer's solution;(19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates, and / or polyanhydrides; and (22) other compatible non-toxic substances used in pharmaceutical formulations.

[0346] Additional, non-limiting examples of suitable agents for formulation with the antisense oligomers, or their pharmaceutically acceptable salts, of this disclosure include: PEG-conjugated nucleic acids; Petition 870260074072, dated 07 / 24 / 2026, page 152 / 448 145 / 207 phospholipid-conjugated nucleic acids; nucleic acids containing lipophilic fractions; phosphorothioates; P-glycoprotein inhibitors (such as Pluronic P85) that can increase drug entry into various tissues; biodegradable polymers, such as poly(D,L-lactide-coglycolide) microspheres for sustained-release distribution after implantation (Emerich, DF et al., 1999, Cell Transplant, 8, 47-58) Alkermes, Inc. Cambridge, Mass.; and charged nanoparticles, such as those made of polybutylcyanoacrylate, which are capable of distributing drugs across the blood-brain barrier and can alter neuronal uptake mechanisms (Prog Neuropsychopharmacol Biol Psychiatry, 23, 941-949, 1999).

[0347] The disclosure also features the use of a composition comprising surface-modified liposomes containing poly(ethylene glycol) (PEG) lipids (PEG-modified, branched and unbranched or combinations thereof, or long-circulating liposomes or stealth liposomes). The oligomer conjugates of the disclosure may also comprise covalently linked PEG molecules of various molecular weights. These formulations offer a method for increasing drug accumulation in target tissues. This class of drug carriers resists opsonization and elimination by the mononuclear phagocytic system (MPS or RES), thus allowing longer blood circulation times and greater tissue exposure to the encapsulated drug (Lasic et al. Chem. Rev. 1995, 95, 2601-2627; Ishiwata et al., Chem. Pharm. Bull. 1995, 43, 1005-1011).It has been shown that such liposomes selectively accumulate in tumors, presumably by extravasation and capture in neovascularized target tissues (Lasic et al., Science 1995, 267, 1275-1276; Oku et al., 1995, Biochim. Biophys. Acta, 1238, 86-90). Long-circulating liposomes enhance the pharmacokinetics and pharmacodynamics of DNA and RNA, particularly compared to conventional cationic liposomes that accumulate in MPS tissues (Liu et al., J. Biol. Chem. 1995, 42, 24864-24870; Choi et al., PCT International Publication No. Petition 870260074072, dated 07 / 24 / 2026, pp. 153 / 448 146 / 207 WO 96 / 10391; Ansell et al., PCT International Publication No. WO 96 / 10390; Holanda et al., PCT International Publication No. WO 96 / 10392). Long-circulating liposomes are also likely to protect drugs against nuclease degradation to a greater extent compared with cationic liposomes, based on their ability to prevent accumulation in metabolically aggressive MPS tissues, such as the liver and spleen.

[0348] In another embodiment, the present disclosure includes pharmaceutical compositions of antisense oligomer (or its pharmaceutically acceptable salt) prepared for delivery as described in U.S. Patent Nos. 6,692,911; 7,163,695; and 7,070,807. In this respect, in one embodiment, the present disclosure provides a conjugate of antisense oligomer and antisense oligomer of the present disclosure in a composition comprising lysine and histidine (HK) copolymers (as described in U.S. Patent Nos. 7,163,695; 7,070,807; and 6,692,911) either alone or in combination with PEG (for example, branched or unbranched PEG or a mixture of both), in combination with PEG and a targeting fraction, or any of the foregoing in combination with a crosslinking agent.In certain embodiments, the present disclosure provides antisense oligomers, or their pharmaceutically acceptable salts, in pharmaceutical compositions comprising gluconic acid-modified polyhistidine or gluconylated polyhistidine / transferrin-polylysine. One skilled in the art will also recognize that amino acids with properties similar to His and Lys may be substituted within the composition.

[0349] Humectants, emulsifiers and lubricants (such as sodium lauryl sulfate and magnesium stearate), coloring agents, release agents, coating agents, sweetening agents, flavoring agents, fragrance agents, preservatives and antioxidants may also be present in the compositions. Petition 870260074072, dated 07 / 24 / 2026, pp. 154 / 448 147 / 207

[0350] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxycanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol and the like; and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0351] The formulations of this disclosure include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and / or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any method well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the subject being treated and the specific route of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of active ingredient that produces a therapeutic effect.Generally, this amount will vary from about 0.1 percent to about ninety-nine percent of the active ingredient, preferably from about 5 percent to about 70 percent, more preferably from about 10 percent to about 30 percent.

[0352] In certain embodiments, a formulation of the present disclosure comprises an excipient selected from cyclodextrins, celluloses, liposomes, micelle-forming agents, for example, bile acids, and polymeric carriers, for example, polyesters and polyanhydrides; and an antisense oligomer, or a pharmaceutically acceptable salt thereof, of the present disclosure. In one embodiment, the antisense oligomer of the formulation conforms to Petition 870260074072, dated 07 / 24 / 2026, pp. 155 / 448 148 / 207 Formula (IV). In certain embodiments, a formulation mentioned above makes an antisense oligomer, or a pharmaceutically acceptable salt thereof, of the present disclosure, orally bioavailable.

[0353] The methods of preparing these pharmaceutical formulations or compositions include the step of bringing together an antisense oligomer, or a pharmaceutically acceptable salt thereof, of the present disclosure with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately combining an antisense oligomer, or a pharmaceutically acceptable salt thereof, of the present disclosure with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0354] The formulations of the disclosure suitable for oral administration may be in the form of capsules, wafers, pills, tablets, lozenges (using a flavored base, generally sucrose and acacia or tragacanth), powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as a liquid oil-in-water or water-in-oil emulsion, or as an elixir or syrup, or as lozenges (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as mouthwashes and the like, each containing a predetermined amount of an antisense oligomer, or pharmaceutically acceptable salt thereof, of the present disclosure as an active ingredient. An antisense oligomer, or pharmaceutically acceptable salt thereof, of the present disclosure may also be administered as a bolus, electuary, or paste.

[0355] In solid dosage forms of the disclosure for oral administration (capsules, tablets, pills, coated tablets, powders, granules, pouches and the like), the active ingredient may be mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) excipients or extenders, such as starches, lactose, sucrose, Petition 870260074072, dated 07 / 24 / 2026, pp. 156 / 448 149 / 207 glucose, mannitol and / or salicylic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) solution retarders, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxamer and sodium lauryl sulfate; (7) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and nonionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid and mixtures thereof; (10) coloring agents;and (11) controlled-release agents, such as crospovidone or ethyl cellulose. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid pharmaceutical compositions of a similar type may also be employed as excipients in soft and hard gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0356] A tablet may be produced by compression or molding, optionally with one or more accessory ingredients. Tablets may be prepared using a binder (e.g., gelatin or hydroxypropyl methylcellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), dispersing agent or surfactant. Molded tablets may be produced by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Petition 870260074072, dated 07 / 24 / 2026, page 157 / 448 150 / 207

[0357] Tablets and other solid dosage forms of the pharmaceutical compositions of this disclosure, such as coated tablets, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may also be formulated to provide slow or controlled release of the active ingredient contained therein using, for example, hydroxypropylmethylcellulose in varying proportions to provide the desired release profile, other polymeric matrices, liposomes and / or microspheres. They may be formulated for rapid release, for example, lyophilized.They can be sterilized by, for example, filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid pharmaceutical compositions that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These pharmaceutical compositions may also optionally contain opacifying agents and may be of a composition that releases the active ingredient(s) only, or preferably, into a certain portion of the gastrointestinal tract, optionally in a delayed manner. Examples of incorporation compositions that may be used include polymeric substances and waxes. The active ingredient may also be in microencapsulated form, if appropriate, with one or more of the excipients described above.

[0358] Liquid dosage forms for oral administration of the pharmaceutically acceptable antisense oligomers, or their salts, of the disclosure include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, of Petition 870260074072, dated 07 / 24 / 2026, pp. 158 / 448 151 / 207 cotton, peanut, corn, germ, olive oil, castor oil and sesame), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and sorbitan fatty acid esters, and mixtures thereof.

[0359] In addition to inert diluents, oral pharmaceutical compositions may also include adjuvants such as humectants, emulsifying and suspending agents, sweeteners, flavorings, colorings, fragrances and preservatives.

[0360] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum meta-hydroxide, bentonite, agar-agar and tragacanth and mixtures thereof.

[0361] Formulations for rectal or vaginal administration may be presented as suppositories, which may be prepared by mixing one or more disclosure compounds with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature but liquid at body temperature and will therefore melt in the rectum or vaginal cavity and release the active compound.

[0362] Formulations or dosage forms for topical or transdermal administration of an oligomer as provided in this document include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. Active oligomer conjugates may be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers, or propellants that may be required. Ointments, pastes, creams, and gels may contain, in addition to an active compound of this disclosure, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, Petition 870260074072, dated 07 / 24 / 2026, page 159 / 448 152 / 207 polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0363] Powders and sprays may contain, in addition to an antisense oligomer, or a pharmaceutically acceptable salt thereof, of this disclosure, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder or mixtures of these substances. Sprays may additionally contain usual propellants such as chlorofluorohydrocarbons and unsubstituted volatile hydrocarbons such as butane and propane.

[0364] Transdermal patches have the added advantage of providing controlled delivery of an antisense oligomer, or a pharmaceutically acceptable salt thereof, from the present disclosure to the body. Such dosage forms can be made by dissolving or dispersing the oligomer in the appropriate medium. Absorption enhancers can also be used to increase the flux of the agent through the skin. The rate of such flux can be controlled by providing a rate-control membrane or by dispersing the agent in a polymeric matrix or gel, among other methods known in the art.

[0365] Pharmaceutical compositions suitable for parenteral administration may comprise one or more oligomer conjugates of the dissemination in combination with one or more pharmaceutically acceptable sterile aqueous or non-aqueous isotonic solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostatic agents, solutes that make the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents. Examples of suitable aqueous and non-aqueous carriers that may be employed in pharmaceutical compositions of the dissemination include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), and mixtures. Petition 870260074072, dated 07 / 24 / 2026, page 160 / 448 153 / 207 suitable of these, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Adequate fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. In one embodiment, the antisense oligomer of the pharmaceutical composition conforms to Formula (IV).

[0366] These pharmaceutical compositions may also contain adjuvants, such as preservatives, humectants, emulsifying agents, and dispersing agents. Prevention of microorganism action on the oligomer conjugates of interest can be ensured by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form can be achieved by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

[0367] In some cases, in order to prolong the effect of a drug, it is desirable to delay the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor solubility in water, among other methods known in the art. The rate of absorption of the drug then depends on its rate of dissolution, which in turn may depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is achieved by dissolving or suspending the drug in an oily vehicle.

[0368] Injectable deposition forms can be made by forming microencapsulated matrices of the oligomer conjugates of interest in biodegradable polymers, such as polylactide-polyglycolide. Depending on the ratio between the oligomer and the polymer and the nature of the particular polymer employed, the rate of Petition 870260074072, dated 07 / 24 / 2026, page 161 / 448 154 / 207 Oligomer release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by trapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0369] When the antisense oligomers, or their pharmaceutically acceptable salts, of this disclosure are administered as pharmaceutical products to humans and animals, they may be administered per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of the antisense oligomer, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

[0370] The formulations or preparations of this disclosure may be administered orally, parenterally, topically or rectally. They are usually administered in forms suitable for each route of administration. For example, they are administered in tablet or capsule form, by injection, inhalation, eye drops, ointment, suppository or infusion; topically by lotion or ointment; or rectally by suppositories.

[0371] Regardless of the route of administration selected, the antisense oligomers, or their pharmaceutically acceptable salts, of this disclosure, which may be used in a suitable hydrated form and / or the pharmaceutical compositions of this disclosure, may be formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art. The actual dosage levels of the active ingredients in the pharmaceutical compositions of this disclosure may vary in order to obtain an amount of the active ingredient that is effective in achieving the desired therapeutic response for a particular patient, composition and route of administration, without being unacceptably toxic to the patient. Petition 870260074072, dated 07 / 24 / 2026, page 162 / 448 155 / 207

[0372] The dosage level selected will depend on a variety of factors, including the activity of the particular antisense oligomer, or its pharmaceutically acceptable salt, of the present disclosure employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular oligomer being employed, the rate and extent of absorption, the duration of treatment, other drugs, compounds and / or materials used in combination with the particular oligomer employed, the age, sex, weight, condition, general health and previous medical history of the patient being treated and similar factors well known in medical techniques.

[0373] A physician or veterinarian skilled in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian may start doses of the antisense oligomers, or their pharmaceutically acceptable salts, of the disclosure employed in the pharmaceutical composition at levels lower than those necessary to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In general, an adequate daily dose of an antisense oligomer, or pharmaceutically acceptable salt thereof, of the disclosure will be that amount of the antisense oligomer, or pharmaceutically acceptable salt thereof, which is the lowest effective dose to produce a therapeutic effect. Such an effective dose will generally depend on the factors described in this document.Generally, the oral, intravenous, intracerebroventricular, and subcutaneous doses of the antisense oligomers, or their pharmaceutically acceptable salts, of this disclosure for a patient, when used for the indicated effects, will range from about 0.0001 to about 100 mg per kilogram of body weight per day.

[0374] In some embodiments, the antisense oligomers, or their pharmaceutically acceptable salt, of this disclosure are administered in doses Petition 870260074072, dated 07 / 24 / 2026, p. 163 / 448 156 / 207 generally from about 1 to about 200 mg / kg. In some embodiments, the doses for IV administration are from about 0.5 mg to about 200 mg / kg.

[0375] In some embodiments, the antisense oligomer, or its pharmaceutically acceptable salt, of Formula (I) is administered in doses generally of about 1 to about 200 mg / kg. In some embodiments, the doses of the antisense oligomer, or its pharmaceutically acceptable salt, of Formula (I) for IV administration are about 0.5 mg to about 200 mg / kg. In some embodiments, the antisense oligomer, or its pharmaceutically acceptable salt, of Formula (II) is administered in doses generally of about 1 to about 200 mg / kg. In some embodiments, the doses of the antisense oligomer, or its pharmaceutically acceptable salt, of Formula (II) for IV administration are about 0.5 mg to about 200 mg / kg. In some embodiments, the antisense oligomer, or its pharmaceutically acceptable salt, of Formula (III) is administered in doses generally of about 1 to about 200 mg / kg.In some embodiments, the doses of the antisense oligomer, or its pharmaceutically acceptable salt, of Formula (III) for IV administration are from about 0.5 mg to about 200 mg / kg. In some embodiments, the antisense oligomer of Formula (IV) is administered in doses generally from about 1 to about 200 mg / kg. In some embodiments, the doses of the antisense oligomer of Formula (IV) for IV administration are from about 0.5 mg to about 200 mg / kg. In some embodiments, the antisense oligomer, or its pharmaceutically acceptable salt, of Formula (V) is administered in doses generally from about 1 to about 200 mg / kg. In some embodiments, the doses of the antisense oligomer, or its pharmaceutically acceptable salt, of Formula (V) for IV administration are from about 0.5 mg to about 200 mg / kg. In some embodiments, the antisense oligomer of Formula (VI) is administered in doses generally of about 1 to about 200 mg / kg. In some embodiments, the doses... Petition 870260074072, dated 07 / 24 / 2026, pp. 164 / 448 Dosages of Formula (VI) antisense oligomer 157 / 207 for IV administration are from about 0.5 mg to about 200 mg / kg.

[0376] If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six, or more subdoses administered separately at appropriate intervals throughout the day, optionally in single-dose forms. In certain situations, the dosage is one administration per day. In certain embodiments, the dosage is one or more administrations every 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 days, or every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 weeks, or every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months, as needed, to maintain the desired expression of a functional dystrophin protein. In certain modalities, the dosage is one or more administrations once every two weeks. In some modalities, the dosage is one administration once every two weeks. In several modalities, the dosage is one or more administrations every month. In certain modalities, the dosage is one administration every month.

[0377] As would be understood in the technique, weekly, bi-weekly, every third week, or monthly administrations may be in one or more administrations or subdoses, as discussed in this document.

[0378] Nucleic acid molecules and antisense oligomers, or pharmaceutically acceptable salts thereof, described herein may be administered to cells by a variety of methods known to those familiar with the art, including, but not limited to, encapsulation in liposomes, by iontophoresis, or by incorporation into other vehicles such as hydrogels, cyclodextrins, biodegradable nanocapsules, and bioadhesive microspheres, as described herein and known in the art. In certain embodiments, microemulsification technology may be used to improve the bioavailability of lipophilic (water-insoluble) pharmaceutical agents. Examples include Trimethrine (Dordunoo, SK, et al.) Petition 870260074072, dated 07 / 24 / 2026, page 165 / 448 158 / 207 al., Drug Development and Industrial Pharmacy, 17(12), 1685-1713, 1991) and REV 5901 (Sheen, PC, et al., J Pharm Sci80(7), 712-714, 1991). Among other benefits, microemulsification provides greater bioavailability, preferentially directing absorption to the lymphatic system rather than the circulatory system, thus bypassing the liver and preventing the destruction of compounds in the hepatobiliary circulation.

[0379] In one aspect of the disclosure, the formulations contain micelles formed from an oligomer as provided in this document and at least one amphiphilic carrier, wherein the micelles have an average diameter less than about 100 nm. More preferred embodiments provide micelles with an average diameter less than about 50 nm, and even more preferred embodiments provide micelles having an average diameter less than about 30 nm, or even less than about 20 nm.

[0380] Although all suitable amphiphilic carriers are contemplated, presently preferred carriers are generally those that have Generally Recognized as Safe (GRAS) status, and that can either solubilize an antisense oligomer, or a pharmaceutically acceptable salt thereof, of the present disclosure and microemulsify at a later stage when the solution comes into contact with a complex aqueous phase (such as one found in the human gastrointestinal tract). Generally, amphiphilic ingredients that meet these requirements have HLB (hydrophilic-to-lipophilic balance) values ​​of 2-20, and their structures contain linear chain aliphatic radicals in the range of C-6 to C-20. Examples are polyethylene glycolized fatty glycerides and polyethylene glycols.

[0381] Examples of amphiphilic carriers include saturated and monounsaturated polyethylene glycolized fatty acid glycerides, such as those obtained from various fully or partially hydrogenated vegetable oils. Such oils may advantageously consist of tri-, di- and mono-fatty acid glycerides and di-fatty acid esters. Petition 870260074072, dated 07 / 24 / 2026, page 166 / 448 159 / 207 and mono-poly(ethylene glycol) of the corresponding fatty acids, with a particularly preferred fatty acid composition including capric acid 4-10%, capric acid 3-9%, lauric acid 40-50%, myristic acid 14-24%, palmitic acid 4-14% and stearic acid 5-15%. Another useful class of amphiphilic carriers includes partially esterified sorbitan and / or sorbitol, with corresponding saturated or monounsaturated fatty acids (SPAN series) or ethoxylated analogues (TWEEN series).

[0382] Commercially available amphiphilic carriers may be particularly useful, including the Gelucire series, Labrafil, Labrasol or Lauroglycol (all manufactured and distributed by Gatteiria Corporation, Saint Priest, France), PEG-monooleate, PEG-di-oleate, PEG-mono-laurate and di-laurate, Lecithin, Polysorbate 80, etc. (produced and distributed by a number of companies in the USA and worldwide).

[0383] In certain embodiments, delivery may occur by use of liposomes, nanocapsules, microparticles, microspheres, lipid particles, vesicles and the like, for the introduction of the pharmaceutical compositions of the present disclosure into suitable host cells. In particular, the pharmaceutical compositions of the present disclosure may be formulated for delivery either encapsulated in a lipid particle, a liposome, a vesicle, a nanosphere, a nanoparticle or the like. The formulation and use of such delivery vehicles may be carried out using known and conventional techniques.

[0384] Hydrophilic polymers suitable for use in the present disclosure are those that are readily soluble in water, can be covalently linked to a vesicle-forming lipid, and are tolerated in vivo without toxic effects (i.e., are biocompatible). Suitable polymers include poly(ethylene glycol) (PEG), polylactic acid (also called polylactide), polyglycolic acid (also called polyglycolide), a polylactic-polyglycolic acid copolymer, and polyvinyl alcohol. In certain embodiments, the polymers have a weighted average molecular weight of approximately Petition 870260074072, dated 07 / 24 / 2026, page 167 / 448 160 / 207 from 100 or 120 daltons to about 5,000 or 10,000 daltons, or from about 300 daltons to about 5,000 daltons. In other embodiments, the polymer is poly(ethylene glycol) with a weighted average molecular weight of about 100 to about 5,000 daltons, or having a weighted average molecular weight of about 300 to about 5,000 daltons. In certain embodiments, the polymer is a poly(ethylene glycol) with a weighted average molecular weight of about 750 daltons, for example, PEG(750). Polymers can also be defined by the number of monomers in them; A preferred embodiment of the present disclosure utilizes polymers of at least about three monomers, such PEG polymers consisting of three monomers having a molecular weight of approximately 132 daltons.

[0385] Other hydrophilic polymers that may be suitable for use in the present disclosure include polyvinylpyrrolidone, polymethoxazoline, polyethyloxazoline, polyhydroxypropyl methacrylamide, polymethacrylamide, polydimethylacrylamide and derivatized celluloses such as hydroxymethylcellulose or hydroxyethylcellulose.

[0386] In certain embodiments, a formulation of the present disclosure comprises a biocompatible polymer selected from the group consisting of polyamides, polycarbonates, polyalkylenes, acrylic and methacrylic ester polymers, polyvinyl polymers, polyglycolides, polysiloxanes, polyurethanes and copolymers thereof, celluloses, polypropylene, polyethylenes, polystyrene, lactic acid and glycolic acid polymers, polyanhydrides, poly(ortho)esters, poly(butic acid), poly(valeric acid), poly(lactide-co-caprolactone), polysaccharides, proteins, polyhyaluronic acids, polycyanoacrylates and blends, mixtures or copolymers thereof.

[0387] Cyclodextrins are cyclic oligosaccharides consisting of 6, 7, or 8 glucose units, indicated by the Greek letters α, β, or γ, respectively. The glucose units are linked by α-1,4-glycosidic bonds. As a consequence of the chair conformation of the sugar units, all secondary hydroxyl groups (at C-2, C-3) are located on one side of the ring, while all the Petition 870260074072, dated 07 / 24 / 2026, pp. 168 / 448 161 / 207 primary hydroxyl groups at C-6 are located on the other side. As a result, the outer faces are hydrophilic, making cyclodextrins water-soluble. In contrast, the cavities of cyclodextrins are hydrophobic, since they are lined by hydrogen from the C-3 and C-5 atoms, and by ether-like oxygens. These matrices allow complexation with a variety of relatively hydrophobic compounds, including, for example, steroid compounds such as 17α-estradiol (see, for example, van Uden et al. Plant Cell Tiss. Org. Culto. 38: 1-3-113 (1994)). Complexation occurs through Van der Waals interactions and hydrogen bonding. For a general analysis of cyclodextrin chemistry, see Wenz, Agnew. Chem. Int. Ed. Engl., 33:803-822 (1994).

[0388] The physicochemical properties of cyclodextrin derivatives depend strongly on the type and degree of substitution. For example, their solubility in water varies from insoluble (e.g., triacetyl-beta-cyclodextrin) to 147% soluble (w / v) (G-2-beta-cyclodextrin). Furthermore, they are soluble in many organic solvents. The properties of cyclodextrins allow control over the solubility of various formulation components, increasing or decreasing their solubility.

[0389] Numerous cyclodextrins and methods for their preparation have been described. For example, Parmeter (I), et al. (US Patent No. 3,453,259) and Gramera, et al. (US Patent No. 3,459,731) described electroneutral cyclodextrins. Other derivatives include cyclodextrins with cationic properties [Parmeter (II), US Patent No. 3,453,257], insoluble crosslinked cyclodextrins (Solms, US Patent No. 3,420,788) and cyclodextrins with anionic properties [Parmeter (III), US Patent No. 3,426,011]. Among the cyclodextrin derivatives with anionic properties, carboxylic acids, phosphorous acids, phosphinic acids, phosphonic acids, thiophosphonic acids, thiosulfinic acids, and sulfonic acids have been attached to the parent cyclodextrin [see, Parmeter (III), Pat. No. 3,453,257]. Furthermore, derivatives of Petition 870260074072, dated 07 / 24 / 2026, page 169 / 448 162 / 207 sulfoalkyl ether cyclodextrin was described by Stella, et al. (U.S. Pat. No. 5,134,127).

[0390] Liposomes consist of at least one lipid bilayer membrane enclosing an aqueous internal compartment. Liposomes can be characterized by membrane type and size. Small unilamellar vesicles (SUVs) have a single membrane and generally range between 0.02 and 0.05 μm in diameter; large unilamellar vesicles (LUVs) are typically larger than 0.05 μm. Large oligolamellar vesicles and multilamellar vesicles have multiple, generally concentric membrane layers and are typically larger than 0.1 μm. Liposomes with multiple non-concentric membranes, i.e., several smaller vesicles contained within a larger vesicle, are termed multivesicular vesicles.

[0391] One aspect of the present disclosure relates to formulations comprising liposomes containing an antisense oligomer, or a pharmaceutically acceptable salt thereof, of the present disclosure, wherein the liposome membrane is formulated to provide a liposome with increased transport capacity. Alternatively or additionally, the antisense oligomer, or a pharmaceutically acceptable salt thereof, of the present disclosure may be contained in or adsorbed onto the liposome bilayer of the liposome. An antisense oligomer, or a pharmaceutically acceptable salt thereof, of the present disclosure may be aggregated with a lipid surfactant and transported within the internal space of the liposome; in these cases, the liposome membrane is formulated to resist the disruptive effects of the active agent-surfactant aggregate.

[0392] According to one embodiment of the present disclosure, the lipid bilayer of a liposome contains lipids derivatized with poly(ethylene glycol) (PEG), such that the PEG chains extend from the inner surface of the bilayer. Petition 870260074072, dated 07 / 24 / 2026, page 170 / 448 163 / 207 lipid in the interior space encapsulated by the liposome and extend from the exterior of the lipid bilayer into the surrounding environment.

[0393] The active agents contained within the liposomes of the present disclosure are in solubilized form. Surfactant and active agent aggregates (such as emulsions or micelles containing the active agent of interest) can be trapped within the interior space of the liposomes according to the present disclosure. A surfactant acts to disperse and solubilize the active agent and can be selected from any suitable aliphatic, cycloaliphatic, or aromatic surfactant, including, but not limited to, biocompatible lysophosphatidylcholines (LPGs) of varying chain lengths (e.g., from about C14 to about C20). Polymer-derivative lipids, such as PEG lipids, can also be used for micelle formation, as they will act to inhibit micelle / membrane fusion, and as the addition of a polymer to the surfactant molecules decreases the CMC of the surfactant and aids in micelle formation.Surfactants with micromolar CMCs are preferred; surfactants with higher CMCs can be used to prepare micelles trapped within the liposomes of the present disclosure.

[0394] Liposomes according to the present disclosure can be prepared by any of a variety of techniques known in the art. See, for example, U.S. Patent No. 4,235,871; Published PCT Application WO 96 / 14057; Novo RRC, Liposomes: A Practical Approach, IRL Press, Oxford (1990), pages 33-104; and Lasic DD, Liposomes from Physics to Applications, Elsevier Science Publishers BV, Amsterdam, 1993. For example, the liposomes of the present disclosure can be prepared by diffusing a lipid derivatized with a hydrophilic polymer into pre-formed liposomes, such as by exposing pre-formed liposomes to micelles composed of lipid-grafted polymers, in lipid concentrations corresponding to the final molar percent of lipid. Petition 870260074072, dated 07 / 24 / 2026, page 171 / 448 164 / 207 derivatized which is desired in the liposome. Liposomes containing a hydrophilic polymer can also be formed by homogenization, hydration in the lipid field, or extrusion techniques, as they are known in the art.

[0395] In another example of a formulation procedure, the active agent is first dispersed by sonication in lysophosphatidylcholine or another low CMC surfactant (including polymer-grafted lipids) that readily solubilize hydrophobic molecules. The resulting micellar suspension of the active agent is then used to rehydrate a dry lipid sample containing an appropriate molar percentage of polymer-grafted lipid, or cholesterol. The lipid and active agent suspension is then formed into liposomes using extrusion techniques as are known in the art, and the resulting liposomes are separated from the unencapsulated solution by standard column separation.

[0396] In one aspect of the present disclosure, liposomes are prepared to have substantially homogeneous sizes within a selected size range. An effective sizing method involves extruding an aqueous suspension of liposomes through a series of polycarbonate membranes with a selected uniform pore size; the pore size of the membrane will correspond approximately to the largest sizes of liposomes produced by extrusion through that membrane. See, for example, U.S. Patent No. 4,737,323 (April 12, 1988). In certain embodiments, reagents such as DharmaFECT® and Lipofectamine® can be used to introduce polynucleotides or proteins into cells.

[0397] The release characteristics of a formulation of the present disclosure depend on the encapsulation material, the concentration of the encapsulated drug, and the presence of release modifiers. For example, release can be manipulated to be pH-dependent, for example, by using a pH-sensitive coating that releases only at a low pH, such as in the stomach, Petition 870260074072, dated 07 / 24 / 2026, page 172 / 448 165 / 207 or at a higher pH, such as in the intestine. An enteric coating can be used to prevent release until after passage through the stomach. Various coatings or mixtures of cyanamide encapsulated in different materials can be used to achieve initial release in the stomach, followed by subsequent release in the intestine. Release can also be manipulated by the inclusion of salts or pore-forming agents, which can increase water absorption or drug release by diffusion from the capsule. Excipients that modify drug solubility can also be used to control the release rate. Agents that enhance matrix degradation or matrix release can also be incorporated. They can be added to the drug, added as a separate phase (i.e., as particulate material), or can be co-dissolved in the polymer phase, depending on the compound.In most cases, the amount should be between 0.1 and 30 percent (w / w of polymer). Types of degradation enhancers include inorganic salts such as ammonium sulfate and ammonium chloride, organic acids such as citric acid, benzoic acid and ascorbic acid, inorganic bases such as sodium carbonate, potassium carbonate, calcium carbonate, zinc carbonate and zinc hydroxide, and organic bases such as protamine sulfate, spermine, choline, ethanolamine, diethanolamine and triethanolamine, and surfactants such as Tween® and Pluronic®. Pore-forming agents that add microstructure to the matrices (i.e., water-soluble compounds such as inorganic salts and sugars) are added as particulate matter. The range is typically between one and thirty percent (w / w of polymer).

[0398] Absorption can also be manipulated by altering the residence time of the particles in the intestine. This can be achieved, for example, by coating the particle with, or selecting as the encapsulation material, a mucosal adhesive polymer. Examples include most polymers with free carboxyl groups, such as chitosan, celluloses, and especially polyacrylates (as used in this Petition 870260074072, dated 07 / 24 / 2026, page 173 / 448 166 / 207 document, polyacrylates refer to polymers including acrylate groups and modified acrylate groups, such as cyanoacrylates and methacrylates).

[0399] An antisense oligomer, or a pharmaceutically acceptable salt thereof, may be formulated to be contained or adapted for release by a surgical or medical device or implant. In certain respects, an implant may be coated or otherwise treated with an antisense oligomer or a pharmaceutically acceptable salt thereof. For example, hydrogels, or other polymers, such as biocompatible and / or biodegradable polymers, may be used to coat an implant with the pharmaceutical compositions of the present disclosure (i.e., the composition may be adapted for use with a medical device using a hydrogel or other polymer). Polymers and copolymers for coating medical devices with an agent are well known in the art.Examples of implants include, but are not limited to, stents, drug-eluting stents, sutures, prostheses, vascular catheters, dialysis catheters, vascular grafts, prosthetic heart valves, cardiac pacemakers, implantable cardioverter defibrillators, IV needles, devices for bone positioning and formation, such as pins, screws, plates and other devices, and artificial tissue matrices for wound healing.

[0400] In addition to the methods provided in this document, antisense oligomers, or their pharmaceutically acceptable salts, for use in accordance with the disclosure may be formulated for administration in any manner convenient for use in human or veterinary medicine, by analogy with other pharmaceutical products. Antisense oligomers, or their pharmaceutically acceptable salts, and their corresponding formulations may be administered alone or in combination with other therapeutic strategies in the treatment of muscular dystrophy, such as myoblast transplantation, stem cell therapies, administration of aminoglycoside antibiotics, proteasome inhibitors, and regulatory therapies. Petition 870260074072, dated 07 / 24 / 2026, page 174 / 448 167 / 207 superior (e.g., upregulation of utrophin, an autosomal paralog of dystrophin).

[0401] In some embodiments, the additional therapeutic may be administered before, concurrently with, or after the administration of the antisense oligomer, or pharmaceutically acceptable salt thereof, of this disclosure. For example, antisense oligomers, or their pharmaceutically acceptable salts, may be administered in combination with a steroid and / or antibiotic. In certain embodiments, antisense oligomers, or their pharmaceutically acceptable salts, are administered to a patient who is on background steroid therapy (e.g., intermittent or chronic / continuous background steroid therapy). For example, in some embodiments, the patient was treated with a corticosteroid before the administration of an antisense oligomer, or pharmaceutically acceptable salt thereof, and continues to receive steroid therapy. In some embodiments, the steroid is a glucocorticoid or prednisone.

[0402] The routes of administration described are intended only as a guide, since one skilled in the art will be able to readily determine the ideal route of administration and any dosage for any specific animal and condition. Multiple approaches to the introduction of new functional genetic material into cells, both in vitro and in vivo, have been attempted (Friedmann (1989) Science, 244: 1275-1280). These approaches include integration of the gene to be expressed into modified retroviruses (Friedmann (1989) supra; Rosenberg (1991) Cancer Research 51 (18), suppl.: 5074S-5079S); integration into non-retroviral vectors (e.g., adeno-associated viral vectors) (Rosenfeld, et al. (1992) Cell, 68:143-155; Rosenfeld, et al. (1991) Science, 252: 431-434); or delivery of a transgene linked to a heterologous promoter-enhancer element via liposomes (Friedmann (1989), supra; Brigham, et al. (1989) Am. J. Med. Sci., 298: 278-281; ​​Nabel, et al.(1990) Science, 249: 1285-1288; Hazinski, et al. (1991) I'm J. Resp. Cell. Petition 870260074072, dated 07 / 24 / 2026, p. 175 / 448 168 / 207 Molec. Biol., 4:206-209; and Wang and Huang (1987) Proc. Natl. Acad. Sci. (USA), 84:785-17855); coupled to transport systems based on specific ligand cations (Wu and Wu (1988) J. Biol. Chem., 263:14621-14624) or the use of pure DNA, expression vectors (Nabel et al. (1990), supra; Wolff et al. (1990) Science, 247:1465-1468). Direct injection of transgenes into tissue produces only localized expression (Rosenfeld (1992) supra; Rosenfeld et al. (1991) supra; Brigham et al. (1989) supra; Nabel (1990) supra; and Hazinski et al. (1991) supra). The Brigham et al. group (Am. J. Med. Sci. (1989) 298: 278-281 and Clinical Research (1991) 39 (abstract)) reported in vivo transfection of mouse lungs only after intravenous or intratracheal administration of a DNA liposome complex. An example of a review article of human gene therapy procedures is: Anderson, Science (1992) 256:808-813.

[0403] In another embodiment, the pharmaceutical compositions of the disclosure may additionally comprise a carbohydrate as provided in Han et al., Nat. Comms. 7, 10981 (2016), the entirety of which is incorporated herein by reference. In some embodiments, the pharmaceutical compositions of the disclosure may comprise 5% of a hexose-type carbohydrate. For example, the pharmaceutical composition of the disclosure may comprise 5% glucose, 5% fructose, or 5% mannose. In certain embodiments, the pharmaceutical compositions of the disclosure may comprise 2.5% glucose and 2.5% fructose.In some embodiments, the pharmaceutical compositions of the disclosure may comprise a carbohydrate selected from: arabinose present in an amount of 5% by volume, glucose present in an amount of 5% by volume, sorbitol present in an amount of 5% by volume, galactose present in an amount of 5% by volume, fructose present in an amount of 5% by volume, xylitol present in an amount of 5% by volume, mannose present in an amount of 5% by volume, or a combination of glucose and fructose, each present in an amount. Petition 870260074072, dated 07 / 24 / 2026, page 176 / 448 169 / 207 of 2.5% by volume, and a combination of glucose present in an amount of 5.7% by volume, fructose present in an amount of 2.86% by volume and xylitol present in an amount of 1.4% by volume. IV. Methods of Use Restoration of the Dystrophin Reading Frame using Exon Jump

[0404] A potential therapeutic approach for the treatment of DMD caused by out-of-frame mutations in the dystrophin d gene is suggested by the milder form of dystrophinopathy known as BMD, which is caused by in-frame mutations. The ability to convert an out-of-frame mutation into an in-frame mutation would hypothetically preserve the mRNA reading frame and produce a still functional dystrophin protein shortened internally. Antisense oligomers, or their pharmaceutically acceptable salts, of the disclosure have been designed to accomplish this.

[0405] Hybridization of the antisense oligomer of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI) with the ta...

Claims

1. A modified antisense oligomer capable of binding to a selected target to induce exon skipping in the human dystrophin gene, CHARACTERIZED in that the modified antisense oligomer comprises a base sequence that is complementary to a target region of exon 2, intron 1, or intron 2 of the dystrophin pre-mRNA designated as an annealing site; wherein the base sequence and / or annealing site are selected from one of the following: Annealing site H2.SA.(-20+05) H2.SA.(-14+11) H2.SA.(-11+14) H2.SA.(-08+17) H2.SA.(-05+20) H2.SA.(-02+23) H2.SA.(+02+26) H2.SA.(+05+29) H2.SA.(+08+32) H2.SA.(+11+35) H2.SA.(+14+38) H2.SA.(+17+41) H2.SA.(+20+44) H2.SA.(+23+47) H2.SA.(+26+50) H2.SA.(+29+53) H2.SA.(+32+56) H2.SA.(+35+59) H2.SA.(+38+62) H2.SD.(+22-03) H2.SD.(+19-06) H2.SD.(+16-09) H2.SD.(+13-12) H2.SD.(+10-15) H2A(+06+30) H2A(+07+31) H2A(+09+33) H2A(+10+34) H2A(-23+02) H2A(-26-02) H2A(-29-05) H2A(-32-08) H2A(-35-11) Base sequence [5' to 3'] TTC ATC TAAAAT GCA AAA TAA AAA A TTC TCT TTC ATC TAA AAT GCA AAA T ATC TTC TCT TTC ATC TAA AAT GCA A AAC ATC TTC TCT TTC ATC TAA AAT G TTG AAC ATC TTC TCT TTC ATC TAA A CTT TTG AAC ATC TTC TCT TTC ATC T TTT CTT TTG AAC ATC TTC TCT TTC A TGT TTT CTT TTG AAC ATC TTC TCT T GAA TGT TTT CTT TTG AAC ATC TTC T TGT GAA TGT TTT CTT TTG AAC ATC T TTT TGT GAA TGT TTT CTT TTG AAC A CCA TTT TGT GAA TGT TTT CTT TTG A TAC CCA TTT TGT GAA TGT TTT CTT T ATT TAC CCA TTT TGT GAA TGT TTT C TGC ATT TAC CCA TTT TGT GAA TGT T TTG TGC ATT TAC CCA TTT TGT GAA T AAA TTG TGC ATT TAC CCA TTT TGT G AGA AAA TTG TGC ATT TAC CCA TTT T CTT AGA AAA TTG TGC ATT TAC CCA T TAC CTT AGA AAA TTG TGC ATT TAC C TCT TAC CTT AGA AAA TTG TGC ATT T CAT TCT TAC CTT AGA AAA TTG TGC A AAC CAT TCT TAC CTT AGA AAA TTG T ACA AAC CAT TCT TAC CTT AGA AAA T ATG TTT TCT TTT GAA CAT CTT CTC T AAT GTT TTC TTT TGA ACA TCT TCT C TGA ATG TTT TCT TTT GAA CAT CTT C GTG AAT GTT TTC TTT TGA ACA TCT T ATC TAA AAT GCA AAA TAA AAAAAT AAA A AAT GCA AAA TAA AAA AAT AAA AGT T GCA AAA TAA AAA AAT AAA AGT TAG G AAA TAA AAA AAT AAA AGT TAG GAA G SEQ ID NO: SEQ ID NO:1 SEQ ID NO:2 SEQ ID NO:3 SEQ ID NO:4 SEQ ID NO:5 SEQ ID NO:6 SEQ ID NO:7 SEQ ID NO:8 SEQ ID NO:9 SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO:10 NO:11 NO:12 NO:13 NO:14 NO:15 NO:16 NO:17 NO:18 NO:19 NO:20 NO:21 NO:22 NO:23 NO:24 NO:25 NO:26 NO:27 NO:28 NO:29 NO:30 NO:31 NO:32 NO:33 Petição 870260074072, de 24 / 07 / 2026, pág. 216 / 448 2 / 11 H2A(-38-14) H2A(-41-17) H2A(+11+29) H2D(+15-08) H2A(+46+62) H2D(+08-09) TAA AAA AAT AAA AGT TAG GAA GCA A AAA AAT AAA AGT TAG GAA GCA ACT T TGT TTT CTT TTG AAC ATC T ATT CTT ACC TTA GAA AAT TGT GC CTT AGA AAA TTG TGC AT CAT TCT TAC CTT AGA AA SEQ ID NO:34 SEQ ID NO:35 SEQ ID NO:36 SEQ ID NO:37 SEQ ID NO:38 SEQ ID NO:39 ; em que T é timina ou uracil.

2. Modified antisense oligomer, according to claim 1, CHARACTERIZED in that the base sequence and / or annealing site are selected from one of the following: Annealing site H2.SA.(-20+05) H2.SA.(-14+11) H2.SA.(-11+14) H2.SA.(-08+17) H2.SA.(-05+20) H2.SA.(-02+23) H2.SA.(+02+26) H2.SA.(+05+29) H2.SA.(+08+32) H2.SA.(+11+35) H2.SA.(+14+38) H2.SA.(+17+41) H2.SA.(+20+44) H2.SA.(+23+47) H2.SA.(+26+50) H2.SA.(+29+53) H2.SA.(+32+56) H2.SA.(+35+59) H2.SD.(+22-03) H2.SD.(+19-06) H2.SD.(+16-09) H2.SD.(+13-12) H2.SD.(+10-15) H2A(+06+30) H2A(+07+31) H2A(+09+33) H2A(+10+34) H2A(-23+02) H2A(-26-02) H2A(-29-05) H2A(-32-08) H2A(-35-11) H2A(-38-14) H2A(-41-17) H2A(+11+29) Base sequence [5' to 3'] TTC ATC TAA AAT GCA AAA TAA AAA A TTC TCT TTC ATC TAA AAT GCA AAA T ATC TTC TCT TTC ATC TAA AAT GCA A AAC ATC TTC TCT TTC ATC TAA AAT G TTG AAC ATC TTC TCT TTC ATC TAA A CTT TTG AAC ATC TTC TCT TTC ATC T TTT CTT TTG AAC ATC TTC TCT TTC A TGT TTT CTT TTG AAC ATC TTC TCT T GAA TGTTTT CTT TTG AAC ATC TTC T TGT GAA TGT TTT CTT TTG AAC ATC T TTT TGT GAA TGT TTT CTT TTG A CCA TTT TGT GAA TGT TTT CTT TTG A TAC CCA TTT TGT GAA TGT TTT CTT T ATT TAC CCA TTT TGT GAA TGT TTT C TGC ATT TAC CCA TTT TGT GAA TGT T TTG TGC ATT TAC CCA TTT TGT G AGA AAA TTG TGC ATT TAC CCA TTT T TAC CTT AGA AAA TTG TGC ATT TAC C TCT TAC CTT AGA AAA TTG TGC ATT T CAT TCT TAC CTT AGA AAA TTG TGC A AAC CAT TCT TAC CTT AGA AAA TTG T ACA AAC CAT TCT TAC CTT AGA AAA TTG T ACA AAC CAT TCT TAC CTT AGA AAA TTG T ACA AAC CAT TCT TAC CTT AGA AAA TTG T ACA AAC CAT TCT TAC CTT AGA AAA TTG T AGA AAA T ATG T TTT TCT TTT GAA CAT CTT CTC T AAT GTT TTC TTT TGA ACA TCT TCT C TGA ATG TTT TCT TTT GAA CAT CTT C GTG AAT GTT TTC TTT TGA ACA TCT T ATC TAA AAT GCA AAA TAA AAA AAT A TAA AAT GCA AAA TAA AAA AAT AAA A AAT GCA AAA TAA AAA AAT AAA AGT T GCA AAA TAA AAA AAT AAA AGT TAG G AAA TAA AAA AAT AAA AGT TAG GAA G TAA AAA AAT AAA AGT TAG GAA GCA A AAA AAT AAA AGT TAG GAA GCA ACT T TGT TTT CTT TTG AAC ATC T SEQ ID NO: SEQ ID NO:1 SEQ ID NO:2 SEQ ID NO:3 SEQ ID NO:4 SEQ ID NO:5 SEQ ID NO:6 SEQ ID NO:7 SEQID NO:8 SEQ ID NO:9 SEQ ID NO:10 SEQ ID NO:11 SEQ ID NO:12 SEQ ID NO:13 SEQ ID NO:14 SEQ ID NO:15 SEQ ID NO:16 SEQ ID NO:17 SEQ ID NO:18 SEQ ID NO:20 SEQ ID NO:21 SEQ ID NO:22 SEQ ID NO:23 SEQ ID NO:24 SEQ ID NO:25 SEQ ID NO:26 SEQ ID NO:27 SEQ ID NO:28 SEQ ID NO:29 SEQ ID NO:30 SEQ ID NO:31 SEQ ID NO:32 SEQ ID NO:33 SEQ ID NO:34 SEQ ID NO:35 SEQ ID NO:36 Petição 870260074072, de 24 / 07 / 2026, pág. 217 / 448 3 / 11 H2D(+15-08) H2A(+46+62) H2D(+08-09) ATT CTT ACC TTA GAA AAT TGT GC CTT AGA AAA TTG TGC AT CAT TCT TAC CTT AGA AA SEQ ID NO:37 SEQ ID NO:38 SEQ ID NO:39 .

3. Modified antisense oligomer, according to claim 1, CHARACTERIZED in that the base sequence and / or annealing site are selected from one of the following: Annealing site H2.SA.(-20+05) H2.SA.(-14+11) H2.SA.(-11+14) H2.SA.(-08+17) H2.SA.(-05+20) H2.SA.(-02+23) H2.SA.(+02+26) H2.SA.(+05+29) H2.SA.(+08+32) H2.SA.(+11+35) H2.SA.(+14+38) H2.SA.(+17+41) H2.SA.(+20+44) H2.SA.(+38+62) H2.SD.(+22-03) H2.SD.(+19-06) H2A(+06+30) H2A(+07+31) H2A(+09+33) H2A(+10+34) H2A(-38-14) H2A(-41-17) H2A(+11+29) Base sequence [5' to 3'] TTC ATC TAA AAT GCA AAA TAA AAA A TTC TCT TTC ATC TAA AAT GCA AAA T ATC TTC TCT TTC ATC TAA AAT GCA A AAC ATC TTC TCT TTC ATC TAA AAT G TTG AAC ATC TTC TCT TTC ATC TAA A CTT TTG AAC ATC TTC TCT TTC ATC T SEQ ID NO: SEQ ID NO:1 SEQ ID NO:2 SEQ ID NO:3 SEQ ID NO:4 SEQ ID NO:5 SEQ ID NO:6 TTT CTT TTG AAC ATC TTC TCT TTC A SEQ ID NO:7 TGT TTT CTT TTG AAC ATC TTC TCT T SEQ ID NO:8 GAA TGT TTT CTT TTG AAC ATC TTC T SEQ ID NO:9 TGT GAA TGT TTT CTTTTG AAC ATC T TTT TGT GAA TGT TTT CTT TTG AAC A CCA TTT TGT GAA TGT TTT CTT TTG A TAC CCA TTT TGT GAA TGT TTT CTT T CTT AGA AAA TTG TGC ATT TAC CCA T TAC CTT AGA AAA TTG TGC ATT TAC C TCT TAC CTT AGA AAA TTG TGC ATT T ATG TTT TCT TTT GAA CAT CTT CTC T AAT GTT TTC TTT TGA ACA TCT TCT C TGA ATG TTT TCT TTT GAA CAT CTT C GTG AAT GTT TTC TTT TGA ACA TCT T TAA AAA AAT AAA AGT TAG GAA GCA A AAA AAT AAA AGT TAG GAA GCA ACT T SEQ ID NO:10 SEQ ID NO:11 SEQ ID NO:12 SEQ ID NO:13 SEQ ID NO:19 SEQ ID NO:20 SEQ ID NO:21 SEQ ID NO:25 SEQ ID NO:26 SEQ ID NO:27 SEQ ID NO:28 SEQ ID NO:34 SEQ ID NO:35 TGT TTT CTT TTG AAC ATC T SEQ ID NO:36 .

4. Modified antisense oligomer, according to claim 1, CHARACTERIZED in that the base sequence and / or annealing site are selected from one of the following: Annealing site H2.SA.(-20+05) H2.SA.(-14+11) H2.SA.(-11+14) H2.SA.(-08+17) H2.SA.(-05+20) H2.SA.(-02+23) H2.SA.(+02+26) H2.SA.(+05+29) H2.SA.(+08+32) H2.SA.(+11+35) H2.SA.(+14+38) Base sequence [5' to 3'] TTC ATC TAA AAT GCA AAA TAA AAA A TTC TCT TTC ATC TAA AAT GCA AAA T ATC TTC TCT TTC ATC TAA AAT GCA A AAC ATC TTC TCT TTC ATC TAA AAT G TTG AAC ATC TTC TCT TTC ATC TAA A CTT TTG AAC ATC TTC TCT TTC ATC T TTT CTT TTG AAC ATC TTC TCT TTC A TGT TTT CTT TTG AAC ATC TTC TCT T GAA TGT TTT CTT TTG AAC ATC TTC T TGT GAA TGT TTT CTT TTG AAC ATC T TTT TGT GAA TGT TTT CTT TTG AAC A SEQ ID NO: SEQ ID NO:1 SEQ ID NO:2 SEQ ID NO:3 SEQ ID NO:4 SEQ ID NO:5 SEQ ID NO:6 SEQ ID NO:7 SEQ ID NO:8 SEQ ID NO:9 SEQ ID NO:10 SEQ ID NO:11 Petition 870260074072, from 07 / 24 / 2026, p. 218 / 448 4 / 11 H2.SA.(+17+41) H2.SA.(+20+44) H2.SD.(+22-03) H2.SD.(+19-06) H2A(+06+30) H2A(+07+31) H2A(+09+33) H2A(+10+34) H2A(-38-14) H2A(-41-17) H2A(+11+29) CCA TTT TGT GAA TGT TTT CTT TTG A SEQ ID NO:12 TAC CCA TTT TGT GAA TGT TTT CTT T SEQ ID NO:13 TAC CTT AGA AAA TTG TGC ATT TAC C SEQ ID NO:20 TCT TAC CTT AGA AAA TTG TGC ATT T ATG TTT TCT TTT GAA CAT CTT CTC T AAT GTT TTC TTT TGA ACA TCT TCT C TGA ATG TTT TCT TTT GAA CAT CTT C GTG AAT GTT TTC TTT TGA ACA TCT T SEQ ID NO:21 SEQ ID NO:25 SEQ ID NO:26 SEQ ID NO:27 SEQ ID NO:28 TAA AAA AAT AAA AGT TAG GAA GCA A SEQ ID NO:34 AAA AAT AAA AGT TAG GAA GCA ACT T SEQ ID NO:35 TGT TTT CTT TTG AAC ATC T SEQ ID NO:36 .

5. Modified antisense oligomer, according to claim 1, CHARACTERIZED in that the base sequence is selected from one of the following: SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, or SEQ ID NO:

35.

6. Modified antisense oligomer, according to claim 1, CHARACTERIZED in that the base sequence is selected from one of the following: SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28 or SEQ ID NO:

35.

7. Modified antisense oligomer, according to claim 1, CHARACTERIZED in that the base sequence is selected from one of the following: SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27 or SEQ ID NO:

28.

8. Modified antisense oligomer, according to claim 1, CHARACTERIZED in that the base sequence is selected from one of the following: SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 25 or SEQ ID NO:

28. Petition 870260074072, dated 07 / 24 / 2026, p. 219 / 448 5 / 11 9. Modified antisense oligomer, according to claim 1, CHARACTERIZED in that the base sequence is SEQ ID NO:

19.

10. Modified antisense oligomer, according to claim 1, CHARACTERIZED in that the base sequence of the annealing site is SEQ ID NO:

37.

11. Modified antisense oligomer, according to any one of claims 1 to 10, CHARACTERIZED in that T is thymine.

12. Modified antisense oligomer, according to any one of claims 1 to 11, CHARACTERIZED in that the nucleobases of the modified antisense oligomer are attached to morpholino ring structures.

13. Modified antisense oligomer, according to claim 12, CHARACTERIZED in that the morpholino ring structures are joined by phosphorus-containing intersubunit linkages that connect a morpholino nitrogen of one ring structure to a 5' exocyclic carbon of an adjacent ring structure.

14. Antisense oligomer CHARACTERIZED in that it conforms to Formula (I): Petition 870260074072, dated 07 / 24 / 2026, page 220 / 448 6 / 11 or a pharmaceutically acceptable salt thereof, wherein: each Nu is a nucleobase which together form a targeting sequence; T' in Formula (I) is a moiety selected from: r200 each R100 and R200 is independently hydrogen or a cell-penetrating peptide and R1 is C1-C6 alkyl; Each Nu from 1 to (n+1) and 5' to 3' corresponds to the nucleobases at one of the following: Annealing site H2.SA.(-20+05) H2.SA.(-14+11) H2.SA.(-11+14) H2.SA.(-08+17) H2.SA.(-05+20) H2.SA.(-02+23) H2.SA.(+02+26) H2.SA.(+05+29) H2.SA.(+08+32) H2.SA.(+11+35) H2.SA.(+14+38) H2.SA.(+17+41) H2.SA.(+20+44) H2.SA.(+23+47) H2.SA.(+26+50) H2.SA.(+29+53) H2.SA.(+32+56) H2.SA.(+35+59) H2.SA.(+38+62) H2.SD.(+22-03) H2.SD.(+19-06) H2.SD.(+16-09) H2.SD.(+13-12) Basic sequence [5' to 3'] TTC ATC TAA AAT GCA AAA TAA AAA A TTC TCT TTC ATC TAA AAT GCA AAA T ATC TTC TCT TTCATC TAA AAT GCA A AAC ATC TTC TCT TTC ATC TAA AAT G TTG AAC ATC TTC TCT TTC ATC TAA A CTT TTG AAC ATC TTC TCT TTC ATC T TTT CTT TTG AAC ATC TTC TCT TTC A TGT TTT CTT TTG AAC ATC TTC TCT T GAA TGT TTT CTT TTG AAC ATC TTC T TGT GAA TGT TTT CTT TTG AAC ATC T TTT TGT GAA TGT TTT CTT TTG AAC A CCA TTT TGT GAA TGT TTT CTT TTG A TAC CCA TTT TGT GAA TGT TTT CTT TTG A TAC CCA TTT TGT GAA TGT TTT C TGC ATT TAC CCA TTT TGT GAA TGT T TTG TGC ATT TAC CCA TTT TGT GAA T AAA TTG TGC ATT TAC CCA TTT TGT G AGA AAA TTG TGC ATT TAC CCA TTT TGT AGA AAA TTG TGC ATT TAC CCA T TAC CTT AGA AAA TTG TGC ATT TAC C TCT TAC CTT AGA AAA TTG TGC ATT T CAT TCT TAC CTT AGA AAA TTG TGC A AAC CAT TCT TAC CTT AGA AAA TTG T SEQ ID NO: SEQ ID NO:1 SEQ ID NO:2 SEQ ID NO:3 SEQ ID NO:4 SEQ ID NO:5 SEQ ID NO:6 SEQ ID NO:7 SEQ ID NO:8 SEQ ID NO:9 SEQ ID NO:10 SEQ ID NO:11 SEQ ID NO:12 SEQ ID NO:13 SEQ ID NO:14 SEQ ID NO:15 SEQ ID NO:16 SEQ ID NO:17 SEQ ID NO:18 SEQ ID NO:19 SEQ ID NO:20 SEQ ID NO:21 SEQ ID NO:22 SEQ ID NO:23Petição 870260074072, de 24 / 07 / 2026, pág. 221 / 448 7 / 11 H2.SD.(+10-15) H2A(+06+30) H2A(+07+31) H2A(+09+33) H2A(+10+34) H2A(-23+02) H2A(-26-02) H2A(-29-05) H2A(-32-08) H2A(-35-11) H2A(-38-14) H2A(-41-17) H2A(+11+29) H2D(+15-08) H2A(+46+62) H2D(+08-09) ACA AAC CAT TCT TAC CTT AGA AAA T ATG TTT TCT TTT GAA CAT CTT CTC T AAT GTT TTC TTT TGA ACA TCT TCT C TGA ATG TTT TCT TTT GAA CAT CTT C GTG AAT GTT TTC TTT TGA ACA TCT T ATC TAA AAT GCA AAA TAA AAA AAT A TAA AAT GCA AAA TAA AAA AAT AAA A AAT GCA AAA TAA AAA AAT AAA AGT T GCA AAA TAA AAA AAT AAA AGT TAG G SEQ ID NO:24 SEQ ID NO:25 SEQ ID NO:26 SEQ ID NO:27 SEQ ID NO:28 SEQ ID NO:29 SEQ ID NO:30 SEQ ID NO:31 SEQ ID NO:32 AAA TAA AAA AAT AAA AGT TAG GAA G SEQ ID NO:33 TAA AAA AAT AAA AGT TAG GAA GCA A SEQ ID NO:34 AAA AAT AAA AGT TAG GAA GCA ACT T SEQ ID NO:35 TGT TTT CTT TTG AAC ATC T SEQ IDNO:36 ATT CTT ACC TTA GAA AAT TGT GC SEQ ID NO:37 CTT AGA AAA TTG TGC AT SEQ IDNO:38 CAT TCT TAC CTT AGA AA SEQ IDNO:39 em que T é timina ou uracil.

15. Antisense oligomer according to claim 14, or a pharmaceutically acceptable salt thereof, CHARACTERIZED in that each Nu from 1 to (n+1) and 5' to 3' of Formula (I) corresponds to the nucleobases at one of the following: Annealing site H2.SA.(-20+05) H2.SA.(-14+11) H2.SA.(-11+14) H2.SA.(-08+17) H2.SA.(-05+20) H2.SA.(-02+23) H2.SA.(+02+26) H2.SA.(+05+29) H2.SA.(+08+32) H2.SA.(+11+35) H2.SA.(+14+38) H2.SA.(+17+41) H2.SA.(+20+44) H2.SA.(+23+47) H2.SA.(+26+50) H2.SA.(+29+53) H2.SA.(+32+56) H2.SA.(+35+59) H2.SD.(+22-03) H2.SD.(+19-06) H2.SD.(+16-09) H2.SD.(+13-12) H2.SD.(+10-15) H2A(+06+30) Base sequence [5' to 3'] TTC ATC TAA AAT GCA AAA TAA AAA A TTC TCT TTC ATC TAA AAT GCA AAA T ATC TTC TCT TTC ATC TAA AAT GCA A AAC ATC TTC TCT TTC ATC TAA AAT G TTG AAC ATC TTC TCT TTC ATC TAA A CTT TTG AAC ATC TTC TCT TTC ATC T TTT CTT TTG AAC ATC TTC TCT TTC A TGT TTT CTT TTG AAC ATC TTC TCT T GAA TGT TTT CTT TTG AAC ATC TTC T TGT GAA TGT TTT CTT TTG AAC ATC T TTT TGT GAA TGT TTT CTTTTG AAC A CCA TTT TGT GAA TGT TTT CTT TTG A TAC CCA TTT TGT GAA TGT TTT CTT T ATT TAC CCA TTT TGT GAA TGT TTT C TGC ATT TAC CCA TTT TGT GAA TGT T TTG TGC ATT TAC CCA TTT TGT GAA T AAA TTG TGC ATT TAC CCA TTT TAC CTT AGA AAA TTG TGC ATT TAC C TCT TAC CTT AGA AAA TTG TGC ATT T CAT TCT TAC CTT AGA AAA TTG TGC A AAC CAT TCT TAC CTT AGA AAA TTG T ACA AAC CAT TCT TAC CTT AGA AAA T ATG TTT TCT TTT GAA CAT CTT CTC T SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO: NO:1 NO:2 NO:3 NO:4 NO:5 NO:6 NO:7 NO:8 NO:9 NO:10 NO:11 NO:12 NO:13 NO:14 NO:15 NO:16 NO:17 NO:18 NO:20 NO:21 NO:22 NO:23 NO:24 NO:25 Petition 870260074072, de 24 / 07 / 2026, pág. 222 / 448 8 / 11 H2A(+07+31) H2A(+09+33) H2a(+10+34) H2A(-23+02) H2A(-26-02) H2A(-29-05) H2A(-32-08) H2A(-35-11) H2A(-38-14) H2A(-41-17) H2A(+11+29) H2A(+46+62) H2D(+08-09) AAT GTT TTC TTT TGA ACATCT TCT C TGA ATG TTT TCT TTT GAA CAT CTT C GTG AAT GTT TTC TTT TGA ACA TCT T ATC TAA AAT GCA AAA TAA AAA AAT A TAA AAT GCA AAA TAA AAA AAT AAA A AAT GCA AAA TAA AAA AAT AAA AGT T GCA AAA TAA AAA AAT AAA AGT TAG G AAA TAA AAA AAT AAA AGT TAG GAA G TAA AAA AAT AAA AGT TAG GAA GCA A AAA AAT AAA AGT TAG GAA GCA ACT T TGT TTT CTT TTG AAC ATC T CTT AGA AAA TTG TGC AT CAT TCT TAC CTT AGA AA SEQ ID NO:26 SEQ ID NO:27 SEQ ID NO:28 SEQ ID NO:29 SEQ ID NO:30 SEQ ID NO:31 SEQ ID NO:32 SEQ ID NO:33 SEQ ID NO:34 SEQ ID NO:35 SEQ ID NO:36 SEQ ID NO:38 SEQ ID NO:39 .

16. Antisense oligomer according to claim 14, or a pharmaceutically acceptable salt thereof, CHARACTERIZED in that each Nu from 1 to (n+1) and 5' to 3' of Formula (I) corresponds to the nucleobases at one of the following: Annulation site H2.SA.(-20+05) H2.SA.(-14+11) H2.SA.(-11+14) H2.SA.(-08+17) H2.SA.(-05+20) H2.SA.(-02+23) H2.SA.(+02+26) H2.SA.(+05+29) H2.SA.(+08+32) H2.SA.(+11+35) H2.SA.(+14+38) H2.SA.(+17+41) H2.SA.(+20+44) H2.SA.(+38+62) H2.SD.(+22-03) H2.SD.(+19-06) H2A(+06+30) H2A(+07+31) H2A(+09+33) H2A(+10+34) H2A(-38-14) H2A(-41-17) H2A(+11+29) Base sequence [5' to 3'] TTC ATC TAA AAT GCA AAA TAA AAA A TTC TCT TTC ATC TAA AAT GCA AAA T ATC TTC TCT TTC ATC TAA AAT GCA A AAC ATC TTC TCT TTC ATC TAA AAT G TTG AAC ATC TTC TCT TTC ATC TAA A CTT TTG AAC ATC TTC TCT TTC ATC T TTT CTT TTG AAC ATC TTC TCT TTC A TGT TTT CTT TTG AAC ATC TTC TCT T GAA TGT TTT CTT TTG AAC ATC TTC T TGT GAA TGT TTT CTT TTG AAC ATC T TTT TGT GAA TGT TTT CTT TTG AAC A CCA TTT TGT GAA TGTTTT CTT TTG A TAC CCA TTT TGT GAA TGT TTT CTT T CTT AGA AAA TTG TGC ATT TAC CCA T TAC CTT AGA AAA TTG TGC ATT TAC C TCT TAC CTT AGA AAA TTG TGC ATT T ATG TTT TCT TTT GAA CAT CTT CTC T AAT GTT TTC TTT TGA ACA TCT TCT C TGA ATG TTT TCT TTT GAA CAT CTT C GTG AAT GTT TTC TTT TGA ACA TCT T TAA AAA AAT AAA AGT TAG GAA GCA A AAA AAT AAA AGT TAG GAA GCA ACT T TGT TTT CTT TTG AAC ATC T SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID SEQ ID NO: NO:1 NO:2 NO:3 NO:4 NO:5 NO:6 NO:7 NO:8 NO:9 NO:10 NO:11 NO:12 NO:13 NO:19 NO:20 NO:21 NO:25 NO:26 NO:27 NO:28 NO:34 NO:35 SEQ ID NO:36 .

17. Antisense oligomer, according to claim 14, or a pharmaceutically acceptable salt thereof, CHARACTERIZED in that each Petition 870260074072, dated 07 / 24 / 2026, p. 223 / 448 9 / 11 Nu from 1 to (n+1) and 5' to 3' of Formula (I) corresponds to the nucleobases at one of the following: Annealing site H2.SA.(-20+05) H2.SA.(-14+11) H2.SA.(-11+14) H2.SA.(-08+17) H2.SA.(-05+20) H2.SA.(-02+23) H2.SA.(+02+26) H2.SA.(+05+29) H2.SA.(+08+32) H2.SA.(+11+35) H2.SA.(+14+38) H2.SA.(+17+41) H2.SA.(+20+44) H2.SD.(+22-03) H2.SD.(+19-06) H2A(+06+30) H2A(+07+31) H2A(+09+33) H2A(+10+34) H2a(-38-14) H2A(-41-17) H2A(+11+29) Base sequence [5' to 3'] TTC ATC TAA AAT GCA AAA TAA ATC TTC TCT T GAA TGT TTT CTT TTG AAC ATC TTC T TGT GAA TGT TTT CTT TTG AAC ATC T TTT TGT GAA TGTTTT CTT TTG AAC A CCA TTT TGT GAA TGT TTT CTT TTG A TAC CCA TTT TGT GAA TGT TTT CTT T TAC CTT AGA AAA TTG TGC ATT TAC C TCT TAC CTT AGA AAA TTG TGC ATT T ATG TTT TCT TTT GAA CAT CTT CTC T AAT GTT TTC TTT TGA ACA TCT TCT C TGA ATG TTT TCT TTT GAA CAT CTT C GTG AAT GTT TTC TTT TGA ACA TCT T TAA AAA AAT AAA AGT TAG GAA GCA A AAA AAT AAA AGT TAG GAA GCA ACT T TGT TTT CTT TTG AAC ATC T SEQ ID NO: SEQ ID NO:1 SEQ ID NO:2 SEQ ID NO:3 SEQ ID NO:4 SEQ ID NO:5 SEQ ID NO:6 SEQ ID NO:7 SEQ ID NO:8 SEQ ID NO:9 SEQ ID NO:10 SEQ ID NO:11 SEQ ID NO:12 SEQ ID NO:13 SEQ ID NO:20 SEQ ID NO:21 SEQ ID NO:25 SEQ ID NO:26 SEQ ID NO:27 SEQ ID NO:28 SEQ ID NO:34 SEQ ID NO:35 SEQ ID NO:36 .

18. Antisense oligomer according to claim 14, CHARACTERIZED in that each Nu from 1 to (n+1) and 5' to 3' of Formula (I) corresponds to one of the following: SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28 or SEQ ID NO:

35.

19. Antisense oligomer according to claim 14, CHARACTERIZED in that each Nu from 1 to (n+1) and 5' to 3' of Formula (I) corresponds to one of the following: SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28 or SEQ ID NO:

35. Petition 870260074072, dated 07 / 24 / 2026, p. 224 / 448 10 / 11 20. Antisense oligomer according to claim 14, CHARACTERIZED in that each Nu from 1 to (n+1) and 5' to 3' of Formula (I) corresponds to one of the following: SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27 or SEQ ID NO:

28.

21. Antisense oligomer according to claim 14, CHARACTERIZED in that each Nu from 1 to (n+1) and 5' to 3' of Formula (I) corresponds to one of the following: SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 25 or SEQ ID NO:

28.

22. Antisense oligomer, according to claim 14, CHARACTERIZED in that each Nu from 1 to (n+1) and 5' to 3' of Formula (I) corresponds to the nucleobases in SEQ ID NO:

19.

23. Antisense oligomer, according to claim 14, CHARACTERIZED in that each Nu from 1 to (n+1) and 5' to 3' of Formula (I) corresponds to the nucleobases in SEQ ID NO:

37.

24. Antisense oligomer, according to any one of claims 14 to 23, CHARACTERIZED in that T is thymine.

25. Antisense oligomer, according to any one of claims 14 to 24, CHARACTERIZED in that: T' is Petition 870260074072, dated 07 / 24 / 2026, page 225 / 448 11 / 11 26. Use of an oligomer, as defined in any one of claims 1 to 25, CHARACTERIZED in that it is for the manufacture of a medicament for the treatment of Duchenne muscular dystrophy.