Compositions and methods for modulating splicing and protein expression

Abstract

Alternative splicing events can lead to non-productive mRNA transcripts which in turn can lead to aberrant protein expression, and therapeutic agents which can target the alternative splicing events in genes can modulate the expression level of functional proteins in diseased patients and / or inhibit aberrant protein expression. Described herein are therapeutic agents and methods that can be used to treat a condition caused by these alternative splicing events.

Description

CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 62 / 888,887, filed August 19, 2019, and U.S. Provisional Application No. 63 / 049,262, filed July 08, 2020, each of which is incorporated herein by reference in its entirety. REFERENCE TO SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on August 19, 2020, is named 47991-727_601_SL.txt and is 17,694,293 bytes in size. BACKGROUND

[0003] Alternative splicing events in genes can lead to non-productive or less productive mRNA transcripts, and therapeutic agents which can target the alternative splicing events in genes can modulate the expression level of functional proteins in patients and / or inhibit aberrant protein expression. Such therapeutic agents can be used to treat a condition or disease caused by protein deficiency. SUMMARY

[0004] In some aspects, provided herein is a composition comprising a non-sense mediated RNA decay alternative exon (NSAE)-modulating agent that interacts with a target motif within a pre-processed mRNA transcript to modulate exclusion of an NSAE from a processed mRNA transcript and to modulate inclusion of a canonical exon in the processed mRNA transcript, wherein the target motif is located (i) in an intronic region between two canonical exons, (ii) in one of the two canonical exons, or (iii) in a region spanning both an intron and canonical exon; and wherein the NSAE comprises (i) only a portion of a canonical exon, or (ii) a canonical exon and at least a portion of an intron adjacent to the canonical exon; wherein the NSAE-modulating agent modulates exclusion of an NSAE from the processed mRNA transcript and modulates inclusion of a canonical exon in the processed mRNA transcript.

[0005] In some aspects, provided herein is a composition comprising a non-sense mediated RNA decay alternative exon (NSAE)-modulating agent that modulates expression of a target protein in a cell comprising a pre-processed mRNA transcript (pre-mRNA) that encodes the target protein and comprises: an alternative nonsense mediated RNA decay-inducing (NMD) exon comprising an alternative 5’ splice site downstream of the 5’ splice site of a canonical exon and within the canonical exon, or upstream of the 5’ splice site of the canonical exon and within an intron, wherein the NSAE-modulating agent modulates processing of an mRNA transcript from the pre-processed mRNA transcript by modulating splicing of the pre-mRNA at the 5’ alternative splice site, wherein the splicing of the pre-mRNA at the 5’ alternative splice site modulates the expression of the target protein in a cell. 2020334067   16 Jul 2026

[0006] In some aspects, provided herein is a composition comprising a non-sense mediated RNA decay alternative exon (NSAE)-modulating agent that modulates expression of a target protein in a cell comprising a pre-processed mRNA transcript (pre-mRNA) that encodes the target protein and comprises: an alternative nonsense mediated RNA decay-inducing (NMD) exon comprising an alternative 3’ splice site upstream of the 3’ splice site of a canonical exon and within the canonical exon, or downstream of the 3’ splice site of the canonical exon and within an intron, wherein the NSAE-modulating agent modulates processing of an mRNA transcript from the pre-processed mRNA transcript by modulating splicing of the pre-mRNA at the 3’ alternative splice site, and wherein the splicing of the pre-mRNA at the 3’ alternative splice site modulates the expression of the target protein in a cell.

[0007] In some aspects, provided herein is a composition comprising a non-sense mediated RNA decay alternative 5’ or 3’ splice site (NSASS)-modulating agent that interacts with a target motif within a preprocessed mRNA transcript to modulate splicing at an alternative 5’ or 3’ splice site of a pre-processed mRNA transcript and to modulate inclusion of a canonical exon in a processed mRNA transcript that is processed from the pre-processed mRNA transcript, wherein the target motif is located in an intronic region between two canonical exons, in one of the two canonical exons, or in a region spanning both an intron and canonical exon; wherein modulating splicing at the alternative 5’ or 3’ splice site of the preprocessed mRNA transcript modulates exclusion of an alternative exon from the processed mRNA transcript, wherein the alternative exon comprises only a portion of a canonical exon, or a canonical exon and at least a portion of an intron adjacent to the canonical exon; and wherein the NSASS-modulating agent modulates exclusion of the alternative exon from the processed mRNA transcript and modulates inclusion of a canonical exon in the processed mRNA transcript.

[0008] In some aspects, provided herein is a composition comprising a non-sense mediated RNA decay alternative 5’ or 3’ splice site (NSASS)-modulating agent that modulates expression of a target protein in a cell comprising a pre-processed mRNA transcript (pre-mRNA) that encodes the target protein, wherein the pre-mRNA comprises an alternative exon comprising an alternative 5’ splice site downstream of the 5’ splice site of a canonical exon and within the canonical exon, or upstream of the 5’ splice site of the canonical exon and within an intron; wherein the NSASS-modulating agent modulates processing of an mRNA transcript from the pre-processed mRNA transcript by modulating splicing of the pre-mRNA at the 5’ alternative splice site, wherein the splicing of the pre-mRNA at the 5’ alternative splice site modulates the expression of the target protein in a cell.

[0009] In some aspects, provided herein is a composition comprising a non-sense mediated RNA decay alternative exon (NSASS)-modulating agent that modulates expression of a target protein in a cell comprising a pre-processed mRNA transcript (pre-mRNA) that encodes the target protein, wherein the pre-mRNA comprises an alternative exon comprising an alternative 3’ splice site upstream of the 3’ splice site of a canonical exon and within the canonical exon, or downstream of the 3’ splice site of the canonical exon and within an intron, wherein the NSASS-modulating agent modulates processing of an mRNA transcript from the pre-processed mRNA transcript by modulating splicing of the pre-mRNA at the 3’ 2020334067   16 Jul 2026 alternative splice site, and wherein the splicing of the pre-mRNA at the 3’ alternative splice site modulates the expression of the target protein in a cell.

[0010] In some embodiments, the agent is a small molecule. In some embodiments the agent is a polypeptide. In some embodiments, the polypeptide is a nucleic acid binding protein. In some embodiments, the nucleic acid binding protein contains a TAL-effector or zinc finger binding domain. In some embodiments, the nucleic acid binding protein is a Cas family protein. In some embodiments, the polypeptide is accompanied by or complexed with one or more nucleic acid molecules. In some embodiments, the Agent is an antisense oligomer (ASO) complementary to the targeted region of the pre-mRNA. In some embodiments, the Agent is at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, complementary to the targeted region of the pre-mRNA encoding the target protein. In some embodiments, the Agent is an antisense oligomer, and wherein the Agent comprises a backbone modification comprising a phosphorothioate linkage or a phosphorodiamidate linkage. In some embodiments, the Agent is an antisense oligomer, and wherein the Agent comprises a phosphorodiamidate morpholino. In some embodiments, the Agent is an antisense oligomer, and wherein the Agent comprises a locked nucleic acid. In some embodiments, the Agent is an antisense oligomer, and wherein the Agent comprises a peptide nucleic acid. In some embodiments, the Agent is an antisense oligomer, and wherein the Agent comprises a 2'- O-methyl. In some embodiments, the Agent is an antisense oligomer, and wherein the Agent comprises a 2'-Fluoro, or a 2'-O-methoxyethyl moiety. In some embodiments, the Agent is an antisense oligomer, and wherein the Agent comprises at least one modified sugar moiety. In some embodiments, each sugar moiety is a modified sugar moiety. In some embodiments, the Agent is an antisense oligomer, and wherein the Agent consists of from 8 to 50 nucleobases, 8 to 40 nucleobases, 8 to 35 nucleobases, 8 to 30 nucleobases, 8 to 25 nucleobases, 8 to 20 nucleobases, 8 to 15 nucleobases, 9 to 50 nucleobases, 9 to 40 nucleobases, 9 to 35 nucleobases, 9 to 30 nucleobases, 9 to 25 nucleobases, 9 to 20 nucleobases, 9 to 15 nucleobases, 10 to 50 nucleobases, 10 to 40 nucleobases, 10 to 35 nucleobases, 10 to 30 nucleobases, 10 to 25 nucleobases, 10 to 20 nucleobases, 10 to 15 nucleobases, 11 to 50 nucleobases, 11 to 40 nucleobases, 11 to 35 nucleobases, 11 to 30 nucleobases, 11 to 25 nucleobases, 11 to 20 nucleobases, 11 to 15 nucleobases, 12 to 50 nucleobases, 12 to 40 nucleobases, 12 to 35 nucleobases, 12 to 30 nucleobases, 12 to 25 nucleobases, 12 to 20 nucleobases, or 12 to 15 nucleobases. Described herein, in some aspects, is a composition of a nucleic acid molecule that encodes for the NSAE-modulating agent. In some embodiments, the nucleic acid molecule is incorporated into a viral delivery system. In some embodiments, the viral delivery system is an adenovirus-associated vector.

[0011] In some aspects, provided herein is a method of modulating protein expression, comprising: (a) contacting a non-sense mediated RNA decay alternative exon (NSAE)-modulating agent to a target motif within a pre-processed mRNA transcript, wherein the NSAE comprises (i) only a portion of a canonical exon, or (ii) a canonical exon and at least a portion of an intron adjacent to the canonical exon; (b) processing a mRNA transcript from the pre-processed mRNA transcript thereby forming a processed mRNA transcript, wherein the NSAE-modulating agent modulates exclusion of an NSAE from the 2020334067   16 Jul 2026 processed mRNA transcript and modulates inclusion of the canonical exon in the processed mRNA transcript; and (c) translating the processed mRNA transcript wherein the exclusion of the NSAE and inclusion of the canonical exon modulates protein expression relative to the protein expression of an equivalent mRNA transcript comprising the NSAE instead of the canonical exon. In some embodiments, the target motif is located in an intronic region between two canonical exons. In some embodiments, the target motif is located in one of the two canonical exons. In some embodiments, the target motif is located in a region spanning both an intron and a canonical exon.

[0012] In some aspects, provided herein is a method of modulating expression of a target protein by a cell having a pre-processed mRNA transcript (pre-mRNA) that encodes the target protein and comprises: an alternative nonsense mediated RNA decay-inducing (NMD) exon comprising an alternative 3’ splice site upstream of the 3’ splice site of a canonical exon and within the canonical exon, or downstream of the 3’ splice site of the canonical exon and within an intron, the method comprising contacting a non-sense mediated RNA decay alternative exon (NSAE)-modulating agent to the cell, wherein the non-sense mediated RNA decay alternative exon (NSAE)-modulating agent modulates processing of an mRNA transcript from the pre-processed mRNA transcript by modulating splicing of the pre-mRNA at the 3’ alternative splice site, and wherein the splicing of the pre-mRNA at the 3’ alternative splice site modulates the expression of the target protein.

[0013] In some aspects, provided herein is a method of modulating expression of a target protein by a cell having a pre-processed mRNA transcript (pre-mRNA) that encodes the target protein and comprises: an alternative nonsense mediated RNA decay-inducing (NMD) exon comprising an alternative 5’ splice site downstream of the 5’ splice site of a canonical exon and within the canonical exon, or upstream of the 5’ splice site of the canonical exon and within an intron, the method comprising contacting a non-sense mediated RNA decay alternative exon (NSAE)-modulating agent to the cell, wherein the non-sense mediated RNA decay alternative exon (NSAE)-modulating agent modulates processing of an mRNA transcript from the pre-processed mRNA transcript by modulating splicing of the pre-mRNA at the 5’ alternative splice site, and wherein the splicing of the pre-mRNA at the 5’ alternative splice site modulates the expression of the target protein.

[0014] In some embodiments, the non-sense mediated RNA decay alternative exon (NSAE)-modulating agent binds to a targeted portion of the pre-processed mRNA transcript. In some embodiments, the wherein the non-sense mediated RNA decay alternative exon (NSAE)-modulating agent binds to a factor involved in splicing of the NSAE or NMD exon. In some embodiments, the wherein the non-sense mediated RNA decay alternative exon (NSAE)-modulating agent inhibits activity of a factor involved in splicing of the NMD exon. In some embodiments, the wherein the non-sense mediated RNA decay alternative exon (NSAE)-modulating agent interferes with binding of a factor involved in splicing of the NMD exon to a region of the targeted portion of the pre-processed mRNA transcript. In some embodiments, modulation of splicing of the pre-mRNA increases the expression of the target protein. In some embodiments, the level the target protein in the cell is increased about 1.1 to about 10-fold, about 1.5 to about 10-fold, about 2 to about 10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1 2020334067   16 Jul 2026 to about 5-fold, about 1.1 to about 6- fold, about 1.1 to about 7-fold, about 1.1 to about 8-fold, about 1.1 to about 9-fold, about 2 to about 5-fold, about 2 to about 6-fold, about 2 to about 7-fold, about 2 to about 8-fold, about 2 to about 9-fold, about 3 to about 6-fold, about 3 to about 7-fold, about 3 to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold, about 4 to about 8-fold, about 4 to about 9-fold, at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 5-fold, or at least about 10-fold, compared to the level of processed mRNA encoding the target protein in a control cell. In some embodiments, modulation of splicing of the pre-mRNA increases production of the processed mRNA encoding the target protein. In some embodiments, the level of processed mRNA encoding the target protein in the cell contacted with the therapeutic agent is increased about 1.1 to about 10-fold, about 1.5 to about 10-fold, about 2 to about 10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1 to about 5-fold, about 1.1 to about 6fold, about 1.1 to about 7-fold, about 1.1 to about 8-fold, about 1.1 to about 9-fold, about 2 to about 5fold, about 2 to about 6-fold, about 2 to about 7-fold, about 2 to about 8-fold, about 2 to about 9-fold, about 3 to about 6-fold, about 3 to about 7-fold, about 3 to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold, about 4 to about 8-fold, about 4 to about 9-fold, at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 5-fold, or at least about 10-fold, compared to the level of processed mRNA encoding the target protein in a control cell. In some embodiments, the target protein is the canonical isoform of the protein. In some embodiments, the target protein is SynGAP1. In some embodiments, the target protein is any one selected from the group consisting of ABCA5, ABCA7, ABCC3, ABCC5, ABCC8, ABCD1, ABR, ACAD9, ACAP1, ACOX2, ACSF3, ACTN4, ADAM17, ADAMTS13, AKR1E2, ALAD, ALG3, ANKRD29, ANKS3, ANO4, AP3B2, AP3M1, AP5Z1, ARNTL, ASAP3, ATRX, BBS2, BBS4, BRD9, CALM3, CARS1, CASP9, CATSPER1, CCDC40, CCDC88B, CD4, CD58, CES2, CHFR, CLCN2, CNOT3, CNTROB, COL5A3, CPSF1, CSPP1, CTF1, CTH, CYP3A5, DAB2IP, DBN1, DDX51, DEAF1, DGKE, DHDDS, DMKN, DNHD1, DOCK8, DOK5, EIF2B5, ELAC2, ELP1, ENTPD4, ESRRA, ESS2, ETAA1, ETHE1, FANCA, FASTK, FASTKD3, FPGS, FREM1, GAS8, GCK, GGA1, GGA3, GGT1, GLMN, GON4L, GRB14, HDAC3, HELQ, HP1BP3, HPS1, HPS4, IDUA, IFT122, IL17RC, IMPDH1, INVS, IRF3, KCTD3, KLKB1, KYAT1, LAMC3, LDAH, LIMS2, MALT1, MAP3K7, MAPK13, MCAT, MCEE, MPI, MSTO1, NBEAL2, NLE1, NLRC5, NOM1, NOP58, NPHP1, NPR1, NUP188, OSGEP, PABPC4, PCOLCE, PHKA2, PIDD1, PKD1, PLA2G6, PLD2, PLEKHG5, PNPO, POLE, PON2, PRMT7, PRODH, PRPF3, PRPF4, PYCR1, RAD52, REXO1, RFX5, RHBDF2, RMND1, ROBO3, RPGRIP1, RTTN, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIK3, SIRT3, SKIV2L, SLC2A13, SLC12A7, SLC22A3, SLC25A13, SLC25A37, SLC27A5, SLC30A9, SLC30A10, SMPD1, SMTN, SNRPB, SP140, STAMBP, STXBP2, SULF2, SYNGAP1, SYNJ2, TAZ, TBL2, TDRD7, TECPR2, TFB1M, TM6SF1, TNK2, TOE1, TOR1B, TRAPPC6B, TRIP4, TRMT2A, TRMU, TRPV4, TTC19, TYMP, UMPS, UROD, WDR11, WDR62, WIPI1, WRAP53, XPO1, YY1AP1, and ZC3H14. In some embodiments, the non-sense mediated RNA decay alternative exon (NSAE)-modulating agent is a composition described herein. 2020334067   16 Jul 2026

[0015] In some aspects, provided herein is a pharmaceutical composition comprising: a therapeutic agent comprising a composition described herein; and a pharmaceutically acceptable excipient and / or a delivery vehicle.

[0016] In some aspects, provided herein is a method of treating or preventing a disease or condition in a subject in need thereof, the method comprising: administering to the subject a pharmaceutical composition described herein.

[0017] In some aspects, provided herein is a method of treating or preventing a disease or condition in a subject in need thereof, the method comprising: administering to the subject a pharmaceutical composition comprising: (a) a non-sense mediated RNA decay alternative exon (NSAE)-modulating agent that interacts with a target motif within a pre-processed mRNA transcript to modulate exclusion of an NSAE from a processed mRNA transcript and to modulate inclusion of a canonical exon in the processed mRNA transcript, wherein the NSAE comprises (i) only a portion of a canonical exon, or (ii) a canonical exon and at least a portion of an intron adjacent to the canonical exon; and (b) a pharmaceutically acceptable excipient and / or a delivery vehicle, wherein the disease or condition is treated or prevented in the subject by the administration of the NSAE-modulating agent by a modulation in expression of a protein translated from the processed mRNA transcript.

[0018] In some aspects, provided herein is a method of treating a disease or condition in a subject in need thereof by modulating expression of a target protein in a cell of the subject, wherein the cell of the subject has a pre-processed mRNA transcript (pre-mRNA) that encodes the target protein and comprises: (a) an exon followed by an intron flanking a 3’ splice site of the exon; and (b) an alternative nonsense mediated RNA decay-inducing (NMD) exon comprising an alternative 3’ splice site upstream of the 3’ splice site of the exon and within the exon, or downstream of the 3’ splice site of the exon and within the intron, the method comprising contacting a therapeutic agent to the cell, wherein the therapeutic agent modulates processing of an mRNA transcript from the pre-processed mRNA transcript by modulating splicing of the pre-mRNA at the 3’ alternative splice site, and wherein the splicing of the pre-mRNA at the 3’ alternative splice site modulates the expression of the target protein in the cell of the subject.

[0019] In some aspects, provided herein is a method of treating a disease or condition in a subject in need thereof by modulating expression of a target protein in a cell of the subject, wherein the cell of the subject has a pre-processed mRNA transcript (pre-mRNA) that encodes the target protein and comprises: (a) an exon preceded by an intron flanking a 5’ splice site of the exon; and (b) an alternative nonsense mediated RNA decay-inducing (NMD) exon comprising an alternative 5’ splice site downstream of the 5’ splice site of the exon and within the exon, or upstream of the 5’ splice site of the exon and within the intron, the method comprising contacting a therapeutic agent to the cell, wherein the therapeutic agent modulates processing of an mRNA transcript from the pre-processed mRNA transcript by modulating splicing of the pre-mRNA at the 5’ alternative splice site, and wherein the splicing of the pre-mRNA at the 5’ alternative splice site modulates the expression of the target protein in the cell of the subject.

[0020] In some embodiments the disease is autosomal dominant mental retardation, epileptic encephalopathy, or autism. In some embodiments, the disease or the condition is caused by a deficient 2020334067   16 Jul 2026 amount or activity of the target protein. In some embodiments, the therapeutic agent increases the level of the processed mRNA encoding the target protein in the cell. In some embodiments, the therapeutic agent increases the expression of the target protein in the cell. In some embodiments, the level of processed mRNA encoding the target protein in the cell contacted with the therapeutic agent is increased about 1.1 to about 10-fold, about 1.5 to about 10-fold, about 2 to about 10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1 to about 5-fold, about 1.1 to about 6- fold, about 1.1 to about 7-fold, about 1.1 to about 8-fold, about 1.1 to about 9-fold, about 2 to about 5-fold, about 2 to about 6-fold, about 2 to about 7-fold, about 2 to about 8-fold, about 2 to about 9-fold, about 3 to about 6-fold, about 3 to about 7-fold, about 3 to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold, about 4 to about 8-fold, about 4 to about 9-fold, at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 5-fold, or at least about 10fold, compared to the level of processed mRNA encoding the target protein in a control cell. In some embodiments, the level the target protein in the cell is increased about 1.1 to about 10-fold, about 1.5 to about 10-fold, about 2 to about 10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1 to about 5-fold, about 1.1 to about 6- fold, about 1.1 to about 7-fold, about 1.1 to about 8-fold, about 1.1 to about 9-fold, about 2 to about 5-fold, about 2 to about 6-fold, about 2 to about 7-fold, about 2 to about 8fold, about 2 to about 9-fold, about 3 to about 6-fold, about 3 to about 7-fold, about 3 to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold, about 4 to about 8-fold, about 4 to about 9-fold, at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 5-fold, or at least about 10-fold, compared to the level of processed mRNA encoding the target protein in a control cell. In some embodiments, the method further comprises assessing mRNA levels or expression levels of the target protein. In some embodiments, the method further comprises assessing the subject’s genome for at least one genetic mutation associated with the disease.

[0021] In some embodiments, the disease or the condition is caused by an excess amount or activity of the target protein. In some embodiments, the therapeutic agent decreases the level of the processed mRNA encoding the target protein in the cell. In some embodiments, the therapeutic agent decreases the expression of the target protein in the cell. In some embodiments, the level of processed mRNA encoding the target protein in the cell contacted with the therapeutic agent is decreased about 1.1 to about 10-fold, about 1.5 to about 10-fold, about 2 to about 10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1 to about 5-fold, about 1.1 to about 6- fold, about 1.1 to about 7-fold, about 1.1 to about 8-fold, about 1.1 to about 9-fold, about 2 to about 5-fold, about 2 to about 6-fold, about 2 to about 7-fold, about 2 to about 8-fold, about 2 to about 9-fold, about 3 to about 6-fold, about 3 to about 7-fold, about 3 to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold, about 4 to about 8-fold, about 4 to about 9-fold, at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3fold, at least about 3.5-fold, at least about 4-fold, at least about 5-fold, or at least about 10-fold, compared to the level of processed mRNA encoding the target protein in a control cell. In some embodiments, the level the target protein in the cell is decreased about 1.1 to about 10-fold, about 1.5 to about 10-fold, about 2020334067   16 Jul 2026 2 to about 10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1 to about 5-fold, about 1.1 to about 6- fold, about 1.1 to about 7-fold, about 1.1 to about 8-fold, about 1.1 to about 9-fold, about 2 to about 5-fold, about 2 to about 6-fold, about 2 to about 7-fold, about 2 to about 8-fold, about 2 to about 9fold, about 3 to about 6-fold, about 3 to about 7-fold, about 3 to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold, about 4 to about 8-fold, about 4 to about 9-fold, at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 5-fold, or at least about 10-fold, compared to the level of processed mRNA encoding the target protein in a control cell.

[0022] In some embodiments, at least one genetic mutation is within a locus of a gene associated with the disease. In some embodiments, at least one genetic mutation is within a locus associated with expression of a gene associated with the disease. In some embodiments, at least one genetic mutation is within the SYNGAP1 gene locus. In some embodiments, at least one genetic mutation is within a locus associated with SYNGAP1 gene expression. In some embodiments, at least one genetic mutation is within a target gene locus, wherein the target gene locus is any one selected from the group consisting of ABCA5, ABCA7, ABCC3, ABCC5, ABCC8, ABCD1, ABR, ACAD9, ACAP1, ACOX2, ACSF3, ACTN4, ADAM17, ADAMTS13, AKR1E2, ALAD, ALG3, ANKRD29, ANKS3, ANO4, AP3B2, AP3M1, AP5Z1, ARNTL, ASAP3, ATRX, BBS2, BBS4, BRD9, CALM3, CARS1, CASP9, CATSPER1, CCDC40, CCDC88B, CD4, CD58, CES2, CHFR, CLCN2, CNOT3, CNTROB, COL5A3, CPSF1, CSPP1, CTF1, CTH, CYP3A5, DAB2IP, DBN1, DDX51, DEAF1, DGKE, DHDDS, DMKN, DNHD1, DOCK8, DOK5, EIF2B5, ELAC2, ELP1, ENTPD4, ESRRA, ESS2, ETAA1, ETHE1, FANCA, FASTK, FASTKD3, FPGS, FREM1, GAS8, GCK, GGA1, GGA3, GGT1, GLMN, GON4L, GRB14, HDAC3, HELQ, HP1BP3, HPS1, HPS4, IDUA, IFT122, IL17RC, IMPDH1, INVS, IRF3, KCTD3, KLKB1, KYAT1, LAMC3, LDAH, LIMS2, MALT1, MAP3K7, MAPK13, MCAT, MCEE, MPI, MSTO1, NBEAL2, NLE1, NLRC5, NOM1, NOP58, NPHP1, NPR1, NUP188, OSGEP, PABPC4, PCOLCE, PHKA2, PIDD1, PKD1, PLA2G6, PLD2, PLEKHG5, PNPO, POLE, PON2, PRMT7, PRODH, PRPF3, PRPF4, PYCR1, RAD52, REXO1, RFX5, RHBDF2, RMND1, ROBO3, RPGRIP1, RTTN, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIK3, SIRT3, SKIV2L, SLC2A13, SLC12A7, SLC22A3, SLC25A13, SLC25A37, SLC27A5, SLC30A9, SLC30A10, SMPD1, SMTN, SNRPB, SP140, STAMBP, STXBP2, SULF2, SYNGAP1, SYNJ2, TAZ, TBL2, TDRD7, TECPR2, TFB1M, TM6SF1, TNK2, TOE1, TOR1B, TRAPPC6B, TRIP4, TRMT2A, TRMU, TRPV4, TTC19, TYMP, UMPS, UROD, WDR11, WDR62, WIPI1, WRAP53, XPO1, YY1AP1, and ZC3H14 gene locus. In some embodiments, at least one genetic mutation is within a locus associated with a target gene expression, wherein the target gene is any one selected from the group consisting of ABCA5, ABCA7, ABCC3, ABCC5, ABCC8, ABCD1, ABR, ACAD9, ACAP1, ACOX2, ACSF3, ACTN4, ADAM17, ADAMTS13, AKR1E2, ALAD, ALG3, ANKRD29, ANKS3, ANO4, AP3B2, AP3M1, AP5Z1, ARNTL, ASAP3, ATRX, BBS2, BBS4, BRD9, CALM3, CARS1, CASP9, CATSPER1, CCDC40, CCDC88B, CD4, CD58, CES2, CHFR, CLCN2, CNOT3, CNTROB, COL5A3, CPSF1, CSPP1, CTF1, CTH, CYP3A5, DAB2IP, DBN1, DDX51, DEAF1, DGKE, DHDDS, DMKN, DNHD1, DOCK8, DOK5, EIF2B5, ELAC2, ELP1, ENTPD4, 2020334067   16 Jul 2026 ESRRA, ESS2, ETAA1, ETHE1, FANCA, FASTK, FASTKD3, FPGS, FREM1, GAS8, GCK, GGA1, GGA3, GGT1, GLMN, GON4L, GRB14, HDAC3, HELQ, HP1BP3, HPS1, HPS4, IDUA, IFT122, IL17RC, IMPDH1, INVS, IRF3, KCTD3, KLKB1, KYAT1, LAMC3, LDAH, LIMS2, MALT1, MAP3K7, MAPK13, MCAT, MCEE, MPI, MSTO1, NBEAL2, NLE1, NLRC5, NOM1, NOP58, NPHP1, NPR1, NUP188, OSGEP, PABPC4, PCOLCE, PHKA2, PIDD1, PKD1, PLA2G6, PLD2, PLEKHG5, PNPO, POLE, PON2, PRMT7, PRODH, PRPF3, PRPF4, PYCR1, RAD52, REXO1, RFX5, RHBDF2, RMND1, ROBO3, RPGRIP1, RTTN, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIK3, SIRT3, SKIV2L, SLC2A13, SLC12A7, SLC22A3, SLC25A13, SLC25A37, SLC27A5, SLC30A9, SLC30A10, SMPD1, SMTN, SNRPB, SP140, STAMBP, STXBP2, SULF2, SYNGAP1, SYNJ2, TAZ, TBL2, TDRD7, TECPR2, TFB1M, TM6SF1, TNK2, TOE1, TOR1B, TRAPPC6B, TRIP4, TRMT2A, TRMU, TRPV4, TTC19, TYMP, UMPS, UROD, WDR11, WDR62, WIPI1, WRAP53, XPO1, YY1AP1, and ZC3H14 genes. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. In some embodiments, the subject is a fetus, an embryo, or a child. In some embodiments, the cell or the cells is ex vivo, or in a tissue, or organ ex vivo. In some embodiments, the therapeutic agent is administered to the subject by intracerebroventricular injection, intraperitoneal injection, intramuscular injection, intrathecal injection, subcutaneous injection, oral administration, synovial injection, intravitreal administration, subretinal injection, topical application, implantation, or intravenous injection.

[0023] In some aspects, provided herein is a therapeutic agent for use in a method described herein.

[0024] In some aspects, provided herein is a pharmaceutical composition comprising a therapeutic agent described herein and a pharmaceutically acceptable excipient.

[0025] In some aspects, provided herein is a method of treating a subject in need thereof, comprising administering a pharmaceutical composition described herein by intracerebroventricular injection, intraperitoneal injection, intramuscular injection, intrathecal injection, subcutaneous injection, oral administration, synovial injection, intravitreal administration, subretinal injection, topical application, implantation, or intravenous injection to the subject. [0025A] In some aspects, provided herein is a composition comprising a non-sense mediated RNA decay alternative exon (NSAE)-modulating agent that interacts with a target motif within a pre-processed mRNA transcript that encodes a target protein to modulate splicing at an alternative 3’ splice site of an intron in the pre-processed mRNA transcript, thereby promoting inclusion of a canonical exon in a processed mRNA transcript that is processed from the pre-processed mRNA transcript, and promoting exclusion of an alternative exon from the pre-processed mRNA transcript; wherein the target motif is located: (i) in the intron between two canonical exons, (ii) in one of the two canonical exons, or (iii) in a region spanning both the intron and one of the canonical exons; and wherein the alternative exon comprises: (1) only a portion of a canonical exon, or (2) a canonical exon and at least a portion of an intron upstream of the canonical exon and adjacent to the canonical exon; wherein the target protein is SYNGAP1; and wherein the target motif comprises a sequence with at least 90% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NOs: 166-169 and 980-983. 2020334067   16 Jul 2026 [0025B] In some aspects, provided herein is a method of modulating expression of a target protein in a cell, comprising contacting a non-sense mediated RNA decay alternative exon (NSAE)-modulating agent with the cell, wherein the NSAE-modulating agent interacts with a target motif within a pre-processed mRNA transcript that encodes the target protein to modulate splicing at an alternative 3’ splice site of the pre-processed mRNA transcript, thereby promoting inclusion of a canonical exon in a processed mRNA transcript that is processed from the pre-processed mRNA transcript, and promoting exclusion of an alternative exon from the pre-processed mRNA transcript, wherein the alternative exon comprises a canonical exon and at least a portion of an intron upstream of the canonical exon and adjacent to the canonical exon; wherein the target protein is SYNGAP1; and wherein the target motif comprises a sequence with at least 90% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NOs: 166-169 and 980-983. [0025C] In some aspects, provided herein is a method A method of treating or preventing a disease or condition in a subject in need thereof, the method comprising: administering to the subject a pharmaceutical composition comprising: (a) a non-sense mediated RNA decay alternative exon (NSAE)-modulating agent that interacts with a target motif within a pre-processed mRNA transcript that encodes a target protein to modulate splicing at an alternative 3’ splice site of the pre-processed mRNA transcript, thereby promoting inclusion of a canonical exon in a processed mRNA transcript that is processed from the pre-processed mRNA transcript, and promoting exclusion of an alternative exon from the preprocessed mRNA transcript, wherein the alternative exon comprises a canonical exon and at least a portion of an intron upstream of the canonical exon and adjacent to the canonical exon, wherein the target protein is SYNGAP1, and wherein the target motif comprises a sequence with at least 90% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO: 166-169 and 980-983; and (b) a pharmaceutically acceptable excipient and / or a delivery vehicle, and wherein the disease or condition is treated or prevented in the subject by the administration of the NSAE-modulating agent to modulate expression of the target protein. [0025D] Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. [0025E] Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present disclosure as it existed before the priority date of each of the appended claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1A depicts an exemplary schematic depicting a wild type cell expressing a pre-mRNA that is alternatively spliced to generate a productive mRNA and a non-productive mRNA. While the nonproductive mRNA is degraded by NMD, the productive mRNA is translated into normal protein levels. 2020334067   16 Jul 2026

[0027] Figure 1B depicts an exemplary schematic depicting a wild type cell treated with a TANGO (Targeted Augmentation of Nuclear Gene Output) ASO targeting the non-productive AS event (e.g. exon inclusion) that prevents the inclusion of the non-productive exon and leads to an increase of the productive mRNA. Increased level of the productive mRNA results in increased protein level beyond 100%.

[0028] Figure 1C depicts an exemplary schematic depicting an example of a haploinsufficient cell containing a wild-type allele (orange) and a mutant allele (red). Both alleles express a pre-mRNA that is alternatively spliced to generate a productive mRNA and a non-productive mRNA. While the nonproductive mRNAs are degraded by NMD, the productive mRNA from the wild-type allele generates 50% of normal protein levels leading to disease.

[0029] Figure 1D depicts an exemplary schematic depicting an example of a haploinsufficient cell treated with a TANGO ASO targeting the non-productive AS event (e.g. exon inclusion) that prevents the inclusion of the non-productive exon and leads to an increase of the productive mRNA from both alleles. While the mutant mRNA won’t produce a functional protein, increased levels of the wild type productive mRNA restores the protein level back to normal.

[0030] Figure 1E depicts an exemplary schematic depicting an alternative 5’ ss of an exon (Exon B) (which corresponds to an alternative 3’ ss of the intron preceding the exon (Intron A). In this example, the alternative exon is longer than the corresponding canonical exon and the alternative intron is shorter than the corresponding canonical intron.

[0031] Figure 1F depicts an exemplary schematic depicting an alternative 5’ ss of an exon (Exon B) (which corresponds to an alternative 3’ ss of the intron preceding the exon (Intron A). In this example, the alternative exon is shorter than the corresponding canonical exon and the alternative intron is longer than the corresponding canonical intron.

[0032] Figure 1G depicts an exemplary schematic depicting an alternative 3’ ss of an exon (Exon B) (which corresponds to an alternative 5’ ss of the intron following the exon (Intron B). In this example, the alternative exon is longer than the corresponding canonical exon and the alternative intron is shorter than the corresponding canonical intron.

[0033] Figure 1H depicts an exemplary schematic depicting an alternative 3’ ss of an exon (Exon B) (which corresponds to an alternative 5’ ss of the intron following the exon (Intron B). In this example, the alternative exon is shorter than the corresponding canonical exon and the alternative intron is longer than the corresponding canonical intron.

[0034] Figure 2 depicts examples of non-productive alternative splicing events that are predicted to lead to premature termination codons and undergo non-sense mediated decay of processed mRNA transcripts. The left panel depicts the types of alternative splicing events (cassette exons, alternative splice sites, and alternative intron) that are predicted to lead to the introduction of a premature termination codon (PTC) and transcript degradation. The horizontal bar graph summarizes the number of protein-coding genes containing each of the non-productive alternative splicing event type. Non-disease-associated genes are depicted by the top bars and disease-associated genes are depicted by bottom bars (based on Orphanet 2020334067   16 Jul 2026 disease database). Exons are denoted by rectangles and introns by lines. Dark gray rectangles or lines denote a non-productive alternative splicing region.

[0035] Figure 3 depicts an exemplary schematic representation of SYNGAP1 NMD-inducing alternative 3’ splice site of an intron (which corresponds to an alternative 5’ ss of the exon downstream of the alternative intron). NMD-inducing alt 3’ss event: UCSC Genome Browser snapshot of a region in the SYNGAP1 gene (exons are rectangles and introns are lines with arrowheads) that contains an NMD-inducing Alternative 3’ splice site event (chr6 33440553 33440728) depicted by the shaded area and black bar on the top. RNA sequencing traces from human middle frontal gyrus samples from individuals at various ages and proliferating or differentiated RenCellVM cells treated with cycloheximide (CHX) or DMSO control are shown.

[0036] Figure 4 depicts an exemplary ASO walk design. The shaded nucleotides correspond to the portion of the extended exon 11 of SYNGAP1 that results from the selection of the indicated Alt 3’ss of the intron (which corresponds to the alternative 5’ ss of the exon downstream of the alternative intron). Figure discloses SEQ ID NOS 10226-10228, respectively, in order of appearance.

[0037] Figures 5A-5C depict graphs showing exemplary ASO walk Taqman qPCR results, e.g., ASO screening by Taqman qPCR.

[0038] Figure 5A depicts exemplary Taqman qPCR results using RNA from HEK293 cells transfected for 24 hrs with 80 nM ASOs from region 1 depicted in Figure 4. The exemplary Taqman probe spans exons 10 and 11 junction and measures productive mRNA.

[0039] Figure 5B depicts exemplary Taqman qPCR results using RNA from HEK293 cells transfected for 24 hrs with 80 nM ASOs from region 2 depicted in Figure 4. The exemplary Taqman probe spans exons 10 and 11 junction and measures productive mRNA.

[0040] Figure 5C depicts exemplary Taqman qPCR results using RNA from HEK293 cells transfected for 24 hrs with 80 nM ASOs from region 3 depicted in Figure 4. The exemplary Taqman probe spans exons 10 and 11 junction and measures productive mRNA.

[0041] Figure 6 depicts the use of antisense oligomers to modulate non-productive alternative splicing events and increase mRNA and protein levels in a dose-dependent manner in vitro. A selected SYNGAP1 ASO targeting an alternative 3’ splice site event was transfected in HEK293 (human embryonic kidney cell) cells at increasing concentrations for 24h and RT-PCR (reverse transcription polymerase chain reaction) and TaqMan qPCR (quantitative polymerase chain reaction) was performed. The bar graph on the left shows a dose-dependent reduction of the non-productive mRNA and the bar graph on the right shows a dose-dependent increase of productive mRNA. A Western blot and protein quantification for SynGAP from HEK293 cells treated with the respective selected ASOs at increasing concentrations for 48 hrs is shown on the right. Equal protein loading was confirmed with Ponceau staining. Fc = fold change over control.

[0042] Figure 7 depicts exemplary RT-PCR and densitometric quantifications of RT-PCR validation in cells treated with 50 ^g / mL of cycloheximide (CHX) or equal volume of DMSO (Dimethyl sulfoxide) for 3 hours for SYNGAP1. 2020334067   16 Jul 2026

[0043] Figure 8 depicts the dose-dependent effect of antisense oligomers that modulate non-productive alternative splicing events. A representative RT-PCR PAGE (polyacrylamide gel electrophoresis) of cells transfected with increasing concentrations of selected antisense oligomers targeting an alternative 3’ss in SYNGAP1 is depicted.

[0044] Figure 9 depicts an exemplary Western blot of SynGAP following treatment with 100 nM siRNA against SYNGAP1 for 48 hours in HEK293 cells.

[0045] Figures 10A-10D depict an exemplary schematic representation, pictures and a graph showing validation of alternative 3’ splice site event of an intron (intron 10) (which corresponds to an alternative 5’ ss of the exon downstream of the alternative intron (exon 11)). * Mouse event has a different size than human event.

[0046] Figure 10A depicts an exemplary schematic representation of an alternative 3’ splice site (Alt 3’ss) event of an intron in SYNGAP1 (intron 10) (which corresponds to an alternative 5’ ss of the exon downstream of the alternative intron (exon 11)).

[0047] Figure 10B depicts exemplary results of RT-PCR to SYNGAP1 using RNA from RenCellsVM (Neural progenitor cells) or Neuro 2A (mouse neuroblastoma cells) treated with either DMSO (-) or cycloheximide (CHX) (+). Primers were positioned in exon 10 and 11.

[0048] Figure 10C depicts exemplary results of RT-PCR to SYNGAP1 using RNA from total mouse brain. Primers were positioned in exon 10 and 11.

[0049] Figure 10D depicts an exemplary quantification of the RT-PCR SYNGAP1 products using RNA from various non-human primates brain regions plotted as percentage of Alt intron 3’ss isoform (Alt downstream exon 5’ss isoform) (Alt intron 3’ss isoform / (Alt intron 3’ss isoform +productive mRNA)*100, i.e. Alt downstream exon 5’ss isoform / (Alt downstream exon 5’ss isoform +productive mRNA).

[0050] Figures 11A-11C depict graphs and pictures showing that an exemplary ASO prevents Alt 3’ss selection and increases SYNGAP1 mRNA and protein.

[0051] Figure 11A and Figure 11B depict exemplary RT-PCR results showing reduction of SYNGAP1 Alt 3’ss isoform and exemplary Taqman qPCR results showing increase of productive mRNA, respectively.

[0052] Figure 11A shows quantification of the RT-PCR products using RNA from HEK293 cells transfected for 24 hrs with selected ASO #1 from region 2 plotted as percentage of Alt intron 3’ss isoform (Alt downstream exon 5’ss isoform) (Alt intron 3’ss isoform / (Alt intron 3’ss isoform +productive mRNA)*100, i.e. Alt downstream exon 5’ss isoform / (Alt downstream exon 5’ss isoform +productive mRNA). Primers were positioned in exons 10 and 11. N=2. NT= non-targeting ASO control.

[0053] Figure 11B shows Taqman qPCR results using a probe that spans the exon 10-11 junction that measures productive mRNA plotted as fold change over no ASO control (-) using the same samples as in Figure 11A. N=2. NT= non-targeting ASO control.

[0054] Figure 11C depicts exemplary Western blot results showing increase of SynGAP protein. Figure 11C shows Western blot analysis using whole cell lysate from HEK293 cells transfected for 48 hrs with a 2020334067   16 Jul 2026 selected ASO. Quantification of bands corresponding to SynGAP were normalized to Ponceau loading control and fold change (fc) over control (-) is shown under the gel.

[0055] Figures 12A-12E depict pictures and graphs showing that exemplary selected MOE (2-methoxyethyl)) lengthmers and PMOs (phosphorodiamidate morpholinos) prevent Alt intron 3’ss selection (Alt downstream exon 5’ss selection) and increase SYNGAP1 mRNA and protein.

[0056] Figure 12A and Figure 12B depict exemplary RT-PCR results showing reduction of SYNGAP1 Alt intron 3’ss isoform (Alt downstream exon 5’ss isoform).

[0057] Figure 12A shows RT-PCR results using RNA from MEF (mouse embryonic fibroblasts) nucleofected for 24 hrs with selected MOE #5 from region 1 and derivative MOE lengthmers and PMOs. Primers were positioned in exons 10 and 11.

[0058] Figure 12B shows quantifications of RT-PCR products shown in Figure 12A plotted as percentage of Alt intron 3’ss isoform (Alt downstream exon 5’ss isoform) (Alt intron 3’ss isoform / (Alt intron 3’ss isoform +productive mRNA)*100, i.e. Alt downstream exon 5’ss isoform / (Alt downstream exon 5’ss isoform +productive mRNA). N=2. - = no ASO control.

[0059] Figure 12C depicts exemplary Taqman qPCR results showing increase of productive mRNA. Figure 12C shows Taqman qPCR results using a probe that spans the exon 10-11 junction that measures productive mRNA plotted as fold change over no ASO control (-) using the same samples as in Figure 12A. N=2. - = no ASO control.

[0060] Figure 12D and Figure 12E depict exemplary Western blot results showing increase of SynGAP protein.

[0061] Figure 12D shows Western blot analysis using whole cell lysate from MEFs nucleofected for 48 hrs with selected ASO #5 (MOE) and # 29 (PMO) I.

[0062] Figure 12E shows quantification of bands corresponding to SynGAP normalized to Ponceau loading control and plotted as fold change (fc) over control (-). N=2. - = no ASO control. DETAILED DESCRIPTION

[0063] Certain specific details of this description are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the present disclosure may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed disclosure.

[0064] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise.

[0065] The coordinate as used herein refers to the coordinate of the genome reference assembly GRCh38 (Genome Research Consortium human build 38), also known as Hg38 (Human genome build 38). 2020334067   16 Jul 2026

[0066] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below.

[0067] As used herein, an alternative 3’ splice site of an intron is equivalent to an alternative 5’ splice site of the exon immediately downstream of that intron.

[0068] As used herein, an alternative 5’ splice site of an intron is equivalent to an alternative 3’ splice site of the exon immediately upstream of that intron. Autosomal Dominant Mental Retardation and SYNGAP1 Gene

[0069] Autosomal dominant mental retardation is an autosomal dominant neurodevelopmental disorder characterized by significantly impaired intellectual functioning and adaptive behaviors, one cause of which is haploinsufficency of SYNGAP1 gene expression. SYNGAP1 codes for SYNGAP1 protein, which is a ras GTPase-activating protein involved in cognitive development and proper synapse function amongst neurons. SYNGAP1 is known to be involved in synaptic plasticity, axon formation, and AMPA receptor trafficking. Generally, SYNGAP1 activity is essential for development and survival. SYNGAP1 deficiencies may be caused by sporadic mutation or alternative splicing events. Deficient SYNGAP1 activity may result in mental retardation, or intellectual disability, epileptic encephalopathy, or autism.

[0070] The present disclosure provides compositions and methods for modulating alternative splicing of SYNGAP1 to modulate the production of functional protein-coding mature mRNA, and thus, translated functional SYNGAP1 protein. These compositions and methods include antisense oligomers (ASOs) that can promote canonical splicing of SYNGAP1 pre-mRNA. In various embodiments, functional SYNGAP1 protein can be increased using the methods of the disclosure to treat a condition caused by SYNGAP1 protein deficiency. In some embodiments, the condition is autosomal dominant mental retardation. In other embodiments, the condition is epileptic encephalopathy or autism.

[0071] In some embodiments, the methods of the invention are used to increase functional SYNGAP1 protein production to treat a condition in a subject in need thereof. In some embodiments, the subject has a condition in which SYNGAP1 is not necessarily deficient relative to wild-type, but where an increase in SYNGAP1 mitigates the condition nonetheless. In some embodiments, the condition is caused by sporadic mutation. In some embodiments, the methods of the invention are used to reduce functional SYNGAP1 protein production to treat a condition in a subject in need thereof. In some embodiments, the methods of the invention are used to modulate functional SYNGAP1 protein production to treat a condition in a subject in need thereof. Target Genes

[0072] The present disclosure provides compositions and methods for modulating alternative splicing of a target to modulate the production of functional protein-coding mature mRNA, and thus, translated functional the target protein, wherein the target is any one selected from the group consisting of ABCA5, ABCA7, ABCC3, ABCC5, ABCC8, ABCD1, ABR, ACAD9, ACAP1, ACOX2, ACSF3, ACTN4, ADAM17, ADAMTS13, AKR1E2, ALAD, ALG3, ANKRD29, ANKS3, ANO4, AP3B2, AP3M1, 2020334067   16 Jul 2026 AP5Z1, ARNTL, ASAP3, ATRX, BBS2, BBS4, BRD9, CALM3, CARS1, CASP9, CATSPER1, CCDC40, CCDC88B, CD4, CD58, CES2, CHFR, CLCN2, CNOT3, CNTROB, COL5A3, CPSF1, CSPP1, CTF1, CTH, CYP3A5, DAB2IP, DBN1, DDX51, DEAF1, DGKE, DHDDS, DMKN, DNHD1, DOCK8, DOK5, EIF2B5, ELAC2, ELP1, ENTPD4, ESRRA, ESS2, ETAA1, ETHE1, FANCA, FASTK, FASTKD3, FPGS, FREM1, GAS8, GCK, GGA1, GGA3, GGT1, GLMN, GON4L, GRB14, HDAC3, HELQ, HP1BP3, HPS1, HPS4, IDUA, IFT122, IL17RC, IMPDH1, INVS, IRF3, KCTD3, KLKB1, KYAT1, LAMC3, LDAH, LIMS2, MALT1, MAP3K7, MAPK13, MCAT, MCEE, MPI, MSTO1, NBEAL2, NLE1, NLRC5, NOM1, NOP58, NPHP1, NPR1, NUP188, OSGEP, PABPC4, PCOLCE, PHKA2, PIDD1, PKD1, PLA2G6, PLD2, PLEKHG5, PNPO, POLE, PON2, PRMT7, PRODH, PRPF3, PRPF4, PYCR1, RAD52, REXO1, RFX5, RHBDF2, RMND1, ROBO3, RPGRIP1, RTTN, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIK3, SIRT3, SKIV2L, SLC2A13, SLC12A7, SLC22A3, SLC25A13, SLC25A37, SLC27A5, SLC30A9, SLC30A10, SMPD1, SMTN, SNRPB, SP140, STAMBP, STXBP2, SULF2, SYNGAP1, SYNJ2, TAZ, TBL2, TDRD7, TECPR2, TFB1M, TM6SF1, TNK2, TOE1, TOR1B, TRAPPC6B, TRIP4, TRMT2A, TRMU, TRPV4, TTC19, TYMP, UMPS, UROD, WDR11, WDR62, WIPI1, WRAP53, XPO1, YY1AP1, and ZC3H14. These compositions and methods include antisense oligomers (ASOs) that can promote canonical splicing of the target pre-mRNA, wherein the target is any one selected from the group consisting of ABCA5, ABCA7, ABCC3, ABCC5, ABCC8, ABCD1, ABR, ACAD9, ACAP1, ACOX2, ACSF3, ACTN4, ADAM17, ADAMTS13, AKR1E2, ALAD, ALG3, ANKRD29, ANKS3, ANO4, AP3B2, AP3M1, AP5Z1, ARNTL, ASAP3, ATRX, BBS2, BBS4, BRD9, CALM3, CARS1, CASP9, CATSPER1, CCDC40, CCDC88B, CD4, CD58, CES2, CHFR, CLCN2, CNOT3, CNTROB, COL5A3, CPSF1, CSPP1, CTF1, CTH, CYP3A5, DAB2IP, DBN1, DDX51, DEAF1, DGKE, DHDDS, DMKN, DNHD1, DOCK8, DOK5, EIF2B5, ELAC2, ELP1, ENTPD4, ESRRA, ESS2, ETAA1, ETHE1, FANCA, FASTK, FASTKD3, FPGS, FREM1, GAS8, GCK, GGA1, GGA3, GGT1, GLMN, GON4L, GRB14, HDAC3, HELQ, HP1BP3, HPS1, HPS4, IDUA, IFT122, IL17RC, IMPDH1, INVS, IRF3, KCTD3, KLKB1, KYAT1, LAMC3, LDAH, LIMS2, MALT1, MAP3K7, MAPK13, MCAT, MCEE, MPI, MSTO1, NBEAL2, NLE1, NLRC5, NOM1, NOP58, NPHP1, NPR1, NUP188, OSGEP, PABPC4, PCOLCE, PHKA2, PIDD1, PKD1, PLA2G6, PLD2, PLEKHG5, PNPO, POLE, PON2, PRMT7, PRODH, PRPF3, PRPF4, PYCR1, RAD52, REXO1, RFX5, RHBDF2, RMND1, ROBO3, RPGRIP1, RTTN, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIK3, SIRT3, SKIV2L, SLC2A13, SLC12A7, SLC22A3, SLC25A13, SLC25A37, SLC27A5, SLC30A9, SLC30A10, SMPD1, SMTN, SNRPB, SP140, STAMBP, STXBP2, SULF2, SYNGAP1, SYNJ2, TAZ, TBL2, TDRD7, TECPR2, TFB1M, TM6SF1, TNK2, TOE1, TOR1B, TRAPPC6B, TRIP4, TRMT2A, TRMU, TRPV4, TTC19, TYMP, UMPS, UROD, WDR11, WDR62, WIPI1, WRAP53, XPO1, YY1AP1, and ZC3H14. In various embodiments, functional target protein can be increased using the methods of the disclosure to treat a condition caused by target protein deficiency, wherein the target is any one selected from the group consisting of ABCA5, ABCA7, ABCC3, ABCC5, ABCC8, ABCD1, ABR, ACAD9, ACAP1, ACOX2, ACSF3, ACTN4, ADAM17, ADAMTS13, AKR1E2, ALAD, ALG3, ANKRD29, ANKS3, ANO4, AP3B2, AP3M1, AP5Z1, ARNTL, ASAP3, ATRX, BBS2, BBS4, BRD9, CALM3, CARS1, CASP9, 2020334067   16 Jul 2026 CATSPER1, CCDC40, CCDC88B, CD4, CD58, CES2, CHFR, CLCN2, CNOT3, CNTROB, COL5A3, CPSF1, CSPP1, CTF1, CTH, CYP3A5, DAB2IP, DBN1, DDX51, DEAF1, DGKE, DHDDS, DMKN, DNHD1, DOCK8, DOK5, EIF2B5, ELAC2, ELP1, ENTPD4, ESRRA, ESS2, ETAA1, ETHE1, FANCA, FASTK, FASTKD3, FPGS, FREM1, GAS8, GCK, GGA1, GGA3, GGT1, GLMN, GON4L, GRB14, HDAC3, HELQ, HP1BP3, HPS1, HPS4, IDUA, IFT122, IL17RC, IMPDH1, INVS, IRF3, KCTD3, KLKB1, KYAT1, LAMC3, LDAH, LIMS2, MALT1, MAP3K7, MAPK13, MCAT, MCEE, MPI, MSTO1, NBEAL2, NLE1, NLRC5, NOM1, NOP58, NPHP1, NPR1, NUP188, OSGEP, PABPC4, PCOLCE, PHKA2, PIDD1, PKD1, PLA2G6, PLD2, PLEKHG5, PNPO, POLE, PON2, PRMT7, PRODH, PRPF3, PRPF4, PYCR1, RAD52, REXO1, RFX5, RHBDF2, RMND1, ROBO3, RPGRIP1, RTTN, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIK3, SIRT3, SKIV2L, SLC2A13, SLC12A7, SLC22A3, SLC25A13, SLC25A37, SLC27A5, SLC30A9, SLC30A10, SMPD1, SMTN, SNRPB, SP140, STAMBP, STXBP2, SULF2, SYNGAP1, SYNJ2, TAZ, TBL2, TDRD7, TECPR2, TFB1M, TM6SF1, TNK2, TOE1, TOR1B, TRAPPC6B, TRIP4, TRMT2A, TRMU, TRPV4, TTC19, TYMP, UMPS, UROD, WDR11, WDR62, WIPI1, WRAP53, XPO1, YY1AP1, and ZC3H14. In some embodiments, the condition is autosomal dominant mental retardation. In other embodiments, the condition is epileptic encephalopathy or autism.

[0073] In some embodiments, the methods of the invention are used to increase functional the target protein production to treat a condition in a subject in need thereof, wherein the target is any one selected from the group consisting of ABCA5, ABCA7, ABCC3, ABCC5, ABCC8, ABCD1, ABR, ACAD9, ACAP1, ACOX2, ACSF3, ACTN4, ADAM17, ADAMTS13, AKR1E2, ALAD, ALG3, ANKRD29, ANKS3, ANO4, AP3B2, AP3M1, AP5Z1, ARNTL, ASAP3, ATRX, BBS2, BBS4, BRD9, CALM3, CARS1, CASP9, CATSPER1, CCDC40, CCDC88B, CD4, CD58, CES2, CHFR, CLCN2, CNOT3, CNTROB, COL5A3, CPSF1, CSPP1, CTF1, CTH, CYP3A5, DAB2IP, DBN1, DDX51, DEAF1, DGKE, DHDDS, DMKN, DNHD1, DOCK8, DOK5, EIF2B5, ELAC2, ELP1, ENTPD4, ESRRA, ESS2, ETAA1, ETHE1, FANCA, FASTK, FASTKD3, FPGS, FREM1, GAS8, GCK, GGA1, GGA3, GGT1, GLMN, GON4L, GRB14, HDAC3, HELQ, HP1BP3, HPS1, HPS4, IDUA, IFT122, IL17RC, IMPDH1, INVS, IRF3, KCTD3, KLKB1, KYAT1, LAMC3, LDAH, LIMS2, MALT1, MAP3K7, MAPK13, MCAT, MCEE, MPI, MSTO1, NBEAL2, NLE1, NLRC5, NOM1, NOP58, NPHP1, NPR1, NUP188, OSGEP, PABPC4, PCOLCE, PHKA2, PIDD1, PKD1, PLA2G6, PLD2, PLEKHG5, PNPO, POLE, PON2, PRMT7, PRODH, PRPF3, PRPF4, PYCR1, RAD52, REXO1, RFX5, RHBDF2, RMND1, ROBO3, RPGRIP1, RTTN, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIK3, SIRT3, SKIV2L, SLC2A13, SLC12A7, SLC22A3, SLC25A13, SLC25A37, SLC27A5, SLC30A9, SLC30A10, SMPD1, SMTN, SNRPB, SP140, STAMBP, STXBP2, SULF2, SYNGAP1, SYNJ2, TAZ, TBL2, TDRD7, TECPR2, TFB1M, TM6SF1, TNK2, TOE1, TOR1B, TRAPPC6B, TRIP4, TRMT2A, TRMU, TRPV4, TTC19, TYMP, UMPS, UROD, WDR11, WDR62, WIPI1, WRAP53, XPO1, YY1AP1, and ZC3H14. In some embodiments, the subject has a condition in which the target protein is not necessarily deficient relative to wild-type, but where an increase in the target protein mitigates the condition nonetheless, wherein the target is any one selected from the group consisting of ABCA5, ABCA7, ABCC3, ABCC5, ABCC8, 2020334067   16 Jul 2026 ABCD1, ABR, ACAD9, ACAP1, ACOX2, ACSF3, ACTN4, ADAM17, ADAMTS13, AKR1E2, ALAD, ALG3, ANKRD29, ANKS3, ANO4, AP3B2, AP3M1, AP5Z1, ARNTL, ASAP3, ATRX, BBS2, BBS4, BRD9, CALM3, CARS1, CASP9, CATSPER1, CCDC40, CCDC88B, CD4, CD58, CES2, CHFR, CLCN2, CNOT3, CNTROB, COL5A3, CPSF1, CSPP1, CTF1, CTH, CYP3A5, DAB2IP, DBN1, DDX51, DEAF1, DGKE, DHDDS, DMKN, DNHD1, DOCK8, DOK5, EIF2B5, ELAC2, ELP1, ENTPD4, ESRRA, ESS2, ETAA1, ETHE1, FANCA, FASTK, FASTKD3, FPGS, FREM1, GAS8, GCK, GGA1, GGA3, GGT1, GLMN, GON4L, GRB14, HDAC3, HELQ, HP1BP3, HPS1, HPS4, IDUA, IFT122, IL17RC, IMPDH1, INVS, IRF3, KCTD3, KLKB1, KYAT1, LAMC3, LDAH, LIMS2, MALT1, MAP3K7, MAPK13, MCAT, MCEE, MPI, MSTO1, NBEAL2, NLE1, NLRC5, NOM1, NOP58, NPHP1, NPR1, NUP188, OSGEP, PABPC4, PCOLCE, PHKA2, PIDD1, PKD1, PLA2G6, PLD2, PLEKHG5, PNPO, POLE, PON2, PRMT7, PRODH, PRPF3, PRPF4, PYCR1, RAD52, REXO1, RFX5, RHBDF2, RMND1, ROBO3, RPGRIP1, RTTN, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIK3, SIRT3, SKIV2L, SLC2A13, SLC12A7, SLC22A3, SLC25A13, SLC25A37, SLC27A5, SLC30A9, SLC30A10, SMPD1, SMTN, SNRPB, SP140, STAMBP, STXBP2, SULF2, SYNGAP1, SYNJ2, TAZ, TBL2, TDRD7, TECPR2, TFB1M, TM6SF1, TNK2, TOE1, TOR1B, TRAPPC6B, TRIP4, TRMT2A, TRMU, TRPV4, TTC19, TYMP, UMPS, UROD, WDR11, WDR62, WIPI1, WRAP53, XPO1, YY1AP1, and ZC3H14. In some embodiments, the condition is caused by sporadic mutation. In some embodiments, the methods of the invention are used to reduce functional target protein production to treat a condition in a subject in need thereof, wherein the target is any one selected from the group consisting of ABCA5, ABCA7, ABCC3, ABCC5, ABCC8, ABCD1, ABR, ACAD9, ACAP1, ACOX2, ACSF3, ACTN4, ADAM17, ADAMTS13, AKR1E2, ALAD, ALG3, ANKRD29, ANKS3, ANO4, AP3B2, AP3M1, AP5Z1, ARNTL, ASAP3, ATRX, BBS2, BBS4, BRD9, CALM3, CARS1, CASP9, CATSPER1, CCDC40, CCDC88B, CD4, CD58, CES2, CHFR, CLCN2, CNOT3, CNTROB, COL5A3, CPSF1, CSPP1, CTF1, CTH, CYP3A5, DAB2IP, DBN1, DDX51, DEAF1, DGKE, DHDDS, DMKN, DNHD1, DOCK8, DOK5, EIF2B5, ELAC2, ELP1, ENTPD4, ESRRA, ESS2, ETAA1, ETHE1, FANCA, FASTK, FASTKD3, FPGS, FREM1, GAS8, GCK, GGA1, GGA3, GGT1, GLMN, GON4L, GRB14, HDAC3, HELQ, HP1BP3, HPS1, HPS4, IDUA, IFT122, IL17RC, IMPDH1, INVS, IRF3, KCTD3, KLKB1, KYAT1, LAMC3, LDAH, LIMS2, MALT1, MAP3K7, MAPK13, MCAT, MCEE, MPI, MSTO1, NBEAL2, NLE1, NLRC5, NOM1, NOP58, NPHP1, NPR1, NUP188, OSGEP, PABPC4, PCOLCE, PHKA2, PIDD1, PKD1, PLA2G6, PLD2, PLEKHG5, PNPO, POLE, PON2, PRMT7, PRODH, PRPF3, PRPF4, PYCR1, RAD52, REXO1, RFX5, RHBDF2, RMND1, ROBO3, RPGRIP1, RTTN, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIK3, SIRT3, SKIV2L, SLC2A13, SLC12A7, SLC22A3, SLC25A13, SLC25A37, SLC27A5, SLC30A9, SLC30A10, SMPD1, SMTN, SNRPB, SP140, STAMBP, STXBP2, SULF2, SYNGAP1, SYNJ2, TAZ, TBL2, TDRD7, TECPR2, TFB1M, TM6SF1, TNK2, TOE1, TOR1B, TRAPPC6B, TRIP4, TRMT2A, TRMU, TRPV4, TTC19, TYMP, UMPS, UROD, WDR11, WDR62, WIPI1, WRAP53, XPO1, YY1AP1, and ZC3H14. In some embodiments, the methods of the invention are used to modulate functional target protein production to treat a condition in a subject in need thereof, wherein the target is any one selected from the group consisting of ABCA5, ABCA7, ABCC3, ABCC5, 2020334067   16 Jul 2026 ABCC8, ABCD1, ABR, ACAD9, ACAP1, ACOX2, ACSF3, ACTN4, ADAM17, ADAMTS13, AKR1E2, ALAD, ALG3, ANKRD29, ANKS3, ANO4, AP3B2, AP3M1, AP5Z1, ARNTL, ASAP3, ATRX, BBS2, BBS4, BRD9, CALM3, CARS1, CASP9, CATSPER1, CCDC40, CCDC88B, CD4, CD58, CES2, CHFR, CLCN2, CNOT3, CNTROB, COL5A3, CPSF1, CSPP1, CTF1, CTH, CYP3A5, DAB2IP, DBN1, DDX51, DEAF1, DGKE, DHDDS, DMKN, DNHD1, DOCK8, DOK5, EIF2B5, ELAC2, ELP1, ENTPD4, ESRRA, ESS2, ETAA1, ETHE1, FANCA, FASTK, FASTKD3, FPGS, FREM1, GAS8, GCK, GGA1, GGA3, GGT1, GLMN, GON4L, GRB14, HDAC3, HELQ, HP1BP3, HPS1, HPS4, IDUA, IFT122, IL17RC, IMPDH1, INVS, IRF3, KCTD3, KLKB1, KYAT1, LAMC3, LDAH, LIMS2, MALT1, MAP3K7, MAPK13, MCAT, MCEE, MPI, MSTO1, NBEAL2, NLE1, NLRC5, NOM1, NOP58, NPHP1, NPR1, NUP188, OSGEP, PABPC4, PCOLCE, PHKA2, PIDD1, PKD1, PLA2G6, PLD2, PLEKHG5, PNPO, POLE, PON2, PRMT7, PRODH, PRPF3, PRPF4, PYCR1, RAD52, REXO1, RFX5, RHBDF2, RMND1, ROBO3, RPGRIP1, RTTN, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIK3, SIRT3, SKIV2L, SLC2A13, SLC12A7, SLC22A3, SLC25A13, SLC25A37, SLC27A5, SLC30A9, SLC30A10, SMPD1, SMTN, SNRPB, SP140, STAMBP, STXBP2, SULF2, SYNGAP1, SYNJ2, TAZ, TBL2, TDRD7, TECPR2, TFB1M, TM6SF1, TNK2, TOE1, TOR1B, TRAPPC6B, TRIP4, TRMT2A, TRMU, TRPV4, TTC19, TYMP, UMPS, UROD, WDR11, WDR62, WIPI1, WRAP53, XPO1, YY1AP1, and ZC3H14. Splicing

[0074] Intervening sequences or introns are removed by a large and highly dynamic RNA-protein complex termed the spliceosome, which orchestrates complex interactions between primary transcripts, small nuclear RNAs (snRNAs) and a large number of proteins. Spliceosomes assemble ad hoc on each intron in an ordered manner, starting with recognition of the 5’ splice site (5’ss) by U1 snRNA or the 3’splice site (3’ss), which involves binding of the U2 auxiliary factor (U2AF) to the 3’ss region to facilitate U2 snRNA binding to the branch point sequence (BPS). U2AF is a stable heterodimer composed of a U2AF2-encoded 65-kD subunit (U2AF65), which binds the polypyrimidine tract (PPT), and a U2AF1-encoded 35-kD subunit (U2AF35), which interacts with highly conserved AG dinucleotides at 3‘ss and stabilizes U2AF65 binding. In addition to the BPS / PPT unit and 3’ss / 5’ss, accurate splicing requires auxiliary sequences or structures that activate or repress splice site recognition, known as intronic or exonic splicing enhancers or silencers. These elements allow genuine splice sites to be recognized among a vast excess of cryptic or pseudo-sites in the genome of higher eukaryotes, which have the same sequences but outnumber authentic sites by an order of magnitude. Although they often have a regulatory function, the exact mechanisms of their activation or repression are poorly understood.

[0075] The decision as to whether splicing occurs can be typically modeled as a stochastic rather than deterministic process, such that even the most defined splicing signals can sometimes splice incorrectly. However, under normal conditions, pre-mRNA splicing proceeds with surprisingly high accuracy. This may be attributed in part to the activity of adjacent cis-acting auxiliary exonic and intronic splicing regulatory elements (ESRs or ISRs). Typically, these functional elements are classified as either exonic or intronic splicing enhancers (ESEs or ISEs) or silencers (ESSs or ISSs) based on their ability to stimulate or inhibit splicing, respectively. Although there is now evidence to suggest that some auxiliary cis-acting 2020334067   16 Jul 2026 elements may act by influencing the kinetics of spliceosome assembly, such as the arrangement of the complex between U1 snRNP and the 5’ss, it seems highly likely that multiple elements function in a coordinated manner with trans-acting RNA-binding proteins (RBPs). For example, the serine- and arginine-rich family of RBPs (SR proteins) is a conserved family of proteins that play a key role in defining exons. SR proteins promote exon recognition by recruiting components of the pre-spliceosome to adjacent splice sites or by antagonizing the effects of ESSs in the vicinity. The repressive effects of ESSs and ISSs can be mediated by members of the heterogeneous nuclear ribonucleoprotein (hnRNP) family and can alter recruitment of core splicing factors to adjacent splice sites. In addition to their roles in splicing regulation, silencer elements have been suggested to play a role in the repression of pseudoexons, which are sets of decoy intronic splice sites with the typical spacing of an exon but without a functional open reading frame. ISEs, ISSs, ESEs and ESSs, in cooperation with their related trans-acting RBPs, represent important components in a set of splicing controls that specify how, where and when mRNAs are assembled from their precursors.

[0076] The sequences marking the exon-intron boundaries are degenerate signals of varying strengths that can occur at high frequency within human genes. In multi-exon genes, different pairs of splice sites can be linked together in many different combinations, creating a diverse array of transcripts from a single gene. This is commonly referred to as alternative pre-mRNA splicing. Although most mRNA isoforms produced by alternative splicing can be exported from the nucleus and translated into functional polypeptides, different mRNA isoforms from a single gene can vary greatly in their translation efficiency. Those mRNA isoforms with premature termination codons (PTCs) at least 50 bp upstream of an exon junction complex are likely to be targeted for degradation by the nonsense-mediated mRNA decay (NMD) pathway. Present in these mRNA isoforms are non-sense mediated RNA decay alternative exons (NSAE), which are alternatively spliced exons that lead to NMD. Mutations in traditional (BPS / PPT / 3’ss / 5’ss) and auxiliary splicing motifs may cause aberrant splicing, such as exon skipping or cryptic (or pseudo-) exon inclusion or splice-site activation, and contribute significantly to human morbidity and mortality. Both aberrant and alternative splicing patterns can be influenced by natural DNA variants in exons and introns. Target Transcripts

[0077] In some embodiments, the methods of the present disclosure exploit the presence of non-sense mediated RNA decay alternative exon-containing pre-mRNA (NSAE pre-mRNA) transcribed from a gene. In some embodiments, the methods of the present disclosure exploit the presence of non-sense mediated RNA decay alternative exon-containing pre-mRNA (NSAE pre-mRNA) transcribed from the SYNGAP1 gene. Canonical splicing of the identified SYNGAP1 NSAE pre-mRNA transcripts to produce functional, mature SYNGAP1 mRNA can be induced using a therapeutic agent, such as an ASO, that promotes constitutive splicing of SYNGAP1 NSAE pre-mRNA at the canonical splice sites. In some embodiments, the resulting functional, mature SYNGAP1 mRNA can be translated normally, thereby increasing the amount of functional SYNGAP1 protein in the patient’s cells and preventing symptoms of SYNGAP1 associated disease. In some embodiments, canonical splicing of the identified SYNGAP1 NSAE pre-mRNA transcripts to produce functional, mature SYNGAP1 mRNA may be reduced using a 2020334067   16 Jul 2026 therapeutic agent, such as an ASO, that inhibits constitutive splicing of SYNGAP1 NSAE pre-mRNA at the canonical splice sites. In some embodiments, the resulting functional, mature SYNGAP1 mRNA can be translated abnormally, thereby decreasing the amount of functional SYNGAP1 protein in the patient’s cells and preventing symptoms of SYNGAP1 associated disease.

[0078] In some embodiments, the methods of the present disclosure exploit the presence of non-sense mediated RNA decay alternative exon-containing pre-mRNA (NSAE pre-mRNA) transcribed from the target gene, wherein the target is any one selected from the group consisting of ABCA5, ABCA7, ABCC3, ABCC5, ABCC8, ABCD1, ABR, ACAD9, ACAP1, ACOX2, ACSF3, ACTN4, ADAM17, ADAMTS13, AKR1E2, ALAD, ALG3, ANKRD29, ANKS3, ANO4, AP3B2, AP3M1, AP5Z1, ARNTL, ASAP3, ATRX, BBS2, BBS4, BRD9, CALM3, CARS1, CASP9, CATSPER1, CCDC40, CCDC88B, CD4, CD58, CES2, CHFR, CLCN2, CNOT3, CNTROB, COL5A3, CPSF1, CSPP1, CTF1, CTH, CYP3A5, DAB2IP, DBN1, DDX51, DEAF1, DGKE, DHDDS, DMKN, DNHD1, DOCK8, DOK5, EIF2B5, ELAC2, ELP1, ENTPD4, ESRRA, ESS2, ETAA1, ETHE1, FANCA, FASTK, FASTKD3, FPGS, FREM1, GAS8, GCK, GGA1, GGA3, GGT1, GLMN, GON4L, GRB14, HDAC3, HELQ, HP1BP3, HPS1, HPS4, IDUA, IFT122, IL17RC, IMPDH1, INVS, IRF3, KCTD3, KLKB1, KYAT1, LAMC3, LDAH, LIMS2, MALT1, MAP3K7, MAPK13, MCAT, MCEE, MPI, MSTO1, NBEAL2, NLE1, NLRC5, NOM1, NOP58, NPHP1, NPR1, NUP188, OSGEP, PABPC4, PCOLCE, PHKA2, PIDD1, PKD1, PLA2G6, PLD2, PLEKHG5, PNPO, POLE, PON2, PRMT7, PRODH, PRPF3, PRPF4, PYCR1, RAD52, REXO1, RFX5, RHBDF2, RMND1, ROBO3, RPGRIP1, RTTN, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIK3, SIRT3, SKIV2L, SLC2A13, SLC12A7, SLC22A3, SLC25A13, SLC25A37, SLC27A5, SLC30A9, SLC30A10, SMPD1, SMTN, SNRPB, SP140, STAMBP, STXBP2, SULF2, SYNGAP1, SYNJ2, TAZ, TBL2, TDRD7, TECPR2, TFB1M, TM6SF1, TNK2, TOE1, TOR1B, TRAPPC6B, TRIP4, TRMT2A, TRMU, TRPV4, TTC19, TYMP, UMPS, UROD, WDR11, WDR62, WIPI1, WRAP53, XPO1, YY1AP1, and ZC3H14. Canonical splicing of the identified target NSAE pre-mRNA transcripts to produce the functional, mature target mRNA can be induced using a therapeutic agent, such as an ASO, that promotes constitutive splicing of the target NSAE pre-mRNA at the canonical splice sites. In some embodiments, the resulting functional, mature target mRNA can be translated normally, thereby increasing the amount of the functional target protein in the patient’s cells and preventing symptoms of the target associated disease. In some embodiments, canonical splicing of the identified target NSAE pre-mRNA transcripts to produce functional, mature target mRNA may be reduced using a therapeutic agent, such as an ASO, that inhibits constitutive splicing of target NSAE pre-mRNA at the canonical splice sites. In some embodiments, the resulting functional, mature target mRNA can be translated abnormally, thereby decreasing the amount of functional target protein in the patient’s cells and preventing symptoms of the target associated disease.

[0079] In various embodiments, the present disclosure provides a therapeutic agent that can target SYNGAP1 pre-mRNA to modulate splicing or protein expression level. The therapeutic agent can be a small molecule, nucleic acid oligomer, or polypeptide. In some embodiments, the therapeutic agent is an ASO. Various regions or sequences on the SYNGAP1 pre-mRNA can be targeted by a therapeutic agent, 2020334067   16 Jul 2026 such as an ASO. In some embodiments, the ASO targets a SYNGAP1 NSAE pre-mRNA transcribed from the SYNGAP1 gene. In some embodiments, the ASO targets a SYNGAP1 NSAE pre-mRNA transcribed from the SYNGAP1 gene comprising non-sense mediated RNA decay alternative exons (NSAEs). In some embodiments, the NSAE is comprises a portion of canonical exon 11 or the entire canonical exon 11 of a SYNGAP1 pre-mRNA transcript. In some embodiments, the NSAE is comprises only a portion of canonical exon 11 of a SYNGAP1 pre-mRNA transcript, or canonical exon 11 of a SYNGAP1 pre-mRNA transcript and at least a portion of the intron upstream of exon 11 of the SYNGAP1 pre-mRNA transcript. In some embodiments, the NSAE is included in a SYNGAP1 pre-mRNA transcript due to aberrant splicing. In some embodiments, the aberrant splicing is caused by a mutation in the SYNGAP1 gene. In some embodiments, the mutation is a G^A mutation at position -1 of the exon 11 splice donor (E8SJM, Exon 11 Splice Junction Mutation, c.894G>A). In some embodiments, the ASO targets a sequence within a NSAE of a SYNGAP1 pre-mRNA transcript. In some embodiments, the NSAE is comprises a portion of canonical exon 11 or the entire canonical exon 11 of a SYNGAP1 pre-mRNA transcript. In some embodiments, the ASO targets a sequence within exon 10 or 11 of a SYNGAP1 pre-mRNA transcript. In some embodiments, the ASO targets an exon sequence upstream (or 5’) from the 5’ splice site of exon 11 of a SYNGAP1 pre-mRNA transcript. In some embodiments, the ASO targets an exon sequence downstream (or 3’) from the 3’ splice site of exon 11 of a SYNGAP1 pre-mRNA transcript. In some embodiments, the ASO targets a sequence within an intron flanking the 3’ splice site of a NSAE of a SYNGAP1 pre-mRNA transcript. In some embodiments, the ASO targets a sequence within intron 10 or 11 of a SYNGAP1 pre-mRNA transcript. In some embodiments, the ASO targets an intron sequence upstream (or 5’) from the 3’ splice site of intron 10 or 11 of a SYNGAP1 pre-mRNA transcript. In some embodiments, the ASO targets an intron sequence downstream (or 3’) from the 5’ splice site of intron 10 or 11 of a SYNGAP1 pre-mRNA transcript. In some embodiments, the ASO targets a sequence within an intron flanking the 5’ splice site of a NSAE of a SYNGAP1 pre-mRNA transcript. In some embodiments, the ASO targets a sequence within intron 10 of a SYNGAP1 pre-mRNA transcript. In some embodiments, the ASO targets a sequence within intron 11 of a SYNGAP1 pre-mRNA transcript. In some embodiments, the ASO targets an intron sequence upstream (or 5’) from the 3’ splice site of intron 10 or 11 of a SYNGAP1 pre-mRNA transcript. In some embodiments, the ASO targets an intron sequence downstream (or 3’) from the 5’ splice site of intron 10 or 11 of a SYNGAP1 pre-mRNA transcript. In some embodiments, the ASO targets a sequence comprising an exon-intron boundary of a SYNGAP1 pre-mRNA transcript. In some embodiments, the exon is a NSAE. An exon-intron boundary can refer to the junction of an exon sequence and an intron sequence. In some embodiments, the intron sequence can flank the 5’ end of the NSAE, or the 3’ end of the exon. In some embodiments, the ASO targets a sequence comprising an exon 10-intron 11 boundary of a SYNGAP1 pre-mRNA transcript. In some embodiments, the ASO targets a sequence comprising an intron 10-exon 11 boundary of a SYNGAP1 NSAE pre-mRNA transcript. In some embodiments, the ASO targets a sequence comprising both a portion of an intron and a portion of an exon. 2020334067   16 Jul 2026

[0080] In various embodiments, the present disclosure provides a therapeutic agent that can target a target pre-mRNA to modulate splicing or protein expression level, wherein the target is any one selected from the group consisting of ABCA5, ABCA7, ABCC3, ABCC5, ABCC8, ABCD1, ABR, ACAD9, ACAP1, ACOX2, ACSF3, ACTN4, ADAM17, ADAMTS13, AKR1E2, ALAD, ALG3, ANKRD29, ANKS3, ANO4, AP3B2, AP3M1, AP5Z1, ARNTL, ASAP3, ATRX, BBS2, BBS4, BRD9, CALM3, CARS1, CASP9, CATSPER1, CCDC40, CCDC88B, CD4, CD58, CES2, CHFR, CLCN2, CNOT3, CNTROB, COL5A3, CPSF1, CSPP1, CTF1, CTH, CYP3A5, DAB2IP, DBN1, DDX51, DEAF1, DGKE, DHDDS, DMKN, DNHD1, DOCK8, DOK5, EIF2B5, ELAC2, ELP1, ENTPD4, ESRRA, ESS2, ETAA1, ETHE1, FANCA, FASTK, FASTKD3, FPGS, FREM1, GAS8, GCK, GGA1, GGA3, GGT1, GLMN, GON4L, GRB14, HDAC3, HELQ, HP1BP3, HPS1, HPS4, IDUA, IFT122, IL17RC, IMPDH1, INVS, IRF3, KCTD3, KLKB1, KYAT1, LAMC3, LDAH, LIMS2, MALT1, MAP3K7, MAPK13, MCAT, MCEE, MPI, MSTO1, NBEAL2, NLE1, NLRC5, NOM1, NOP58, NPHP1, NPR1, NUP188, OSGEP, PABPC4, PCOLCE, PHKA2, PIDD1, PKD1, PLA2G6, PLD2, PLEKHG5, PNPO, POLE, PON2, PRMT7, PRODH, PRPF3, PRPF4, PYCR1, RAD52, REXO1, RFX5, RHBDF2, RMND1, ROBO3, RPGRIP1, RTTN, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIK3, SIRT3, SKIV2L, SLC2A13, SLC12A7, SLC22A3, SLC25A13, SLC25A37, SLC27A5, SLC30A9, SLC30A10, SMPD1, SMTN, SNRPB, SP140, STAMBP, STXBP2, SULF2, SYNGAP1, SYNJ2, TAZ, TBL2, TDRD7, TECPR2, TFB1M, TM6SF1, TNK2, TOE1, TOR1B, TRAPPC6B, TRIP4, TRMT2A, TRMU, TRPV4, TTC19, TYMP, UMPS, UROD, WDR11, WDR62, WIPI1, WRAP53, XPO1, YY1AP1, and ZC3H14. The therapeutic agent can be a small molecule, nucleic acid oligomer, or polypeptide. In some embodiments, the therapeutic agent is an ASO. Various regions or sequences on the target pre-mRNA can be targeted by a therapeutic agent, such as an ASO. In some embodiments, the ASO targets a target NSAE pre-mRNA transcribed from the target gene. In some embodiments, the ASO targets a target NSAE pre-mRNA transcribed from the target gene comprising non-sense mediated RNA decay alternative exons (NSAEs). In some embodiments, the NSAE is comprises a portion of a canonical exon or the entire canonical exon of a target pre-mRNA transcript. In some embodiments, the NSAE is comprises only a portion of a canonical exon of a target pre-mRNA transcript, or a canonical exon of a target pre-mRNA transcript and at least a portion of the intron upstream of the exon of the target pre-mRNA transcript. In some embodiments, the NSAE is included in a target pre-mRNA transcript due to aberrant splicing. In some embodiments, the aberrant splicing is caused by a mutation in the target gene. In some embodiments, the ASO targets a sequence within a NSAE of a target pre-mRNA transcript. In some embodiments, the NSAE is comprises a portion of a canonical exon or the entire canonical exon of a target pre-mRNA transcript. In some embodiments, the ASO targets a sequence within a exon of a target pre-mRNA transcript. In some embodiments, the ASO targets an exon sequence upstream (or 5’) from the 5’ splice site of a exon of a target pre-mRNA transcript. In some embodiments, the ASO targets an exon sequence downstream (or 3’) from the 3’ splice site of a exon of a target pre-mRNA transcript. In some embodiments, the ASO targets a sequence within an intron flanking the 3’ splice site of a NSAE of a target pre-mRNA transcript. In some embodiments, the ASO targets a sequence within an intron of a 2020334067   16 Jul 2026 target pre-mRNA transcript. In some embodiments, the ASO targets an intron sequence upstream (or 5’) from the 3’ splice site of an intron of a target pre-mRNA transcript. In some embodiments, the ASO targets an intron sequence downstream (or 3’) from the 5’ splice site of an intron of a target pre-mRNA transcript. In some embodiments, the ASO targets a sequence within an intron flanking the 5’ splice site of a NSAE of a target pre-mRNA transcript. In some embodiments, the ASO targets a sequence within an intron of a target pre-mRNA transcript. In some embodiments, the ASO targets an intron sequence upstream (or 5’) from the 3’ splice site of an intron of a target pre-mRNA transcript. In some embodiments, the ASO targets an intron sequence downstream (or 3’) from the 5’ splice site of an intron of a target pre-mRNA transcript. In some embodiments, the ASO targets a sequence comprising an exonintron boundary of a target pre-mRNA transcript. In some embodiments, the exon is a NSAE. An exonintron boundary can refer to the junction of an exon sequence and an intron sequence. In some embodiments, the intron sequence can flank the 5’ end of the NSAE, or the 3’ end of the exon. In some embodiments, the ASO targets a sequence comprising an exon-intron boundary of a target pre-mRNA transcript. In some embodiments, the ASO targets a sequence comprising an intron-exon boundary of a target NSAE pre-mRNA transcript. In some embodiments, the ASO targets a sequence comprising both a portion of an intron and a portion of an exon.

[0081] In some embodiments, the ASO targets a sequence about 4 to about 300 nucleotides upstream (or 5’) from the 3’ splice site of a NSAE of a SYNGAP1 pre-mRNA transcript. In some embodiments, the ASO targets a sequence about 1 to about 20 nucleotides, about 20 to about 50 nucleotides, about 50 to about 100 nucleotides, about 100 to about 150 nucleotides, about 150 to about 200 nucleotides, about 200 to about 250 nucleotides, or about 250 to about 300 nucleotides upstream (or 5’) from the 3’ splice site of the NSAE of a SYNGAP1 pre-mRNA transcript. In some embodiments, the ASO may target a sequence more than 300 nucleotides upstream from the 3’ splice site of the NSAE of a SYNGAP1pre-mRNA transcript. In some embodiments, the ASO targets a sequence about 4 to about 300 nucleotides downstream (or 3’) from the 3’ splice site of a NSAE of a SYNGAP1 pre-mRNA transcript. In some embodiments, the ASO targets a sequence about 1 to about 20 nucleotides, about 20 to about 50 nucleotides, about 50 to about 100 nucleotides, about 100 to about 150 nucleotides, about 150 to about 200 nucleotides, about 200 to about 250 nucleotides, or about 250 to about 300 nucleotides downstream (or 3’) from the 3’ splice site of the NSAE of a SYNGAP1 pre-mRNA transcript. In some embodiments, the ASO may target a sequence more than 300 nucleotides downstream from the 3’ splice site of the NSAE of a SYNGAP1 pre-mRNA transcript. In some embodiments, the ASO targets a sequence about 4 to about 300 nucleotides downstream (or 3’) from the 5’ splice site of the NSAE of a SYNGAP1 pre-mRNA transcript. In some embodiments, the ASO targets a sequence about 1 to about 20 nucleotides, about 20 to about 50 nucleotides, about 50 to about 100 nucleotides, about 100 to about 150 nucleotides, about 150 to about 200 nucleotides, about 200 to about 250 nucleotides, or about 250 to about 300 nucleotides downstream from the 5’ splice site of the NSAE of a SYNGAP1 pre-mRNA transcript. In some embodiments, the ASO targets a sequence more than 300 nucleotides downstream from the 5’ splice site of the NSAE of a SYNGAP1 pre-mRNA transcript. In some embodiments, the ASO targets a sequence 2020334067   16 Jul 2026 about 4 to about 300 nucleotides upstream (or 5’) from the 5’ splice site of the NSAE of a SYNGAP1 pre-mRNA transcript. In some embodiments, the ASO targets a sequence about 1 to about 20 nucleotides, about 20 to about 50 nucleotides, about 50 to about 100 nucleotides, about 100 to about 150 nucleotides, about 150 to about 200 nucleotides, about 200 to about 250 nucleotides, or about 250 to about 300 nucleotides upstream from the 5’ splice site of the NSAE exon of a SYNGAP1 pre-mRNA transcript. In some embodiments, the ASO targets a sequence more than 300 nucleotides upstream from the 5’ splice site of the NSAE exon of a SYNGAP1 pre-mRNA transcript.

[0082] In some embodiments, the ASO targets a sequence about 4 to about 300 nucleotides upstream (or 5’) from the 3’ splice site of a NSAE of a target pre-mRNA transcript, wherein the target is any one selected from the group consisting of ABCA5, ABCA7, ABCC3, ABCC5, ABCC8, ABCD1, ABR, ACAD9, ACAP1, ACOX2, ACSF3, ACTN4, ADAM17, ADAMTS13, AKR1E2, ALAD, ALG3, ANKRD29, ANKS3, ANO4, AP3B2, AP3M1, AP5Z1, ARNTL, ASAP3, ATRX, BBS2, BBS4, BRD9, CALM3, CARS1, CASP9, CATSPER1, CCDC40, CCDC88B, CD4, CD58, CES2, CHFR, CLCN2, CNOT3, CNTROB, COL5A3, CPSF1, CSPP1, CTF1, CTH, CYP3A5, DAB2IP, DBN1, DDX51, DEAF1, DGKE, DHDDS, DMKN, DNHD1, DOCK8, DOK5, EIF2B5, ELAC2, ELP1, ENTPD4, ESRRA, ESS2, ETAA1, ETHE1, FANCA, FASTK, FASTKD3, FPGS, FREM1, GAS8, GCK, GGA1, GGA3, GGT1, GLMN, GON4L, GRB14, HDAC3, HELQ, HP1BP3, HPS1, HPS4, IDUA, IFT122, IL17RC, IMPDH1, INVS, IRF3, KCTD3, KLKB1, KYAT1, LAMC3, LDAH, LIMS2, MALT1, MAP3K7, MAPK13, MCAT, MCEE, MPI, MSTO1, NBEAL2, NLE1, NLRC5, NOM1, NOP58, NPHP1, NPR1, NUP188, OSGEP, PABPC4, PCOLCE, PHKA2, PIDD1, PKD1, PLA2G6, PLD2, PLEKHG5, PNPO, POLE, PON2, PRMT7, PRODH, PRPF3, PRPF4, PYCR1, RAD52, REXO1, RFX5, RHBDF2, RMND1, ROBO3, RPGRIP1, RTTN, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIK3, SIRT3, SKIV2L, SLC2A13, SLC12A7, SLC22A3, SLC25A13, SLC25A37, SLC27A5, SLC30A9, SLC30A10, SMPD1, SMTN, SNRPB, SP140, STAMBP, STXBP2, SULF2, SYNGAP1, SYNJ2, TAZ, TBL2, TDRD7, TECPR2, TFB1M, TM6SF1, TNK2, TOE1, TOR1B, TRAPPC6B, TRIP4, TRMT2A, TRMU, TRPV4, TTC19, TYMP, UMPS, UROD, WDR11, WDR62, WIPI1, WRAP53, XPO1, YY1AP1, and ZC3H14. In some embodiments, the ASO targets a sequence about 1 to about 20 nucleotides, about 20 to about 50 nucleotides, about 50 to about 100 nucleotides, about 100 to about 150 nucleotides, about 150 to about 200 nucleotides, about 200 to about 250 nucleotides, or about 250 to about 300 nucleotides upstream (or 5’) from the 3’ splice site of the NSAE of a target pre-mRNA transcript. In some embodiments, the ASO may target a sequence more than 300 nucleotides upstream from the 3’ splice site of the NSAE of a target pre-mRNA transcript. In some embodiments, the ASO targets a sequence about 4 to about 300 nucleotides downstream (or 3’) from the 3’ splice site of a NSAE of a target pre-mRNA transcript. In some embodiments, the ASO targets a sequence about 1 to about 20 nucleotides, about 20 to about 50 nucleotides, about 50 to about 100 nucleotides, about 100 to about 150 nucleotides, about 150 to about 200 nucleotides, about 200 to about 250 nucleotides, or about 250 to about 300 nucleotides downstream (or 3’) from the 3’ splice site of the NSAE of a target pre-mRNA transcript. In some embodiments, the ASO may target a sequence more than 300 nucleotides downstream from the 3’ splice site of the NSAE of 2020334067   16 Jul 2026 a target pre-mRNA transcript. In some embodiments, the ASO targets a sequence about 4 to about 300 nucleotides downstream (or 3’) from the 5’ splice site of the NSAE of a target pre-mRNA transcript. In some embodiments, the ASO targets a sequence about 1 to about 20 nucleotides, about 20 to about 50 nucleotides, about 50 to about 100 nucleotides, about 100 to about 150 nucleotides, about 150 to about 200 nucleotides, about 200 to about 250 nucleotides, or about 250 to about 300 nucleotides downstream from the 5’ splice site of the NSAE of a target pre-mRNA transcript. In some embodiments, the ASO targets a sequence more than 300 nucleotides downstream from the 5’ splice site of the NSAE of a target pre-mRNA transcript. In some embodiments, the ASO targets a sequence about 4 to about 300 nucleotides upstream (or 5’) from the 5’ splice site of the NSAE of a target pre-mRNA transcript. In some embodiments, the ASO targets a sequence about 1 to about 20 nucleotides, about 20 to about 50 nucleotides, about 50 to about 100 nucleotides, about 100 to about 150 nucleotides, about 150 to about 200 nucleotides, about 200 to about 250 nucleotides, or about 250 to about 300 nucleotides upstream from the 5’ splice site of the NSAE exon of a target pre-mRNA transcript. In some embodiments, the ASO targets a sequence more than 300 nucleotides upstream from the 5’ splice site of the NSAE exon of a target pre-mRNA transcript.

[0083] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a genomic sequence selected from the group consisting of ABCA5, ABCA7, ABCC3, ABCC5, ABCC8, ABCD1, ABR, ACAD9, ACAP1, ACOX2, ACSF3, ACTN4, ADAM17, ADAMTS13, AKR1E2, ALAD, ALG3, ANKRD29, ANKS3, ANO4, AP3B2, AP3M1, AP5Z1, ARNTL, ASAP3, ATRX, BBS2, BBS4, BRD9, CALM3, CARS1, CASP9, CATSPER1, CCDC40, CCDC88B, CD4, CD58, CES2, CHFR, CLCN2, CNOT3, CNTROB, COL5A3, CPSF1, CSPP1, CTF1, CTH, CYP3A5, DAB2IP, DBN1, DDX51, DEAF1, DGKE, DHDDS, DMKN, DNHD1, DOCK8, DOK5, EIF2B5, ELAC2, ELP1, ENTPD4, ESRRA, ESS2, ETAA1, ETHE1, FANCA, FASTK, FASTKD3, FPGS, FREM1, GAS8, GCK, GGA1, GGA3, GGT1, GLMN, GON4L, GRB14, HDAC3, HELQ, HP1BP3, HPS1, HPS4, IDUA, IFT122, IL17RC, IMPDH1, INVS, IRF3, KCTD3, KLKB1, KYAT1, LAMC3, LDAH, LIMS2, MALT1, MAP3K7, MAPK13, MCAT, MCEE, MPI, MSTO1, NBEAL2, NLE1, NLRC5, NOM1, NOP58, NPHP1, NPR1, NUP188, OSGEP, PABPC4, PCOLCE, PHKA2, PIDD1, PKD1, PLA2G6, PLD2, PLEKHG5, PNPO, POLE, PON2, PRMT7, PRODH, PRPF3, PRPF4, PYCR1, RAD52, REXO1, RFX5, RHBDF2, RMND1, ROBO3, RPGRIP1, RTTN, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIK3, SIRT3, SKIV2L, SLC2A13, SLC12A7, SLC22A3, SLC25A13, SLC25A37, SLC27A5, SLC30A9, SLC30A10, SMPD1, SMTN, SNRPB, SP140, STAMBP, STXBP2, SULF2, SYNGAP1, SYNJ2, TAZ, TBL2, TDRD7, TECPR2, TFB1M, TM6SF1, TNK2, TOE1, TOR1B, TRAPPC6B, TRIP4, TRMT2A, TRMU, TRPV4, TTC19, TYMP, UMPS, UROD, WDR11, WDR62, WIPI1, WRAP53, XPO1, YY1AP1, and ZC3H14 genomic sequences. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a genomic sequence comprising a NSAE exon selected from the group consisting of ABCA5, ABCA7, ABCC3, ABCC5, ABCC8, ABCD1, ABR, ACAD9, ACAP1, ACOX2, ACSF3, ACTN4, ADAM17, ADAMTS13, AKR1E2, ALAD, ALG3, ANKRD29, ANKS3, ANO4, AP3B2, AP3M1, AP5Z1, ARNTL, ASAP3, ATRX, BBS2, BBS4, BRD9, CALM3, CARS1, CASP9, CATSPER1, CCDC40, CCDC88B, 2020334067   16 Jul 2026 CD4, CD58, CES2, CHFR, CLCN2, CNOT3, CNTROB, COL5A3, CPSF1, CSPP1, CTF1, CTH, CYP3A5, DAB2IP, DBN1, DDX51, DEAF1, DGKE, DHDDS, DMKN, DNHD1, DOCK8, DOK5, EIF2B5, ELAC2, ELP1, ENTPD4, ESRRA, ESS2, ETAA1, ETHE1, FANCA, FASTK, FASTKD3, FPGS, FREM1, GAS8, GCK, GGA1, GGA3, GGT1, GLMN, GON4L, GRB14, HDAC3, HELQ, HP1BP3, HPS1, HPS4, IDUA, IFT122, IL17RC, IMPDH1, INVS, IRF3, KCTD3, KLKB1, KYAT1, LAMC3, LDAH, LIMS2, MALT1, MAP3K7, MAPK13, MCAT, MCEE, MPI, MSTO1, NBEAL2, NLE1, NLRC5, NOM1, NOP58, NPHP1, NPR1, NUP188, OSGEP, PABPC4, PCOLCE, PHKA2, PIDD1, PKD1, PLA2G6, PLD2, PLEKHG5, PNPO, POLE, PON2, PRMT7, PRODH, PRPF3, PRPF4, PYCR1, RAD52, REXO1, RFX5, RHBDF2, RMND1, ROBO3, RPGRIP1, RTTN, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIK3, SIRT3, SKIV2L, SLC2A13, SLC12A7, SLC22A3, SLC25A13, SLC25A37, SLC27A5, SLC30A9, SLC30A10, SMPD1, SMTN, SNRPB, SP140, STAMBP, STXBP2, SULF2, SYNGAP1, SYNJ2, TAZ, TBL2, TDRD7, TECPR2, TFB1M, TM6SF1, TNK2, TOE1, TOR1B, TRAPPC6B, TRIP4, TRMT2A, TRMU, TRPV4, TTC19, TYMP, UMPS, UROD, WDR11, WDR62, WIPI1, WRAP53, XPO1, YY1AP1, and ZC3H14 genomic sequences. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon selected from the group consisting of ABCA5, ABCA7, ABCC3, ABCC5, ABCC8, ABCD1, ABR, ACAD9, ACAP1, ACOX2, ACSF3, ACTN4, ADAM17, ADAMTS13, AKR1E2, ALAD, ALG3, ANKRD29, ANKS3, ANO4, AP3B2, AP3M1, AP5Z1, ARNTL, ASAP3, ATRX, BBS2, BBS4, BRD9, CALM3, CARS1, CASP9, CATSPER1, CCDC40, CCDC88B, CD4, CD58, CES2, CHFR, CLCN2, CNOT3, CNTROB, COL5A3, CPSF1, CSPP1, CTF1, CTH, CYP3A5, DAB2IP, DBN1, DDX51, DEAF1, DGKE, DHDDS, DMKN, DNHD1, DOCK8, DOK5, EIF2B5, ELAC2, ELP1, ENTPD4, ESRRA, ESS2, ETAA1, ETHE1, FANCA, FASTK, FASTKD3, FPGS, FREM1, GAS8, GCK, GGA1, GGA3, GGT1, GLMN, GON4L, GRB14, HDAC3, HELQ, HP1BP3, HPS1, HPS4, IDUA, IFT122, IL17RC, IMPDH1, INVS, IRF3, KCTD3, KLKB1, KYAT1, LAMC3, LDAH, LIMS2, MALT1, MAP3K7, MAPK13, MCAT, MCEE, MPI, MSTO1, NBEAL2, NLE1, NLRC5, NOM1, NOP58, NPHP1, NPR1, NUP188, OSGEP, PABPC4, PCOLCE, PHKA2, PIDD1, PKD1, PLA2G6, PLD2, PLEKHG5, PNPO, POLE, PON2, PRMT7, PRODH, PRPF3, PRPF4, PYCR1, RAD52, REXO1, RFX5, RHBDF2, RMND1, ROBO3, RPGRIP1, RTTN, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIK3, SIRT3, SKIV2L, SLC2A13, SLC12A7, SLC22A3, SLC25A13, SLC25A37, SLC27A5, SLC30A9, SLC30A10, SMPD1, SMTN, SNRPB, SP140, STAMBP, STXBP2, SULF2, SYNGAP1, SYNJ2, TAZ, TBL2, TDRD7, TECPR2, TFB1M, TM6SF1, TNK2, TOE1, TOR1B, TRAPPC6B, TRIP4, TRMT2A, TRMU, TRPV4, TTC19, TYMP, UMPS, UROD, WDR11, WDR62, WIPI1, WRAP53, XPO1, YY1AP1, and ZC3H14 genomic sequences. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of the pre-mRNA transcripts of Table 4. In some embodiments, the ASO targets a pre-mRNA sequence comprising a NSAE exon selected from the group consisting of ABCA5, ABCA7, ABCC3, ABCC5, ABCC8, ABCD1, ABR, ACAD9, ACAP1, ACOX2, ACSF3, ACTN4, ADAM17, ADAMTS13, AKR1E2, ALAD, ALG3, ANKRD29, ANKS3, ANO4, AP3B2, AP3M1, AP5Z1, ARNTL, 2020334067   16 Jul 2026 ASAP3, ATRX, BBS2, BBS4, BRD9, CALM3, CARS1, CASP9, CATSPER1, CCDC40, CCDC88B, CD4, CD58, CES2, CHFR, CLCN2, CNOT3, CNTROB, COL5A3, CPSF1, CSPP1, CTF1, CTH, CYP3A5, DAB2IP, DBN1, DDX51, DEAF1, DGKE, DHDDS, DMKN, DNHD1, DOCK8, DOK5, EIF2B5, ELAC2, ELP1, ENTPD4, ESRRA, ESS2, ETAA1, ETHE1, FANCA, FASTK, FASTKD3, FPGS, FREM1, GAS8, GCK, GGA1, GGA3, GGT1, GLMN, GON4L, GRB14, HDAC3, HELQ, HP1BP3, HPS1, HPS4, IDUA, IFT122, IL17RC, IMPDH1, INVS, IRF3, KCTD3, KLKB1, KYAT1, LAMC3, LDAH, LIMS2, MALT1, MAP3K7, MAPK13, MCAT, MCEE, MPI, MSTO1, NBEAL2, NLE1, NLRC5, NOM1, NOP58, NPHP1, NPR1, NUP188, OSGEP, PABPC4, PCOLCE, PHKA2, PIDD1, PKD1, PLA2G6, PLD2, PLEKHG5, PNPO, POLE, PON2, PRMT7, PRODH, PRPF3, PRPF4, PYCR1, RAD52, REXO1, RFX5, RHBDF2, RMND1, ROBO3, RPGRIP1, RTTN, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIK3, SIRT3, SKIV2L, SLC2A13, SLC12A7, SLC22A3, SLC25A13, SLC25A37, SLC27A5, SLC30A9, SLC30A10, SMPD1, SMTN, SNRPB, SP140, STAMBP, STXBP2, SULF2, SYNGAP1, SYNJ2, TAZ, TBL2, TDRD7, TECPR2, TFB1M, TM6SF1, TNK2, TOE1, TOR1B, TRAPPC6B, TRIP4, TRMT2A, TRMU, TRPV4, TTC19, TYMP, UMPS, UROD, WDR11, WDR62, WIPI1, WRAP53, XPO1, YY1AP1, and ZC3H14 pre-mRNA sequences. In some embodiments, the ASO targets a pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon selected from the group consisting of ABCA5, ABCA7, ABCC3, ABCC5, ABCC8, ABCD1, ABR, ACAD9, ACAP1, ACOX2, ACSF3, ACTN4, ADAM17, ADAMTS13, AKR1E2, ALAD, ALG3, ANKRD29, ANKS3, ANO4, AP3B2, AP3M1, AP5Z1, ARNTL, ASAP3, ATRX, BBS2, BBS4, BRD9, CALM3, CARS1, CASP9, CATSPER1, CCDC40, CCDC88B, CD4, CD58, CES2, CHFR, CLCN2, CNOT3, CNTROB, COL5A3, CPSF1, CSPP1, CTF1, CTH, CYP3A5, DAB2IP, DBN1, DDX51, DEAF1, DGKE, DHDDS, DMKN, DNHD1, DOCK8, DOK5, EIF2B5, ELAC2, ELP1, ENTPD4, ESRRA, ESS2, ETAA1, ETHE1, FANCA, FASTK, FASTKD3, FPGS, FREM1, GAS8, GCK, GGA1, GGA3, GGT1, GLMN, GON4L, GRB14, HDAC3, HELQ, HP1BP3, HPS1, HPS4, IDUA, IFT122, IL17RC, IMPDH1, INVS, IRF3, KCTD3, KLKB1, KYAT1, LAMC3, LDAH, LIMS2, MALT1, MAP3K7, MAPK13, MCAT, MCEE, MPI, MSTO1, NBEAL2, NLE1, NLRC5, NOM1, NOP58, NPHP1, NPR1, NUP188, OSGEP, PABPC4, PCOLCE, PHKA2, PIDD1, PKD1, PLA2G6, PLD2, PLEKHG5, PNPO, POLE, PON2, PRMT7, PRODH, PRPF3, PRPF4, PYCR1, RAD52, REXO1, RFX5, RHBDF2, RMND1, ROBO3, RPGRIP1, RTTN, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIK3, SIRT3, SKIV2L, SLC2A13, SLC12A7, SLC22A3, SLC25A13, SLC25A37, SLC27A5, SLC30A9, SLC30A10, SMPD1, SMTN, SNRPB, SP140, STAMBP, STXBP2, SULF2, SYNGAP1, SYNJ2, TAZ, TBL2, TDRD7, TECPR2, TFB1M, TM6SF1, TNK2, TOE1, TOR1B, TRAPPC6B, TRIP4, TRMT2A, TRMU, TRPV4, TTC19, TYMP, UMPS, UROD, WDR11, WDR62, WIPI1, WRAP53, XPO1, YY1AP1, and ZC3H14 pre-mRNA sequences. In some embodiments, the ASO targets a pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon selected from the group consisting of ABCA5, ABCA7, ABCC3, ABCC5, ABCC8, ABCD1, ABR, ACAD9, ACAP1, ACOX2, ACSF3, ACTN4, ADAM17, ADAMTS13, AKR1E2, ALAD, ALG3, ANKRD29, ANKS3, ANO4, AP3B2, AP3M1, AP5Z1, ARNTL, ASAP3, ATRX, BBS2, BBS4, BRD9, CALM3, CARS1, CASP9, CATSPER1, CCDC40, CCDC88B, CD4, CD58, 2020334067   16 Jul 2026 CES2, CHFR, CLCN2, CNOT3, CNTROB, COL5A3, CPSF1, CSPP1, CTF1, CTH, CYP3A5, DAB2IP, DBN1, DDX51, DEAF1, DGKE, DHDDS, DMKN, DNHD1, DOCK8, DOK5, EIF2B5, ELAC2, ELP1, ENTPD4, ESRRA, ESS2, ETAA1, ETHE1, FANCA, FASTK, FASTKD3, FPGS, FREM1, GAS8, GCK, GGA1, GGA3, GGT1, GLMN, GON4L, GRB14, HDAC3, HELQ, HP1BP3, HPS1, HPS4, IDUA, IFT122, IL17RC, IMPDH1, INVS, IRF3, KCTD3, KLKB1, KYAT1, LAMC3, LDAH, LIMS2, MALT1, MAP3K7, MAPK13, MCAT, MCEE, MPI, MSTO1, NBEAL2, NLE1, NLRC5, NOM1, NOP58, NPHP1, NPR1, NUP188, OSGEP, PABPC4, PCOLCE, PHKA2, PIDD1, PKD1, PLA2G6, PLD2, PLEKHG5, PNPO, POLE, PON2, PRMT7, PRODH, PRPF3, PRPF4, PYCR1, RAD52, REXO1, RFX5, RHBDF2, RMND1, ROBO3, RPGRIP1, RTTN, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIK3, SIRT3, SKIV2L, SLC2A13, SLC12A7, SLC22A3, SLC25A13, SLC25A37, SLC27A5, SLC30A9, SLC30A10, SMPD1, SMTN, SNRPB, SP140, STAMBP, STXBP2, SULF2, SYNGAP1, SYNJ2, TAZ, TBL2, TDRD7, TECPR2, TFB1M, TM6SF1, TNK2, TOE1, TOR1B, TRAPPC6B, TRIP4, TRMT2A, TRMU, TRPV4, TTC19, TYMP, UMPS, UROD, WDR11, WDR62, WIPI1, WRAP53, XPO1, YY1AP1, and ZC3H14 pre-mRNA sequences. In some embodiments, the transcript is selected from the group consisting of the transcripts of Table 4.

[0084] In some embodiments, the pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a pre-mRNA transcript selected from the group consisting of ABCA5, ABCA7, ABCC3, ABCC5, ABCC8, ABCD1, ABR, ACAD9, ACAP1, ACOX2, ACSF3, ACTN4, ADAM17, ADAMTS13, AKR1E2, ALAD, ALG3, ANKRD29, ANKS3, ANO4, AP3B2, AP3M1, AP5Z1, ARNTL, ASAP3, ATRX, BBS2, BBS4, BRD9, CALM3, CARS1, CASP9, CATSPER1, CCDC40, CCDC88B, CD4, CD58, CES2, CHFR, CLCN2, CNOT3, CNTROB, COL5A3, CPSF1, CSPP1, CTF1, CTH, CYP3A5, DAB2IP, DBN1, DDX51, DEAF1, DGKE, DHDDS, DMKN, DNHD1, DOCK8, DOK5, EIF2B5, ELAC2, ELP1, ENTPD4, ESRRA, ESS2, ETAA1, ETHE1, FANCA, FASTK, FASTKD3, FPGS, FREM1, GAS8, GCK, GGA1, GGA3, GGT1, GLMN, GON4L, GRB14, HDAC3, HELQ, HP1BP3, HPS1, HPS4, IDUA, IFT122, IL17RC, IMPDH1, INVS, IRF3, KCTD3, KLKB1, KYAT1, LAMC3, LDAH, LIMS2, MALT1, MAP3K7, MAPK13, MCAT, MCEE, MPI, MSTO1, NBEAL2, NLE1, NLRC5, NOM1, NOP58, NPHP1, NPR1, NUP188, OSGEP, PABPC4, PCOLCE, PHKA2, PIDD1, PKD1, PLA2G6, PLD2, PLEKHG5, PNPO, POLE, PON2, PRMT7, PRODH, PRPF3, PRPF4, PYCR1, RAD52, REXO1, RFX5, RHBDF2, RMND1, ROBO3, RPGRIP1, RTTN, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIK3, SIRT3, SKIV2L, SLC2A13, SLC12A7, SLC22A3, SLC25A13, SLC25A37, SLC27A5, SLC30A9, SLC30A10, SMPD1, SMTN, SNRPB, SP140, STAMBP, STXBP2, SULF2, SYNGAP1, SYNJ2, TAZ, TBL2, TDRD7, TECPR2, TFB1M, TM6SF1, TNK2, TOE1, TOR1B, TRAPPC6B, TRIP4, TRMT2A, TRMU, TRPV4, TTC19, TYMP, UMPS, UROD, WDR11, WDR62, WIPI1, WRAP53, XPO1, YY1AP1, and ZC3H14 pre-mRNA transcripts or a complement thereof described herein.

[0085] In some embodiments, the targeted portion of the pre-mRNA selected from the group consisting of ABCA5, ABCA7, ABCC3, ABCC5, ABCC8, ABCD1, ABR, ACAD9, ACAP1, ACOX2, ACSF3, ACTN4, ADAM17, ADAMTS13, AKR1E2, ALAD, ALG3, ANKRD29, ANKS3, ANO4, AP3B2, 2020334067   16 Jul 2026 AP3M1, AP5Z1, ARNTL, ASAP3, ATRX, BBS2, BBS4, BRD9, CALM3, CARS1, CASP9, CATSPER1, CCDC40, CCDC88B, CD4, CD58, CES2, CHFR, CLCN2, CNOT3, CNTROB, COL5A3, CPSF1, CSPP1, CTF1, CTH, CYP3A5, DAB2IP, DBN1, DDX51, DEAF1, DGKE, DHDDS, DMKN, DNHD1, DOCK8, DOK5, EIF2B5, ELAC2, ELP1, ENTPD4, ESRRA, ESS2, ETAA1, ETHE1, FANCA, FASTK, FASTKD3, FPGS, FREM1, GAS8, GCK, GGA1, GGA3, GGT1, GLMN, GON4L, GRB14, HDAC3, HELQ, HP1BP3, HPS1, HPS4, IDUA, IFT122, IL17RC, IMPDH1, INVS, IRF3, KCTD3, KLKB1, KYAT1, LAMC3, LDAH, LIMS2, MALT1, MAP3K7, MAPK13, MCAT, MCEE, MPI, MSTO1, NBEAL2, NLE1, NLRC5, NOM1, NOP58, NPHP1, NPR1, NUP188, OSGEP, PABPC4, PCOLCE, PHKA2, PIDD1, PKD1, PLA2G6, PLD2, PLEKHG5, PNPO, POLE, PON2, PRMT7, PRODH, PRPF3, PRPF4, PYCR1, RAD52, REXO1, RFX5, RHBDF2, RMND1, ROBO3, RPGRIP1, RTTN, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIK3, SIRT3, SKIV2L, SLC2A13, SLC12A7, SLC22A3, SLC25A13, SLC25A37, SLC27A5, SLC30A9, SLC30A10, SMPD1, SMTN, SNRPB, SP140, STAMBP, STXBP2, SULF2, SYNGAP1, SYNJ2, TAZ, TBL2, TDRD7, TECPR2, TFB1M, TM6SF1, TNK2, TOE1, TOR1B, TRAPPC6B, TRIP4, TRMT2A, TRMU, TRPV4, TTC19, TYMP, UMPS, UROD, WDR11, WDR62, WIPI1, WRAP53, XPO1, YY1AP1, and ZC3H14 pre-mRNAs comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of the pre-mRNA transcripts of Table 4 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the pre-mRNA selected from the group consisting of ABCA5, ABCA7, ABCC3, ABCC5, ABCC8, ABCD1, ABR, ACAD9, ACAP1, ACOX2, ACSF3, ACTN4, ADAM17, ADAMTS13, AKR1E2, ALAD, ALG3, ANKRD29, ANKS3, ANO4, AP3B2, AP3M1, AP5Z1, ARNTL, ASAP3, ATRX, BBS2, BBS4, BRD9, CALM3, CARS1, CASP9, CATSPER1, CCDC40, CCDC88B, CD4, CD58, CES2, CHFR, CLCN2, CNOT3, CNTROB, COL5A3, CPSF1, CSPP1, CTF1, CTH, CYP3A5, DAB2IP, DBN1, DDX51, DEAF1, DGKE, DHDDS, DMKN, DNHD1, DOCK8, DOK5, EIF2B5, ELAC2, ELP1, ENTPD4, ESRRA, ESS2, ETAA1, ETHE1, FANCA, FASTK, FASTKD3, FPGS, FREM1, GAS8, GCK, GGA1, GGA3, GGT1, GLMN, GON4L, GRB14, HDAC3, HELQ, HP1BP3, HPS1, HPS4, IDUA, IFT122, IL17RC, IMPDH1, INVS, IRF3, KCTD3, KLKB1, KYAT1, LAMC3, LDAH, LIMS2, MALT1, MAP3K7, MAPK13, MCAT, MCEE, MPI, MSTO1, NBEAL2, NLE1, NLRC5, NOM1, NOP58, NPHP1, NPR1, NUP188, OSGEP, PABPC4, PCOLCE, PHKA2, PIDD1, PKD1, PLA2G6, PLD2, PLEKHG5, PNPO, POLE, PON2, PRMT7, PRODH, PRPF3, PRPF4, PYCR1, RAD52, REXO1, RFX5, RHBDF2, RMND1, ROBO3, RPGRIP1, RTTN, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIK3, SIRT3, SKIV2L, SLC2A13, SLC12A7, SLC22A3, SLC25A13, SLC25A37, SLC27A5, SLC30A9, SLC30A10, SMPD1, SMTN, SNRPB, SP140, STAMBP, STXBP2, SULF2, SYNGAP1, SYNJ2, TAZ, TBL2, TDRD7, TECPR2, TFB1M, TM6SF1, TNK2, TOE1, TOR1B, TRAPPC6B, TRIP4, TRMT2A, TRMU, TRPV4, TTC19, TYMP, UMPS, UROD, WDR11, WDR62, WIPI1, WRAP53, XPO1, YY1AP1, and ZC3H14 pre-mRNAs comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO: 170 - SEQ ID NO: 1098 or complements thereof. In some embodiments, the targeted portion of the pre-mRNA selected from the 2020334067   16 Jul 2026 group consisting of ABCA5, ABCA7, ABCC3, ABCC5, ABCC8, ABCD1, ABR, ACAD9, ACAP1, ACOX2, ACSF3, ACTN4, ADAM17, ADAMTS13, AKR1E2, ALAD, ALG3, ANKRD29, ANKS3, ANO4, AP3B2, AP3M1, AP5Z1, ARNTL, ASAP3, ATRX, BBS2, BBS4, BRD9, CALM3, CARS1, CASP9, CATSPER1, CCDC40, CCDC88B, CD4, CD58, CES2, CHFR, CLCN2, CNOT3, CNTROB, COL5A3, CPSF1, CSPP1, CTF1, CTH, CYP3A5, DAB2IP, DBN1, DDX51, DEAF1, DGKE, DHDDS, DMKN, DNHD1, DOCK8, DOK5, EIF2B5, ELAC2, ELP1, ENTPD4, ESRRA, ESS2, ETAA1, ETHE1, FANCA, FASTK, FASTKD3, FPGS, FREM1, GAS8, GCK, GGA1, GGA3, GGT1, GLMN, GON4L, GRB14, HDAC3, HELQ, HP1BP3, HPS1, HPS4, IDUA, IFT122, IL17RC, IMPDH1, INVS, IRF3, KCTD3, KLKB1, KYAT1, LAMC3, LDAH, LIMS2, MALT1, MAP3K7, MAPK13, MCAT, MCEE, MPI, MSTO1, NBEAL2, NLE1, NLRC5, NOM1, NOP58, NPHP1, NPR1, NUP188, OSGEP, PABPC4, PCOLCE, PHKA2, PIDD1, PKD1, PLA2G6, PLD2, PLEKHG5, PNPO, POLE, PON2, PRMT7, PRODH, PRPF3, PRPF4, PYCR1, RAD52, REXO1, RFX5, RHBDF2, RMND1, ROBO3, RPGRIP1, RTTN, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIK3, SIRT3, SKIV2L, SLC2A13, SLC12A7, SLC22A3, SLC25A13, SLC25A37, SLC27A5, SLC30A9, SLC30A10, SMPD1, SMTN, SNRPB, SP140, STAMBP, STXBP2, SULF2, SYNGAP1, SYNJ2, TAZ, TBL2, TDRD7, TECPR2, TFB1M, TM6SF1, TNK2, TOE1, TOR1B, TRAPPC6B, TRIP4, TRMT2A, TRMU, TRPV4, TTC19, TYMP, UMPS, UROD, WDR11, WDR62, WIPI1, WRAP53, XPO1, YY1AP1, and ZC3H14 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0086] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a SYNGAP1 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a SYNGAP1 genomic sequence comprising a NSAE exon. In some embodiments the NSAE exon is exon 11. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a SYNGAP1 genomic sequence comprising exon 11. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a SYNGAP1 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the intron flanking the 3’ splice site of the NSAE exon is intron 10 and the intron flanking the 5’ splice site of a NSAE exon is intron 11. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a SYNGAP1 genomic sequence comprising intron 10, exon 11 and intron 11. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000293748.9, premrna_ENST00000418600.7, premrna_ENST00000428982.4, premrna_ENST00000449372.7, premrna_ENST00000470232.1, premrna_ENST00000479510.2, premrna_ENST00000628646.2, premrna_ENST00000629380.3, premrna_ENST00000635885.1, premrna_ENST00000636075.1, premrna_ENST00000636116.1, premrna_ENST00000636146.1, premrna_ENST00000636193.1, premrna_ENST00000636436.1, premrna_ENST00000636443.1, premrna_ENST00000636640.1, premrna_ENST00000636731.1, premrna_ENST00000636905.1, premrna_ENST00000637052.1, premrna_ENST00000637194.1, premrna_ENST00000637490.1, premrna_ENST00000637587.1, premrna_ENST00000637671.1, premrna_ENST00000637721.1, 2020334067   16 Jul 2026 premrna_ENST00000637911.1, premrna_ENST00000638127.1, premrna_ENST00000638142.2, premrna_ENST00000644458.1, premrna_ENST00000645250.1, premrna_ENST00000646630.1. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising exon 10 and exon 11. In some embodiments, the ASO targets a SYNGAP1 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a SYNGAP1 pre-mRNA sequence comprising exon 11. In some embodiments, the ASO targets a SYNGAP1 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a SYNGAP1 pre-mRNA sequence comprising intron 10. In some embodiments, the ASO targets a SYNGAP1 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000293748.9, transcript_ENST00000418600.7, transcript_ENST00000428982.4, transcript_ENST00000449372.7, transcript_ENST00000470232.1, transcript_ENST00000479510.2, transcript_ENST00000628646.2, transcript_ENST00000629380.3, transcript_ENST00000635885.1, transcript_ENST00000636075.1, transcript_ENST00000636116.1, transcript_ENST00000636146.1, transcript_ENST00000636193.1, transcript_ENST00000636436.1, transcript_ENST00000636443.1, transcript_ENST00000636640.1, transcript_ENST00000636731.1, transcript_ENST00000636905.1, transcript_ENST00000637052.1, transcript_ENST00000637194.1, transcript_ENST00000637490.1, transcript_ENST00000637587.1, transcript_ENST00000637671.1, transcript_ENST00000637721.1, transcript_ENST00000637911.1, transcript_ENST00000638127.1, transcript_ENST00000638142.2, transcript_ENST00000644458.1, transcript_ENST00000645250.1 and transcript_ENST00000646630.1.

[0087] In some embodiments, the SYNGAP1 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000227460.8 or ENSG00000197283.17 or a complement thereof. In some embodiments, the SYNGAP1 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a SYNGAP1 pre-mRNA transcript or a complement thereof described herein.

[0088] In some embodiments, the targeted portion of the SYNGAP1 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000293748.9, premrna_ENST00000418600.7, premrna_ENST00000428982.4, premrna_ENST00000449372.7, premrna_ENST00000470232.1, premrna_ENST00000479510.2, premrna_ENST00000628646.2, premrna_ENST00000629380.3, premrna_ENST00000635885.1, premrna_ENST00000636075.1, premrna_ENST00000636116.1, premrna_ENST00000636146.1, premrna_ENST00000636193.1, premrna_ENST00000636436.1, premrna_ENST00000636443.1, premrna_ENST00000636640.1, premrna_ENST00000636731.1, premrna_ENST00000636905.1, premrna_ENST00000637052.1, premrna_ENST00000637194.1, premrna_ENST00000637490.1, premrna_ENST00000637587.1, premrna_ENST00000637671.1, premrna_ENST00000637721.1, premrna_ENST00000637911.1, premrna_ENST00000638127.1, premrna_ENST00000638142.2, premrna_ENST00000644458.1, 2020334067   16 Jul 2026 premrna_ENST00000645250.1, premrna_ENST00000646630.1 or a sequence of Table 2 or complements thereof. In some embodiments, the targeted portion of the SYNGAP1 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 166 - SEQ ID NO. 169 or complements thereof. In some embodiments, the ASO comprises a sequence that is at least about 80%, 85%, 90%, 95%, 97%, or 100% identical to any one the sequences of Table 1 or complements thereof.

[0089] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a ABCA5 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ABCA5 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ABCA5 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000392676.8, premrna_ENST00000586601.1, premrna_ENST00000586811.1, premrna_ENST00000586995.5, premrna_ENST00000587607.5, premrna_ENST00000588106.1, premrna_ENST00000588665.5, premrna_ENST00000588877.5, premrna_ENST00000589609.1, premrna_ENST00000589975.5, premrna_ENST00000591234.5, premrna_ENST00000592568.1, premrna_ENST00000593153.5, and premrna_ENST00000593253.5. In some embodiments, the ASO targets a ABCA5 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a ABCA5 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a ABCA5 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000392676.8, transcript_ENST00000586601.1, transcript_ENST00000586811.1, transcript_ENST00000586995.5, transcript_ENST00000587607.5, transcript_ENST00000588106.1, transcript_ENST00000588665.5, transcript_ENST00000588877.5, transcript_ENST00000589609.1, transcript_ENST00000589975.5, transcript_ENST00000591234.5, transcript_ENST00000592568.1, transcript_ENST00000593153.5, and transcript_ENST00000593253.5.

[0090] In some embodiments, the ABCA5 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000154265.16 or a complement thereof. In some embodiments, the ABCA5 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a ABCA5 pre-mRNA transcript or a complement thereof described herein.

[0091] In some embodiments, the targeted portion of the ABCA5 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000392676.8, premrna_ENST00000586601.1, premrna_ENST00000586811.1, premrna_ENST00000586995.5, premrna_ENST00000587607.5, premrna_ENST00000588106.1, premrna_ENST00000588665.5, 2020334067   16 Jul 2026 premrna_ENST00000588877.5, premrna_ENST00000589609.1, premrna_ENST00000589975.5, premrna_ENST00000591234.5, premrna_ENST00000592568.1, premrna_ENST00000593153.5, premrna_ENST00000593253.5, or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the ABCA5 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 170 - SEQ ID NO. 173 or complements thereof. In some embodiments, the targeted portion of the ABCA5 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0092] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a ABCA7 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ABCA7 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ABCA7 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000263094.11, premrna_ENST00000433129.6, premrna_ENST00000435683.7, premrna_ENST00000524383.1, premrna_ENST00000524850.5, premrna_ENST00000525073.6, premrna_ENST00000525238.2, premrna_ENST00000526885.5, premrna_ENST00000527496.1, premrna_ENST00000529442.7, premrna_ENST00000530092.2, premrna_ENST00000530703.1, premrna_ENST00000531467.5, premrna_ENST00000531478.5, premrna_ENST00000532194.3, premrna_ENST00000533574.1, premrna_ENST00000612569.1, and premrna_ENST00000673773.1. In some embodiments, the ASO targets a ABCA7 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a ABCA7 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a ABCA7 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000263094.11, transcript_ENST00000433129.6, transcript_ENST00000435683.7, transcript_ENST00000524383.1, transcript_ENST00000524850.5, transcript_ENST00000525073.6, transcript_ENST00000525238.2, transcript_ENST00000526885.5, transcript_ENST00000527496.1, transcript_ENST00000529442.7, transcript_ENST00000530092.2, transcript_ENST00000530703.1, transcript_ENST00000531467.5, transcript_ENST00000531478.5, transcript_ENST00000532194.3, transcript_ENST00000533574.1, transcript_ENST00000612569.1, and transcript_ENST00000673773.1.

[0093] In some embodiments, the ABCA7 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000064687.13 or a complement thereof. In some embodiments, the ABCA7 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a ABCA7 pre-mRNA transcript or a complement thereof described herein. 2020334067   16 Jul 2026

[0094] In some embodiments, the targeted portion of the ABCA7 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000263094.11, premrna_ENST00000433129.6, premrna_ENST00000435683.7, premrna_ENST00000524383.1, premrna_ENST00000524850.5, premrna_ENST00000525073.6, premrna_ENST00000525238.2, premrna_ENST00000526885.5, premrna_ENST00000527496.1, premrna_ENST00000529442.7, premrna_ENST00000530092.2, premrna_ENST00000530703.1, premrna_ENST00000531467.5, premrna_ENST00000531478.5, premrna_ENST00000532194.3, premrna_ENST00000533574.1, premrna_ENST00000612569.1, premrna_ENST00000673773.1 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the ABCA7 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 174 - SEQ ID NO. 177 or complements thereof. In some embodiments, the targeted portion of the ABCA7 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0095] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a ABCC3 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ABCC3 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ABCC3 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000285238.13, premrna_ENST00000427699.5, premrna_ENST00000502426.5, premrna_ENST00000503304.1, premrna_ENST00000503337.1, premrna_ENST00000504586.1, premrna_ENST00000505699.5, premrna_ENST00000506464.5, premrna_ENST00000508929.1, premrna_ENST00000510633.5, premrna_ENST00000510891.1, premrna_ENST00000513511.5, premrna_ENST00000513589.1, premrna_ENST00000513745.1, premrna_ENST00000515070.1, premrna_ENST00000515585.1, premrna_ENST00000515707.1, and premrna_ENST00000571855.1 In some embodiments, the ASO targets a ABCC3 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a ABCC3 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a ABCC3 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000285238.13, transcript_ENST00000427699.5, transcript_ENST00000502426.5, transcript_ENST00000503304.1, transcript_ENST00000503337.1, transcript_ENST00000504586.1, transcript_ENST00000505699.5, transcript_ENST00000506464.5, transcript_ENST00000508929.1, transcript_ENST00000510633.5, transcript_ENST00000510891.1, transcript_ENST00000513511.5, transcript_ENST00000513589.1, transcript_ENST00000513745.1, transcript_ENST00000515070.1, transcript_ENST00000515585.1, transcript_ENST00000515707.1, and transcript_ENST00000571855.1. 2020334067   16 Jul 2026

[0096] In some embodiments, the ABCC3 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000108846.16 or a complement thereof. In some embodiments, the ABCC3 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a ABCC3 pre-mRNA transcript or a complement thereof described herein.

[0097] In some embodiments, the targeted portion of the ABCC3 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000285238.13, premrna_ENST00000427699.5, premrna_ENST00000502426.5, premrna_ENST00000503304.1, premrna_ENST00000503337.1, premrna_ENST00000504586.1, premrna_ENST00000505699.5, premrna_ENST00000506464.5, premrna_ENST00000508929.1, premrna_ENST00000510633.5, premrna_ENST00000510891.1, premrna_ENST00000513511.5, premrna_ENST00000513589.1, premrna_ENST00000513745.1, premrna_ENST00000515070.1, premrna_ENST00000515585.1, premrna_ENST00000515707.1, premrna_ENST00000571855.1 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the ABCC3 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 178 - SEQ ID NO. 181 or complements thereof. In some embodiments, the targeted portion of the ABCC3 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0098] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a ABCC5 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ABCC5 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ABCC5 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000265586.10, premrna_ENST00000334444.11, premrna_ENST00000382494.6, premrna_ENST00000392579.6, premrna_ENST00000427120.6, premrna_ENST00000437205.5, premrna_ENST00000437341.5, premrna_ENST00000438979.6, premrna_ENST00000443376.5, premrna_ENST00000443497.1, premrna_ENST00000446941.2, premrna_ENST00000476402.1, and premrna_ENST00000492216.1. In some embodiments, the ASO targets a ABCC5 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a ABCC5 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a ABCC5 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000265586.10, transcript_ENST00000334444.11, transcript_ENST00000382494.6, transcript_ENST00000392579.6, transcript_ENST00000427120.6, transcript_ENST00000437205.5, transcript_ENST00000437341.5, 2020334067   16 Jul 2026 transcript_ENST00000438979.6, transcript_ENST00000443376.5, transcript_ENST00000443497.1, transcript_ENST00000446941.2, transcript_ENST00000476402.1, and transcript_ENST00000492216.1.

[0099] In some embodiments, the ABCC5 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000114770.17 or a complement thereof. In some embodiments, the ABCC5 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a ABCC5 pre-mRNA transcript or a complement thereof described herein.

[0100] In some embodiments, the targeted portion of the ABCC5 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000265586.10, premrna_ENST00000334444.11, premrna_ENST00000382494.6, premrna_ENST00000392579.6, premrna_ENST00000427120.6, premrna_ENST00000437205.5, premrna_ENST00000437341.5, premrna_ENST00000438979.6, premrna_ENST00000443376.5, premrna_ENST00000443497.1, premrna_ENST00000446941.2, premrna_ENST00000476402.1, premrna_ENST00000492216.1 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the ABCC5 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 182 - SEQ ID NO. 185 or complements thereof. In some embodiments, the targeted portion of the ABCC5 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0101] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a ABCC8 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ABCC8 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ABCC8 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000302539.9, premrna_ENST00000389817.7, premrna_ENST00000524561.1, premrna_ENST00000525022.1, premrna_ENST00000526002.1, premrna_ENST00000526037.5, premrna_ENST00000526168.5, premrna_ENST00000526921.5, premrna_ENST00000527905.5, premrna_ENST00000528202.5, premrna_ENST00000528374.1, premrna_ENST00000529967.5, premrna_ENST00000530147.5, premrna_ENST00000531137.1, premrna_ENST00000531642.5, premrna_ENST00000531891.1, premrna_ENST00000531911.1, premrna_ENST00000532220.1, premrna_ENST00000532728.6, premrna_ENST00000612903.1, premrna_ENST00000635881.1, premrna_ENST00000642271.1, premrna_ENST00000642579.1, premrna_ENST00000642611.1, premrna_ENST00000642902.1, premrna_ENST00000643260.1, premrna_ENST00000643562.1, premrna_ENST00000643925.1, premrna_ENST00000644057.1, premrna_ENST00000644447.1, 2020334067   16 Jul 2026 premrna_ENST00000644472.1, premrna_ENST00000644484.1, premrna_ENST00000644542.1, premrna_ENST00000644649.1, premrna_ENST00000644675.1, premrna_ENST00000644757.1, premrna_ENST00000644772.1, premrna_ENST00000645004.1, premrna_ENST00000645076.1, premrna_ENST00000645417.1, premrna_ENST00000645744.1, premrna_ENST00000645760.1, premrna_ENST00000645884.1, premrna_ENST00000646003.1, premrna_ENST00000646207.1, premrna_ENST00000646276.1, premrna_ENST00000646592.1, premrna_ENST00000646737.1, premrna_ENST00000646902.1, premrna_ENST00000646993.1, premrna_ENST00000647013.1, premrna_ENST00000647015.1, premrna_ENST00000647086.1, and premrna_ENST00000647158.1. In some embodiments, the ASO targets a ABCC8 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a ABCC8 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a ABCC8 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000302539.9, transcript_ENST00000389817.7, transcript_ENST00000524561.1, transcript_ENST00000525022.1, transcript_ENST00000526002.1, transcript_ENST00000526037.5, transcript_ENST00000526168.5, transcript_ENST00000526921.5, transcript_ENST00000527905.5, transcript_ENST00000528202.5, transcript_ENST00000528374.1, transcript_ENST00000529967.5, transcript_ENST00000530147.5, transcript_ENST00000531137.1, transcript_ENST00000531642.5, transcript_ENST00000531891.1, transcript_ENST00000531911.1, transcript_ENST00000532220.1, transcript_ENST00000532728.6, transcript_ENST00000612903.1, transcript_ENST00000635881.1, transcript_ENST00000642271.1, transcript_ENST00000642579.1, transcript_ENST00000642611.1, transcript_ENST00000642902.1, transcript_ENST00000643260.1, transcript_ENST00000643562.1, transcript_ENST00000643925.1, transcript_ENST00000644057.1, transcript_ENST00000644447.1, transcript_ENST00000644472.1, transcript_ENST00000644484.1, transcript_ENST00000644542.1, transcript_ENST00000644649.1, transcript_ENST00000644675.1, transcript_ENST00000644757.1, transcript_ENST00000644772.1, transcript_ENST00000645004.1, transcript_ENST00000645076.1, transcript_ENST00000645417.1, transcript_ENST00000645744.1, transcript_ENST00000645760.1, transcript_ENST00000645884.1, transcript_ENST00000646003.1, transcript_ENST00000646207.1, transcript_ENST00000646276.1, transcript_ENST00000646592.1, transcript_ENST00000646737.1, transcript_ENST00000646902.1, transcript_ENST00000646993.1, transcript_ENST00000647013.1, transcript_ENST00000647015.1, transcript_ENST00000647086.1, and transcript_ENST00000647158.1.

[0102] In some embodiments, the ABCC8 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000006071.15 or a complement thereof. In some embodiments, the ABCC8 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a ABCC8 pre-mRNA transcript or a complement thereof described herein. 2020334067   16 Jul 2026

[0103] In some embodiments, the targeted portion of the ABCC8 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000302539.9, premrna_ENST00000389817.7, premrna_ENST00000524561.1, premrna_ENST00000525022.1, premrna_ENST00000526002.1, premrna_ENST00000526037.5, premrna_ENST00000526168.5, premrna_ENST00000526921.5, premrna_ENST00000527905.5, premrna_ENST00000528202.5, premrna_ENST00000528374.1, premrna_ENST00000529967.5, premrna_ENST00000530147.5, premrna_ENST00000531137.1, premrna_ENST00000531642.5, premrna_ENST00000531891.1, premrna_ENST00000531911.1, premrna_ENST00000532220.1, premrna_ENST00000532728.6, premrna_ENST00000612903.1, premrna_ENST00000635881.1, premrna_ENST00000642271.1, premrna_ENST00000642579.1, premrna_ENST00000642611.1, premrna_ENST00000642902.1, premrna_ENST00000643260.1, premrna_ENST00000643562.1, premrna_ENST00000643925.1, premrna_ENST00000644057.1, premrna_ENST00000644447.1, premrna_ENST00000644472.1, premrna_ENST00000644484.1, premrna_ENST00000644542.1, premrna_ENST00000644649.1, premrna_ENST00000644675.1, premrna_ENST00000644757.1, premrna_ENST00000644772.1, premrna_ENST00000645004.1, premrna_ENST00000645076.1, premrna_ENST00000645417.1, premrna_ENST00000645744.1, premrna_ENST00000645760.1, premrna_ENST00000645884.1, premrna_ENST00000646003.1, premrna_ENST00000646207.1, premrna_ENST00000646276.1, premrna_ENST00000646592.1, premrna_ENST00000646737.1, premrna_ENST00000646902.1, premrna_ENST00000646993.1, premrna_ENST00000647013.1, premrna_ENST00000647015.1, premrna_ENST00000647086.1, premrna_ENST00000647158.1 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the ABCC8 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 186 - SEQ ID NO. 189 or complements thereof. In some embodiments, the targeted portion of the ABCC8 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0104] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a ABCD1 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ABCD1 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ABCD1 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000218104.6, premrna_ENST00000370129.4, and premrna_ENST00000443684.2. In some embodiments, the ASO targets a ABCD1 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a ABCD1 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a ABCD1 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is 2020334067   16 Jul 2026 selected from the group consisting of transcript_ENST00000218104.6, transcript_ENST00000370129.4, and transcript_ENST00000443684.2.

[0105] In some embodiments, the ABCD1 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000101986.12 or a complement thereof. In some embodiments, the ABCD1 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a ABCD1 pre-mRNA transcript or a complement thereof described herein.

[0106] In some embodiments, the targeted portion of the ABCD1 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000218104.6, premrna_ENST00000370129.4, premrna_ENST00000443684.2 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the ABCD1 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 190 - SEQ ID NO. 193 or complements thereof. In some embodiments, the targeted portion of the ABCD1 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0107] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a ABR genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ABR genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ABR genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000291107.6, premrna_ENST00000302538.9, premrna_ENST00000536794.6, premrna_ENST00000543210.6, premrna_ENST00000544583.6, premrna_ENST00000570441.5, premrna_ENST00000570525.5, premrna_ENST00000570688.1, premrna_ENST00000571022.5, premrna_ENST00000571120.5, premrna_ENST00000571306.1, premrna_ENST00000571383.5, premrna_ENST00000571543.1, premrna_ENST00000571797.5, premrna_ENST00000571945.5, premrna_ENST00000572152.5, premrna_ENST00000572441.5, premrna_ENST00000572585.5, premrna_ENST00000572650.1, premrna_ENST00000573325.1, premrna_ENST00000573559.3, premrna_ENST00000573667.1, premrna_ENST00000573895.1, premrna_ENST00000574048.2, premrna_ENST00000574139.6, premrna_ENST00000574257.5, premrna_ENST00000574266.1, premrna_ENST00000574437.5, premrna_ENST00000574544.1, premrna_ENST00000574632.5, premrna_ENST00000574875.1, premrna_ENST00000575770.5, premrna_ENST00000575934.5, premrna_ENST00000576668.1, premrna_ENST00000576964.5, and premrna_ENST00000577052.5. In some embodiments, the ASO targets a ABR pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a ABR pre-mRNA sequence comprising an intron flanking the 3’ splice site 2020334067   16 Jul 2026 of the NSAE exon. In some embodiments, the ASO targets a ABR pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000291107.6, transcript_ENST00000302538.9, transcript_ENST00000536794.6, transcript_ENST00000543210.6, transcript_ENST00000544583.6, transcript_ENST00000570441.5, transcript_ENST00000570525.5, transcript_ENST00000570688.1, transcript_ENST00000571022.5, transcript_ENST00000571120.5, transcript_ENST00000571306.1, transcript_ENST00000571383.5, transcript_ENST00000571543.1, transcript_ENST00000571797.5, transcript_ENST00000571945.5, transcript_ENST00000572152.5, transcript_ENST00000572441.5, transcript_ENST00000572585.5, transcript_ENST00000572650.1, transcript_ENST00000573325.1, transcript_ENST00000573559.3, transcript_ENST00000573667.1, transcript_ENST00000573895.1, transcript_ENST00000574048.2, transcript_ENST00000574139.6, transcript_ENST00000574257.5, transcript_ENST00000574266.1, transcript_ENST00000574437.5, transcript_ENST00000574544.1, transcript_ENST00000574632.5, transcript_ENST00000574875.1, transcript_ENST00000575770.5, transcript_ENST00000575934.5, transcript_ENST00000576668.1, transcript_ENST00000576964.5, and transcript_ENST00000577052.5.

[0108] In some embodiments, the ABR pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000276016.4, ENSG00000278741.4 or ENSG00000159842.15 or a complement thereof. In some embodiments, the ABR pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a ABR pre-mRNA transcript or a complement thereof described herein.

[0109] In some embodiments, the targeted portion of the ABR pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000291107.6, premrna_ENST00000302538.9, premrna_ENST00000536794.6, premrna_ENST00000543210.6, premrna_ENST00000544583.6, premrna_ENST00000570441.5, premrna_ENST00000570525.5, premrna_ENST00000570688.1, premrna_ENST00000571022.5, premrna_ENST00000571120.5, premrna_ENST00000571306.1, premrna_ENST00000571383.5, premrna_ENST00000571543.1, premrna_ENST00000571797.5, premrna_ENST00000571945.5, premrna_ENST00000572152.5, premrna_ENST00000572441.5, premrna_ENST00000572585.5, premrna_ENST00000572650.1, premrna_ENST00000573325.1, premrna_ENST00000573559.3, premrna_ENST00000573667.1, premrna_ENST00000573895.1, premrna_ENST00000574048.2, premrna_ENST00000574139.6, premrna_ENST00000574257.5, premrna_ENST00000574266.1, premrna_ENST00000574437.5, premrna_ENST00000574544.1, premrna_ENST00000574632.5, premrna_ENST00000574875.1, premrna_ENST00000575770.5, premrna_ENST00000575934.5, premrna_ENST00000576668.1, premrna_ENST00000576964.5, premrna_ENST00000577052.5 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the ABR pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence 2020334067   16 Jul 2026 selected from the group consisting of SEQ ID NO. 194 - SEQ ID NO. 201 or complements thereof. In some embodiments, the targeted portion of the ABR pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0110] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a ACAD9 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ACAD9 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ACAD9 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000308982.12, premrna_ENST00000505192.5, premrna_ENST00000505602.1, premrna_ENST00000505867.5, premrna_ENST00000508971.1, premrna_ENST00000511227.5, premrna_ENST00000511325.1, premrna_ENST00000511526.5, premrna_ENST00000512801.5, premrna_ENST00000514336.1, premrna_ENST00000514643.5, and premrna_ENST00000515429.1. In some embodiments, the ASO targets a ACAD9 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a ACAD9 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a ACAD9 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000308982.12, transcript_ENST00000505192.5, transcript_ENST00000505602.1, transcript_ENST00000505867.5, transcript_ENST00000508971.1, transcript_ENST00000511227.5, transcript_ENST00000511325.1, transcript_ENST00000511526.5, transcript_ENST00000512801.5, transcript_ENST00000514336.1, transcript_ENST00000514643.5, and transcript_ENST00000515429.1.

[0111] In some embodiments, the ACAD9 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000177646.19 or a complement thereof. In some embodiments, the ACAD9 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a ACAD9 pre-mRNA transcript or a complement thereof described herein.

[0112] In some embodiments, the targeted portion of the ACAD9 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000308982.12, premrna_ENST00000505192.5, premrna_ENST00000505602.1, premrna_ENST00000505867.5, premrna_ENST00000508971.1, premrna_ENST00000511227.5, premrna_ENST00000511325.1, premrna_ENST00000511526.5, premrna_ENST00000512801.5, premrna_ENST00000514336.1, premrna_ENST00000514643.5, premrna_ENST00000515429.1 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the ACAD9 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 2020334067   16 Jul 2026 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 202 - SEQ ID NO. 207 or complements thereof. In some embodiments, the targeted portion of the ACAD9 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0113] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a ACAP1 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ACAP1 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ACAP1 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000308982.12, premrna_ENST00000505192.5, premr-na_ENST00000505602.1, premrna_ENST00000505867.5, premrna_ENST00000508971.1, premr-na_ENST00000511227.5, premrna_ENST00000511325.1, premrna_ENST00000511526.5, premr-na_ENST00000512801.5, premrna_ENST00000514336.1, premrna_ENST00000514643.5, and premrna_ENST00000515429.1. In some embodiments, the ASO targets a ACAP1 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a ACAP1 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a ACAP1 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000308982.12, transcript_ENST00000505192.5, tran-script_ENST00000505602.1, transcript_ENST00000505867.5, transcript_ENST00000508971.1, transcript_ENST00000511227.5, transcript_ENST00000511325.1, tran-script_ENST00000511526.5, transcript_ENST00000512801.5, transcript_ENST00000514336.1, transcript_ENST00000514643.5, and transcript_ENST00000515429.1.

[0114] In some embodiments, the ACAP1 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000072818.12 or ENSG00000288169.1 or a complement thereof. In some embodiments, the ACAP1 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a ACAP1 pre-mRNA transcript or a complement thereof described herein.

[0115] In some embodiments, the targeted portion of the ACAP1 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000308982.12, premrna_ENST00000505192.5, premr-na_ENST00000505602.1, premrna_ENST00000505867.5, premrna_ENST00000508971.1, premrna_ENST00000511227.5, premrna_ENST00000511325.1, premrna_ENST00000511526.5, premrna_ENST00000512801.5, premrna_ENST00000514336.1, premrna_ENST00000514643.5, premrna_ENST00000515429.1, or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the ACAP1 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 2020334067   16 Jul 2026 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 208 - SEQ ID NO. 211 or complements thereof. In some embodiments, the targeted portion of the ACAP1 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0116] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a ACOX2 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ACOX2 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ACOX2 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000302819.10, premrna_ENST00000459701.6, premrna_ENST00000459888.1, premrna_ENST00000460921.1, premrna_ENST00000466689.1, premrna_ENST00000466810.5, premrna_ENST00000467738.1, premrna_ENST00000474098.1, premrna_ENST00000475143.5, premrna_ENST00000480791.1, premrna_ENST00000481527.5, premrna_ENST00000489472.1, and premrna_ENST00000492530.1. In some embodiments, the ASO targets a ACOX2 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a ACOX2 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a ACOX2 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000302819.10, transcript_ENST00000459701.6, transcript_ENST00000459888.1, transcript_ENST00000460921.1, transcript_ENST00000466689.1, transcript_ENST00000466810.5, transcript_ENST00000467738.1, transcript_ENST00000474098.1, transcript_ENST00000475143.5, transcript_ENST00000480791.1, transcript_ENST00000481527.5, transcript_ENST00000489472.1, and transcript_ENST00000492530.1.

[0117] In some embodiments, the ACOX2 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000168306.13 or a complement thereof. In some embodiments, the ACOX2 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a ACOX2 pre-mRNA transcript or a complement thereof described herein.

[0118] In some embodiments, the targeted portion of the ACOX2 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000302819.10, premrna_ENST00000459701.6, premrna_ENST00000459888.1, premrna_ENST00000460921.1, premrna_ENST00000466689.1, premrna_ENST00000466810.5, premrna_ENST00000467738.1, premrna_ENST00000474098.1, premrna_ENST00000475143.5, premrna_ENST00000480791.1, premrna_ENST00000481527.5, premrna_ENST00000489472.1, premrna_ENST00000492530.1 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the ACOX2 2020334067   16 Jul 2026 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 212 - SEQ ID NO. : 215 or complements thereof. In some embodiments, the targeted portion of the ACOX2 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0119] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a ACSF3 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ACSF3 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ACSF3 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000317447.9, premrna_ENST00000378345.8, premrna_ENST00000393145.5, premrna_ENST00000406948.7, premrna_ENST00000535176.1, premrna_ENST00000537116.5, premrna_ENST00000537155.1, premrna_ENST00000537290.5, premrna_ENST00000537895.5, premrna_ENST00000538340.5, premrna_ENST00000540697.5, premrna_ENST00000541755.2, premrna_ENST00000542688.5, premrna_ENST00000543676.1, premrna_ENST00000544543.5, premrna_ENST00000562204.1, premrna_ENST00000562750.1, premrna_ENST00000614302.5, and premrna_ENST00000649953.1. In some embodiments, the ASO targets a ACSF3 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a ACSF3 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a ACSF3 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000317447.9, transcript_ENST00000378345.8, transcript_ENST00000393145.5, transcript_ENST00000406948.7, transcript_ENST00000535176.1, transcript_ENST00000537116.5, transcript_ENST00000537155.1, transcript_ENST00000537290.5, transcript_ENST00000537895.5, transcript_ENST00000538340.5, transcript_ENST00000540697.5, transcript_ENST00000541755.2, transcript_ENST00000542688.5, transcript_ENST00000543676.1, transcript_ENST00000544543.5, transcript_ENST00000562204.1, transcript_ENST00000562750.1, transcript_ENST00000614302.5, and transcript_ENST00000649953.1.

[0120] In some embodiments, the ACSF3 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000176715.17 or a complement thereof. In some embodiments, the ACSF3 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a ACSF3 pre-mRNA transcript or a complement thereof described herein.

[0121] In some embodiments, the targeted portion of the ACSF3 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000317447.9, 2020334067   16 Jul 2026 premrna_ENST00000378345.8, premrna_ENST00000393145.5, premrna_ENST00000406948.7, premrna_ENST00000535176.1, premrna_ENST00000537116.5, premrna_ENST00000537155.1, premrna_ENST00000537290.5, premrna_ENST00000537895.5, premrna_ENST00000538340.5, premrna_ENST00000540697.5, premrna_ENST00000541755.2, premrna_ENST00000542688.5, premrna_ENST00000543676.1, premrna_ENST00000544543.5, premrna_ENST00000562204.1, premrna_ENST00000562750.1, premrna_ENST00000614302.5, premrna_ENST00000649953.1 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the ACSF3 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 216 - SEQ ID NO. 221 or complements thereof. In some embodiments, the targeted portion of the ACSF3 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0122] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a ACTN4 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ACTN4 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ACTN4 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000252699.7, premrna_ENST00000390009.7, premrna_ENST00000424234.6, premrna_ENST00000440400.1, premrna_ENST00000477174.1, premrna_ENST00000489451.1, premrna_ENST00000495553.1, premrna_ENST00000497637.5, premrna_ENST00000586538.1, premrna_ENST00000588618.5, and premrna_ENST00000589528.1. In some embodiments, the ASO targets a ACTN4 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a ACTN4 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a ACTN4 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000252699.7, transcript_ENST00000390009.7, transcript_ENST00000424234.6, transcript_ENST00000440400.1, transcript_ENST00000477174.1, transcript_ENST00000489451.1, transcript_ENST00000495553.1, transcript_ENST00000497637.5, transcript_ENST00000586538.1, transcript_ENST00000588618.5, and transcript_ENST00000589528.1.

[0123] In some embodiments, the ACTN4 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000130402.12 or ENSG00000282844.2 or a complement thereof. In some embodiments, the ACTN4 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a ACTN4 pre-mRNA transcript or a complement thereof described herein. 2020334067   16 Jul 2026

[0124] In some embodiments, the targeted portion of the ACTN4 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000252699.7, premrna_ENST00000390009.7, premrna_ENST00000424234.6, premrna_ENST00000440400.1, premrna_ENST00000477174.1, premrna_ENST00000489451.1, premrna_ENST00000495553.1, premrna_ENST00000497637.5, premrna_ENST00000586538.1, premrna_ENST00000588618.5, premrna_ENST00000589528.1 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the ACTN4 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 222 - SEQ ID NO. 225 or complements thereof. In some embodiments, the targeted portion of the ACTN4 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0125] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a ADAM17 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ADAM17 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ADAM17 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000310823.8, premrna_ENST00000478059.1, premrna_ENST00000618923.2, premrna_ENST00000647610.1, premrna_ENST00000647622.1, premrna_ENST00000647979.1, premrna_ENST00000648002.1, premrna_ENST00000648548.1, premrna_ENST00000648857.1, premrna_ENST00000649068.1, premrna_ENST00000649227.1, premrna_ENST00000649686.1, premrna_ENST00000649798.1, premrna_ENST00000649972.1, premrna_ENST00000650116.1, and premrna_ENST00000650241.1 In some embodiments, the ASO targets a ADAM17 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a ADAM17 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a ADAM17 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000310823.8, transcript_ENST00000478059.1, transcript_ENST00000618923.2, transcript_ENST00000647610.1, transcript_ENST00000647622.1, transcript_ENST00000647979.1, transcript_ENST00000648002.1, transcript_ENST00000648548.1, transcript_ENST00000648857.1, transcript_ENST00000649068.1, transcript_ENST00000649227.1, transcript_ENST00000649686.1, transcript_ENST00000649798.1, transcript_ENST00000649972.1, transcript_ENST00000650116.1, and transcript_ENST00000650241.1.

[0126] In some embodiments, the ADAM17 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000151694.14 or a complement thereof. In some embodiments, the ADAM17 2020334067   16 Jul 2026 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a ADAM17 pre-mRNA transcript or a complement thereof described herein.

[0127] In some embodiments, the targeted portion of the ADAM17 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000310823.8, premrna_ENST00000478059.1, premrna_ENST00000618923.2, premrna_ENST00000647610.1, premrna_ENST00000647622.1, premrna_ENST00000647979.1, premrna_ENST00000648002.1, premrna_ENST00000648548.1, premrna_ENST00000648857.1, premrna_ENST00000649068.1, premrna_ENST00000649227.1, premrna_ENST00000649686.1, premrna_ENST00000649798.1, premrna_ENST00000649972.1, premrna_ENST00000650116.1, premrna_ENST00000650241.1 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the ADAM17 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 226 - SEQ ID NO. 229 or complements thereof. In some embodiments, the targeted portion of the ADAM17 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0128] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a ADAMTS13 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ADAMTS13 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ADAMTS13 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000355699.6, premrna_ENST00000356589.6, premrna_ENST00000371910.1, premrna_ENST00000371911.7, premrna_ENST00000371916.5, premrna_ENST00000371929.7, premrna_ENST00000474918.1, premrna_ENST00000485925.5, and premrna_ENST00000495234.5. In some embodiments, the ASO targets a ADAMTS13 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a ADAMTS13 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a ADAMTS13 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000355699.6, transcript_ENST00000356589.6, transcript_ENST00000371910.1, transcript_ENST00000371911.7, transcript_ENST00000371916.5, transcript_ENST00000371929.7, transcript_ENST00000474918.1, transcript_ENST00000485925.5, and transcript_ENST00000495234.5.

[0129] In some embodiments, the ADAMTS13 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000160323.18 or ENSG00000281244.2 or a complement thereof. In 2020334067   16 Jul 2026 some embodiments, the ADAMTS13 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a ADAMTS13 pre-mRNA transcript or a complement thereof described herein.

[0130] In some embodiments, the targeted portion of the ADAMTS13 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000355699.6, premrna_ENST00000356589.6, premrna_ENST00000371910.1, premrna_ENST00000371911.7, premrna_ENST00000371916.5, premrna_ENST00000371929.7, premrna_ENST00000474918.1, premrna_ENST00000485925.5, premrna_ENST00000495234.5, or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the ADAMTS13 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 230 - SEQ ID NO. 238 or complements thereof. In some embodiments, the targeted portion of the ADAMTS13 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0131] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a AKR1E2 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a AKR1E2 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a AKR1E2 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000298375.12, premrna_ENST00000334019.4, premrna_ENST00000345253.9, premrna_ENST00000441590.5, premrna_ENST00000462718.7, premrna_ENST00000463345.5, premrna_ENST00000474119.5, premrna_ENST00000487985.1, premrna_ENST00000525281.5, premrna_ENST00000525572.1, premrna_ENST00000525627.1, premrna_ENST00000532248.5, and premrna_ENST00000533295.5. In some embodiments, the ASO targets a AKR1E2 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a AKR1E2 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a AKR1E2 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000298375.12, transcript_ENST00000334019.4, transcript_ENST00000345253.9, transcript_ENST00000441590.5, transcript_ENST00000462718.7, transcript_ENST00000463345.5, transcript_ENST00000474119.5, transcript_ENST00000487985.1, transcript_ENST00000525281.5, transcript_ENST00000525572.1, transcript_ENST00000525627.1, transcript_ENST00000532248.5, and transcript_ENST00000533295.5.

[0132] In some embodiments, the AKR1E2 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000165568.18 or a complement thereof. In some embodiments, the AKR1E2 2020334067   16 Jul 2026 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a AKR1E2 pre-mRNA transcript or a complement thereof described herein.

[0133] In some embodiments, the targeted portion of the AKR1E2 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000298375.12, premrna_ENST00000334019.4, premrna_ENST00000345253.9, premrna_ENST00000441590.5, premrna_ENST00000462718.7, premrna_ENST00000463345.5, premrna_ENST00000474119.5, premrna_ENST00000487985.1, premrna_ENST00000525281.5, premrna_ENST00000525572.1, premrna_ENST00000525627.1, premrna_ENST00000532248.5, premrna_ENST00000533295.5 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the AKR1E2 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 239 - SEQ ID NO. 242 or complements thereof. In some embodiments, the targeted portion of the AKR1E2 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0134] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a ALAD genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ALAD genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ALAD genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000409155.8, premrna_ENST00000445750.1, premrna_ENST00000448137.5, premrna_ENST00000452726.1, premrna_ENST00000464749.5, premrna_ENST00000468504.5, premrna_ENST00000482001.1, premrna_ENST00000482847.5, and premrna_ENST00000494848.1. In some embodiments, the ASO targets a ALAD pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a ALAD pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a ALAD pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000409155.8, transcript_ENST00000445750.1, transcript_ENST00000448137.5, transcript_ENST00000452726.1, transcript_ENST00000464749.5, transcript_ENST00000468504.5, transcript_ENST00000482001.1, transcript_ENST00000482847.5, and transcript_ENST00000494848.1.

[0135] In some embodiments, the ALAD pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000148218.16 or a complement thereof. In some embodiments, the ALAD pre- 2020334067   16 Jul 2026 mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a ALAD pre-mRNA transcript or a complement thereof described herein.

[0136] In some embodiments, the targeted portion of the ALAD pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000409155.8, premrna_ENST00000445750.1, premrna_ENST00000448137.5, premrna_ENST00000452726.1, premrna_ENST00000464749.5, premrna_ENST00000468504.5, premrna_ENST00000482001.1, premrna_ENST00000482847.5, premrna_ENST00000494848.1 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the ALAD pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 243 - SEQ ID NO. 248 or complements thereof. In some embodiments, the targeted portion of the ALAD pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0137] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a ALG3 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ALG3 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ALG3 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000397676.8, premrna_ENST00000411922.5, premrna_ENST00000414845.5, premrna_ENST00000423996.5, premrna_ENST00000445626.6, premrna_ENST00000446569.1, premrna_ENST00000455059.5, premrna_ENST00000461415.5, premrna_ENST00000462735.6, premrna_ENST00000463495.5, premrna_ENST00000477959.1, premrna_ENST00000482048.1, premrna_ENST00000485912.1, premrna_ENST00000488976.5. In some embodiments, the ASO targets a ALG3 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a ALG3 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a ALG3 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000397676.8, transcript_ENST00000411922.5, transcript_ENST00000414845.5, transcript_ENST00000423996.5, transcript_ENST00000445626.6, transcript_ENST00000446569.1, transcript_ENST00000455059.5, transcript_ENST00000461415.5, transcript_ENST00000462735.6, transcript_ENST00000463495.5, transcript_ENST00000477959.1, transcript_ENST00000482048.1, transcript_ENST00000485912.1, and transcript_ENST00000488976.5.

[0138] In some embodiments, the ALG3 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000214160.10 or a complement thereof. In some embodiments, the ALG3 pre- 2020334067   16 Jul 2026 mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a ALG3 pre-mRNA transcript or a complement thereof described herein.

[0139] In some embodiments, the targeted portion of the ALG3 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000397676.8, premrna_ENST00000411922.5, premr-na_ENST00000414845.5, premrna_ENST00000423996.5, premrna_ENST00000445626.6, premrna_ENST00000446569.1, premrna_ENST00000455059.5, premrna_ENST00000461415.5, premrna_ENST00000462735.6, premrna_ENST00000463495.5, premrna_ENST00000477959.1, premrna_ENST00000482048.1, premrna_ENST00000485912.1, premrna_ENST00000488976.5, or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the ALG3 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 249 - SEQ ID NO. 255 or complements thereof. In some embodiments, the targeted portion of the ALG3 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0140] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a ANKRD29 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ANKRD29 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ANKRD29 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000322980.13, premrna_ENST00000585908.2, premrna_ENST00000586087.1, premrna_ENST00000586511.1, premrna_ENST00000587763.1, premrna_ENST00000591280.5, premrna_ENST00000591617.1, and premrna_ENST00000592179.6. In some embodiments, the ASO targets a ANKRD29 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a ANKRD29 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a ANKRD29 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000322980.13, transcript_ENST00000585908.2, transcript_ENST00000586087.1, transcript_ENST00000586511.1, transcript_ENST00000587763.1, transcript_ENST00000591280.5, transcript_ENST00000591617.1, and transcript_ENST00000592179.6.

[0141] In some embodiments, the ANKRD29 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000154065.17 or a complement thereof. In some embodiments, the ANKRD29 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 2020334067   16 Jul 2026 99% or 100% sequence identity to a ANKRD29 pre-mRNA transcript or a complement thereof described herein.

[0142] In some embodiments, the targeted portion of the ANKRD29 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000322980.13, premrna_ENST00000585908.2, premrna_ENST00000586087.1, premrna_ENST00000586511.1, premrna_ENST00000587763.1, premrna_ENST00000591280.5, premrna_ENST00000591617.1, premrna_ENST00000592179.6 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the ANKRD29 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 256 - SEQ ID NO. 259 or complements thereof. In some embodiments, the targeted portion of the ANKRD29 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0143] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a ANKS3 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ANKS3 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ANKS3 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000304283.9, premrna_ENST00000446014.6, premrna_ENST00000450067.6, premrna_ENST00000585773.5, premrna_ENST00000586159.5, premrna_ENST00000586166.5, premrna_ENST00000586605.5, premrna_ENST00000586632.1, premrna_ENST00000587005.5, premrna_ENST00000588398.1, premrna_ENST00000588513.1, premrna_ENST00000589035.5, premrna_ENST00000589065.5, premrna_ENST00000590147.5, premrna_ENST00000590193.5, premrna_ENST00000590689.1, premrna_ENST00000590730.5, premrna_ENST00000590803.5, premrna_ENST00000591185.5, premrna_ENST00000591281.5, premrna_ENST00000591653.5, premrna_ENST00000592068.5, premrna_ENST00000592077.5, premrna_ENST00000592190.1, premrna_ENST00000592421.5, premrna_ENST00000592698.5, premrna_ENST00000592711.5, premrna_ENST00000592840.1, premrna_ENST00000593120.5, and premrna_ENST00000614075.4. In some embodiments, the ASO targets a ANKS3 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a ANKS3 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a ANKS3 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000304283.9, transcript_ENST00000446014.6, transcript_ENST00000450067.6, transcript_ENST00000585773.5, transcript_ENST00000586159.5, transcript_ENST00000586166.5, transcript_ENST00000586605.5, transcript_ENST00000586632.1, transcript_ENST00000587005.5, transcript_ENST00000588398.1, transcript_ENST00000588513.1, 2020334067   16 Jul 2026 transcript_ENST00000589035.5, transcript_ENST00000589065.5, transcript_ENST00000590147.5, transcript_ENST00000590193.5, transcript_ENST00000590689.1, transcript_ENST00000590730.5, transcript_ENST00000590803.5, transcript_ENST00000591185.5, transcript_ENST00000591281.5, transcript_ENST00000591653.5, transcript_ENST00000592068.5, transcript_ENST00000592077.5, transcript_ENST00000592190.1, transcript_ENST00000592421.5, transcript_ENST00000592698.5, transcript_ENST00000592711.5, transcript_ENST00000592840.1, transcript_ENST00000593120.5, and transcript_ENST00000614075.4.

[0144] In some embodiments, the ANKS3 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000168096.15 or a complement thereof. In some embodiments, the ANKS3 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a ANKS3 pre-mRNA transcript or a complement thereof described herein.

[0145] In some embodiments, the targeted portion of the ANKS3 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000304283.9, premrna_ENST00000446014.6, premrna_ENST00000450067.6, premrna_ENST00000585773.5, premrna_ENST00000586159.5, premrna_ENST00000586166.5, premrna_ENST00000586605.5, premrna_ENST00000586632.1, premrna_ENST00000587005.5, premrna_ENST00000588398.1, premrna_ENST00000588513.1, premrna_ENST00000589035.5, premrna_ENST00000589065.5, premrna_ENST00000590147.5, premrna_ENST00000590193.5, premrna_ENST00000590689.1, premrna_ENST00000590730.5, premrna_ENST00000590803.5, premrna_ENST00000591185.5, premrna_ENST00000591281.5, premrna_ENST00000591653.5, premrna_ENST00000592068.5, premrna_ENST00000592077.5, premrna_ENST00000592190.1, premrna_ENST00000592421.5, premrna_ENST00000592698.5, premrna_ENST00000592711.5, premrna_ENST00000592840.1, premrna_ENST00000593120.5, premrna_ENST00000614075.4, or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the ANKS3 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 260 - SEQ ID NO. 263 or complements thereof. In some embodiments, the targeted portion of the ANKS3 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0146] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a ANO4 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ANO4 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ANO4 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of 2020334067   16 Jul 2026 premrna_ENST00000392977.8, premrna_ENST00000392979.7, premrna_ENST00000546991.1, premrna_ENST00000548940.1, premrna_ENST00000549155.6, premrna_ENST00000549234.1, premrna_ENST00000550015.1, premrna_ENST00000551148.1, and premrna_ENST00000644049.1. In some embodiments, the ASO targets a ANO4 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a ANO4 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a ANO4 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000392977.8, transcript_ENST00000392979.7, transcript_ENST00000546991.1, transcript_ENST00000548940.1, transcript_ENST00000549155.6, transcript_ENST00000549234.1, transcript_ENST00000550015.1, transcript_ENST00000551148.1, and transcript_ENST00000644049.1.

[0147] In some embodiments, the ANO4 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000151572.18 or ENSG00000262139.9 or a complement thereof. In some embodiments, the ANO4 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a ANO4 pre-mRNA transcript or a complement thereof described herein.

[0148] In some embodiments, the targeted portion of the ANO4 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000392977.8, premrna_ENST00000392979.7, premrna_ENST00000546991.1, premrna_ENST00000548940.1, premrna_ENST00000549155.6, premrna_ENST00000549234.1, premrna_ENST00000550015.1, premrna_ENST00000551148.1, premrna_ENST00000644049.1 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the ANO4 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 264 - SEQ ID NO. 267 or complements thereof. In some embodiments, the targeted portion of the ANO4 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0149] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a AP3B2 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a AP3B2 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a AP3B2 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000261722.8, premrna_ENST00000535348.5, premrna_ENST00000535359.6, premrna_ENST00000535385.6, premrna_ENST00000535513.2, premrna_ENST00000537735.2, premrna_ENST00000541693.5, premrna_ENST00000542200.2, premrna_ENST00000543938.6, 2020334067   16 Jul 2026 premrna_ENST00000559888.1, premrna_ENST00000560529.1, premrna_ENST00000561455.5, premrna_ENST00000620652.4, premrna_ENST00000642989.2, premrna_ENST00000652847.1, premrna_ENST00000657321.1, premrna_ENST00000659252.1, premrna_ENST00000660624.1, premrna_ENST00000661532.1, premrna_ENST00000663651.1, premrna_ENST00000664460.1, premrna_ENST00000665513.1, premrna_ENST00000666055.1, premrna_ENST00000666672.1, premrna_ENST00000666894.1, premrna_ENST00000666973.1, premrna_ENST00000667758.1, premrna_ENST00000668385.1, premrna_ENST00000668458.1, premrna_ENST00000668990.2, premrna_ENST00000669880.1, and premrna_ENST00000669930.1. In some embodiments, the ASO targets a AP3B2 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a AP3B2 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a AP3B2 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000261722.8, transcript_ENST00000535348.5, transcript_ENST00000535359.6, transcript_ENST00000535385.6, transcript_ENST00000535513.2, transcript_ENST00000537735.2, transcript_ENST00000541693.5, transcript_ENST00000542200.2, transcript_ENST00000543938.6, transcript_ENST00000559888.1, transcript_ENST00000560529.1, transcript_ENST00000561455.5, transcript_ENST00000620652.4, transcript_ENST00000642989.2, transcript_ENST00000652847.1, transcript_ENST00000657321.1, transcript_ENST00000659252.1, transcript_ENST00000660624.1, transcript_ENST00000661532.1, transcript_ENST00000663651.1, transcript_ENST00000664460.1, transcript_ENST00000665513.1, transcript_ENST00000666055.1, transcript_ENST00000666672.1, transcript_ENST00000666894.1, transcript_ENST00000666973.1, transcript_ENST00000667758.1, transcript_ENST00000668385.1, transcript_ENST00000668458.1, transcript_ENST00000668990.2, transcript_ENST00000669880.1, and transcript_ENST00000669930.1.

[0150] In some embodiments, the AP3B2 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000103723.15 or a complement thereof. In some embodiments, the AP3B2 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a AP3B2 pre-mRNA transcript or a complement thereof described herein.

[0151] In some embodiments, the targeted portion of the AP3B2 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000261722.8, premrna_ENST00000535348.5, premrna_ENST00000535359.6, premrna_ENST00000535385.6, premrna_ENST00000535513.2, premrna_ENST00000537735.2, premrna_ENST00000541693.5, premrna_ENST00000542200.2, premrna_ENST00000543938.6, premrna_ENST00000559888.1, premrna_ENST00000560529.1, premrna_ENST00000561455.5, premrna_ENST00000620652.4, premrna_ENST00000642989.2, premrna_ENST00000652847.1, premrna_ENST00000657321.1, premrna_ENST00000659252.1, premrna_ENST00000660624.1, premrna_ENST00000661532.1, 2020334067   16 Jul 2026 premrna_ENST00000663651.1, premrna_ENST00000664460.1, premrna_ENST00000665513.1, premrna_ENST00000666055.1, premrna_ENST00000666672.1, premrna_ENST00000666894.1, premrna_ENST00000666973.1, premrna_ENST00000667758.1, premrna_ENST00000668385.1, premrna_ENST00000668458.1, premrna_ENST00000668990.2, premrna_ENST00000669880.1, premrna_ENST00000669930.1 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the AP3B2 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 268 - SEQ ID NO. 271 or complements thereof. In some embodiments, the targeted portion of the AP3B2 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0152] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a AP3M1 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a AP3M1 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a AP3M1 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000355264.8, premrna_ENST00000372745.1, premrna_ENST00000480373.1, and premrna_ENST00000487653.1. In some embodiments, the ASO targets a AP3M1 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a AP3M1 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a AP3M1 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000355264.8, transcript_ENST00000372745.1, transcript_ENST00000480373.1, and transcript_ENST00000487653.1.

[0153] In some embodiments, the AP3M1 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000185009.12 or a complement thereof. In some embodiments, the AP3M1 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a AP3M1 pre-mRNA transcript or a complement thereof described herein.

[0154] In some embodiments, the targeted portion of the AP3M1 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000355264.8, premrna_ENST00000372745.1, premrna_ENST00000480373.1, premrna_ENST00000487653.1 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the AP3M1 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 272 - SEQ ID NO. 275 or complements thereof. In some embodiments, the targeted 2020334067   16 Jul 2026 portion of the AP3M1 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0155] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a AP5Z1 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a AP5Z1 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a AP5Z1 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000469614.1, premrna_ENST00000477454.1, premrna_ENST00000477680.6, premrna_ENST00000490487.1, premrna_ENST00000491375.1, premrna_ENST00000496303.6, premrna_ENST00000647628.1, premrna_ENST00000647984.1, premrna_ENST00000648237.1, premrna_ENST00000648360.1, premrna_ENST00000648765.1, premrna_ENST00000648925.1, premrna_ENST00000649063.2, premrna_ENST00000649315.1, premrna_ENST00000649419.1, premrna_ENST00000649736.1, premrna_ENST00000650310.1, premrna_ENST00000650451.1, and premrna_ENST00000650581.1. In some embodiments, the ASO targets a AP5Z1 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a AP5Z1 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a AP5Z1 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000469614.1, transcript_ENST00000477454.1, transcript_ENST00000477680.6, transcript_ENST00000490487.1, transcript_ENST00000491375.1, transcript_ENST00000496303.6, transcript_ENST00000647628.1, transcript_ENST00000647984.1, transcript_ENST00000648237.1, transcript_ENST00000648360.1, transcript_ENST00000648765.1, transcript_ENST00000648925.1, transcript_ENST00000649063.2, transcript_ENST00000649315.1, transcript_ENST00000649419.1, transcript_ENST00000649736.1, transcript_ENST00000650310.1, transcript_ENST00000650451.1, and transcript_ENST00000650581.1.

[0156] In some embodiments, the AP5Z1 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000242802.9 or a complement thereof. In some embodiments, the AP5Z1 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a AP5Z1 pre-mRNA transcript or a complement thereof described herein.

[0157] In some embodiments, the targeted portion of the AP5Z1 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000469614.1, premrna_ENST00000477454.1, premrna_ENST00000477680.6, premrna_ENST00000490487.1, premrna_ENST00000491375.1, premrna_ENST00000496303.6, premrna_ENST00000647628.1, premrna_ENST00000647984.1, premrna_ENST00000648237.1, premrna_ENST00000648360.1, premrna_ENST00000648765.1, premrna_ENST00000648925.1, premrna_ENST00000649063.2, 2020334067   16 Jul 2026 premrna_ENST00000649315.1, premrna_ENST00000649419.1, premrna_ENST00000649736.1, premrna_ENST00000650310.1, premrna_ENST00000650451.1, premrna_ENST00000650581.1 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the AP5Z1 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 276 - SEQ ID NO. 279 or complements thereof. In some embodiments, the targeted portion of the AP5Z1 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0158] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a ARNTL genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ARNTL genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ARNTL genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000389707.8, premrna_ENST00000401424.6, premrna_ENST00000403290.5, premrna_ENST00000403482.7, premrna_ENST00000403510.8, premrna_ENST00000472842.1, premrna_ENST00000480685.5, premrna_ENST00000482049.6, premrna_ENST00000485918.2, premrna_ENST00000497429.5, premrna_ENST00000524392.5, premrna_ENST00000527998.5, premrna_ENST00000529050.5, premrna_ENST00000529388.6, premrna_ENST00000529390.1, premrna_ENST00000529825.6, premrna_ENST00000530357.6, premrna_ENST00000531665.5, premrna_ENST00000533520.5, premrna_ENST00000534102.1, premrna_ENST00000534544.5, premrna_ENST00000673626.1, premrna_ENST00000673817.1, premrna_ENST00000673834.1, premrna_ENST00000673837.1, premrna_ENST00000673868.1, premrna_ENST00000673888.1, premrna_ENST00000673892.1, and premrna_ENST00000674108.1,. In some embodiments, the ASO targets a ARNTL pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a ARNTL pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a ARNTL pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000389707.8, transcript_ENST00000401424.6, transcript_ENST00000403290.5, transcript_ENST00000403482.7, transcript_ENST00000403510.8, transcript_ENST00000472842.1, transcript_ENST00000480685.5, transcript_ENST00000482049.6, transcript_ENST00000485918.2, transcript_ENST00000497429.5, transcript_ENST00000524392.5, transcript_ENST00000527998.5, transcript_ENST00000529050.5, transcript_ENST00000529388.6, transcript_ENST00000529390.1, transcript_ENST00000529825.6, transcript_ENST00000530357.6, transcript_ENST00000531665.5, transcript_ENST00000533520.5, transcript_ENST00000534102.1, transcript_ENST00000534544.5, transcript_ENST00000673626.1, transcript_ENST00000673817.1, transcript_ENST00000673834.1, 2020334067   16 Jul 2026 transcript_ENST00000673837.1, transcript_ENST00000673868.1, transcript_ENST00000673888.1, transcript_ENST00000673892.1, and transcript_ENST00000674108.1.

[0159] In some embodiments, the ARNTL pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000133794.19 or a complement thereof. In some embodiments, the ARNTL pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a ARNTL pre-mRNA transcript or a complement thereof described herein.

[0160] In some embodiments, the targeted portion of the ARNTL pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000389707.8, premrna_ENST00000401424.6, premrna_ENST00000403290.5, premrna_ENST00000403482.7, premrna_ENST00000403510.8, premrna_ENST00000472842.1, premrna_ENST00000480685.5, premrna_ENST00000482049.6, premrna_ENST00000485918.2, premrna_ENST00000497429.5, premrna_ENST00000524392.5, premrna_ENST00000527998.5, premrna_ENST00000529050.5, premrna_ENST00000529388.6, premrna_ENST00000529390.1, premrna_ENST00000529825.6, premrna_ENST00000530357.6, premrna_ENST00000531665.5, premrna_ENST00000533520.5, premrna_ENST00000534102.1, premrna_ENST00000534544.5, premrna_ENST00000673626.1, premrna_ENST00000673817.1, premrna_ENST00000673834.1, premrna_ENST00000673837.1, premrna_ENST00000673868.1, premrna_ENST00000673888.1, premrna_ENST00000673892.1, premrna_ENST00000674108.1, or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the ARNTL pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 280 - SEQ ID NO. 283 or complements thereof. In some embodiments, the targeted portion of the ARNTL pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0161] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a ASAP3 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ASAP3 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ASAP3 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000336689.8, premrna_ENST00000437606.6, premrna_ENST00000449467.2, premrna_ENST00000465372.5, premrna_ENST00000475814.5, premrna_ENST00000478858.5, premrna_ENST00000484418.1, premrna_ENST00000492982.6, premrna_ENST00000495646.5, premrna_ENST00000530874.1, premrna_ENST00000608765.1, and premrna_ENST00000618240.4. In some embodiments, the ASO targets a ASAP3 pre-mRNA sequence comprising a NSAE exon. In some 2020334067   16 Jul 2026 embodiments, the ASO targets a ASAP3 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a ASAP3 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000336689.8, transcript_ENST00000437606.6, transcript_ENST00000449467.2, transcript_ENST00000465372.5, transcript_ENST00000475814.5, transcript_ENST00000478858.5, transcript_ENST00000484418.1, transcript_ENST00000492982.6, transcript_ENST00000495646.5, transcript_ENST00000530874.1, transcript_ENST00000608765.1, and transcript_ENST00000618240.4.

[0162] In some embodiments, the ASAP3 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000088280.19 or ENSG00000282854.2 a complement thereof. In some embodiments, the ASAP3 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a ASAP3 pre-mRNA transcript or a complement thereof described herein.

[0163] In some embodiments, the targeted portion of the ASAP3 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000336689.8, premrna_ENST00000437606.6, premrna_ENST00000449467.2, premrna_ENST00000465372.5, premrna_ENST00000475814.5, premrna_ENST00000478858.5, premrna_ENST00000484418.1, premrna_ENST00000492982.6, premrna_ENST00000495646.5, premrna_ENST00000530874.1, premrna_ENST00000608765.1, premrna_ENST00000618240.4, or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the ASAP3 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 284 - SEQ ID NO. 287 or complements thereof. In some embodiments, the targeted portion of the ASAP3 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0164] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a ATRX genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ATRX genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a ATRX genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000373344.10, premrna_ENST00000395603.7, premrna_ENST00000400866.4, premrna_ENST00000460639.2, premrna_ENST00000479487.1, premrna_ENST00000480283.5, premrna_ENST00000493470.2, premrna_ENST00000622960.1, premrna_ENST00000623242.3, premrna_ENST00000623316.1, premrna_ENST00000623321.3, premrna_ENST00000623706.3, premrna_ENST00000624032.3, premrna_ENST00000624166.3, premrna_ENST00000624193.1, 2020334067   16 Jul 2026 premrna_ENST00000624403.1, premrna_ENST00000624668.3, premrna_ENST00000624766.1, premrna_ENST00000625063.3, premrna_ENST00000635865.1, premrna_ENST00000636152.1, premrna_ENST00000636868.1, premrna_ENST00000637175.1, and premrna_ENST00000637959.1. In some embodiments, the ASO targets a ATRX pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a ATRX pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a ATRX pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000373344.10, transcript_ENST00000395603.7, transcript_ENST00000400866.4, transcript_ENST00000460639.2, transcript_ENST00000479487.1, transcript_ENST00000480283.5, transcript_ENST00000493470.2, transcript_ENST00000622960.1, transcript_ENST00000623242.3, transcript_ENST00000623316.1, transcript_ENST00000623321.3, transcript_ENST00000623706.3, transcript_ENST00000624032.3, transcript_ENST00000624166.3, transcript_ENST00000624193.1, transcript_ENST00000624403.1, transcript_ENST00000624668.3, transcript_ENST00000624766.1, transcript_ENST00000625063.3, transcript_ENST00000635865.1, transcript_ENST00000636152.1, transcript_ENST00000636868.1, transcript_ENST00000637175.1, and transcript_ENST00000637959.1.

[0165] In some embodiments, the ATRX pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000085224.22 or a complement thereof. In some embodiments, the ATRX pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a ATRX pre-mRNA transcript or a complement thereof described herein.

[0166] In some embodiments, the targeted portion of the ATRX pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000373344.10, premrna_ENST00000395603.7, premrna_ENST00000400866.4, premrna_ENST00000460639.2, premrna_ENST00000479487.1, premrna_ENST00000480283.5, premrna_ENST00000493470.2, premrna_ENST00000622960.1, premrna_ENST00000623242.3, premrna_ENST00000623316.1, premrna_ENST00000623321.3, premrna_ENST00000623706.3, premrna_ENST00000624032.3, premrna_ENST00000624166.3, premrna_ENST00000624193.1, premrna_ENST00000624403.1, premrna_ENST00000624668.3, premrna_ENST00000624766.1, premrna_ENST00000625063.3, premrna_ENST00000635865.1, premrna_ENST00000636152.1, premrna_ENST00000636868.1, premrna_ENST00000637175.1, premrna_ENST00000637959.1 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the ATRX pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 288 - SEQ ID NO. 297 or complements thereof. In some embodiments, the targeted portion of the ATRX pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof. 2020334067   16 Jul 2026

[0167] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a BBS2 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a BBS2 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a BBS2 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000245157.10, premrna_ENST00000561853.1, premrna_ENST00000561877.1, premrna_ENST00000561951.5, premrna_ENST00000562012.1, premrna_ENST00000562059.1, premrna_ENST00000562813.1, premrna_ENST00000564123.6, premrna_ENST00000564459.5, premrna_ENST00000565378.1, premrna_ENST00000565781.5, premrna_ENST00000565859.1, premrna_ENST00000566210.1, premrna_ENST00000566410.1, premrna_ENST00000566452.1, premrna_ENST00000566495.1, premrna_ENST00000566689.5, premrna_ENST00000568104.5, premrna_ENST00000569192.5, premrna_ENST00000569342.5, and premrna_ENST00000569941.5. In some embodiments, the ASO targets a BBS2 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a BBS2 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a BBS2 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000245157.10, transcript_ENST00000561853.1, transcript_ENST00000561877.1, transcript_ENST00000561951.5, transcript_ENST00000562012.1, transcript_ENST00000562059.1, transcript_ENST00000562813.1, transcript_ENST00000564123.6, transcript_ENST00000564459.5, transcript_ENST00000565378.1, transcript_ENST00000565781.5, transcript_ENST00000565859.1, transcript_ENST00000566210.1, transcript_ENST00000566410.1, transcript_ENST00000566452.1, transcript_ENST00000566495.1, transcript_ENST00000566689.5, transcript_ENST00000568104.5, transcript_ENST00000569192.5, transcript_ENST00000569342.5, and transcript_ENST00000569941.5.

[0168] In some embodiments, the BBS2 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000125124.12 or a complement thereof. In some embodiments, the BBS2 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a BBS2 pre-mRNA transcript or a complement thereof described herein.

[0169] In some embodiments, the targeted portion of the BBS2 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000245157.10, premrna_ENST00000561853.1, premrna_ENST00000561877.1, premrna_ENST00000561951.5, premrna_ENST00000562012.1, premrna_ENST00000562059.1, premrna_ENST00000562813.1, premrna_ENST00000564123.6, premrna_ENST00000564459.5, premrna_ENST00000565378.1, premrna_ENST00000565781.5, premrna_ENST00000565859.1, premrna_ENST00000566210.1, premrna_ENST00000566410.1, premrna_ENST00000566452.1, premrna_ENST00000566495.1, premrna_ENST00000566689.5, 2020334067   16 Jul 2026 premrna_ENST00000568104.5, premrna_ENST00000569192.5, premrna_ENST00000569342.5, premrna_ENST00000569941.5 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the BBS2 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 298 - SEQ ID NO. 301 or complements thereof. In some embodiments, the targeted portion of the BBS2 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0170] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a BBS4 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a BBS4 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a BBS4 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000268057.9, premrna_ENST00000395205.6, premrna_ENST00000561914.5, premrna_ENST00000562084.5, premrna_ENST00000562219.1, premrna_ENST00000563600.5, premrna_ENST00000564239.1, premrna_ENST00000565160.5, premrna_ENST00000566197.1, premrna_ENST00000566400.5, premrna_ENST00000566829.1, premrna_ENST00000566938.5, premrna_ENST00000567279.5, premrna_ENST00000568535.1, premrna_ENST00000569001.1, premrna_ENST00000569151.1, premrna_ENST00000569338.5, and premrna_ENST00000569440.5. In some embodiments, the ASO targets a BBS4 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a BBS4 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a BBS4 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000268057.9, transcript_ENST00000395205.6, transcript_ENST00000561914.5, transcript_ENST00000562084.5, transcript_ENST00000562219.1, transcript_ENST00000563600.5, transcript_ENST00000564239.1, transcript_ENST00000565160.5, transcript_ENST00000566197.1, transcript_ENST00000566400.5, transcript_ENST00000566829.1, transcript_ENST00000566938.5, transcript_ENST00000567279.5, transcript_ENST00000568535.1, transcript_ENST00000569001.1, transcript_ENST00000569151.1, transcript_ENST00000569338.5, and transcript_ENST00000569440.5.

[0171] In some embodiments, the BBS4 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000140463.14 or a complement thereof. In some embodiments, the BBS4 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a BBS4 pre-mRNA transcript or a complement thereof described herein.

[0172] In some embodiments, the targeted portion of the BBS4 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous 2020334067   16 Jul 2026 nucleic acids of a sequence of premrna_ENST00000268057.9, premrna_ENST00000395205.6, premrna_ENST00000561914.5, premrna_ENST00000562084.5, premrna_ENST00000562219.1, premrna_ENST00000563600.5, premrna_ENST00000564239.1, premrna_ENST00000565160.5, premrna_ENST00000566197.1, premrna_ENST00000566400.5, premrna_ENST00000566829.1, premrna_ENST00000566938.5, premrna_ENST00000567279.5, premrna_ENST00000568535.1, premrna_ENST00000569001.1, premrna_ENST00000569151.1, premrna_ENST00000569338.5, premrna_ENST00000569440.5 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the BBS4 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 302 - SEQ ID NO. 309 or complements thereof. In some embodiments, the targeted portion of the BBS4 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0173] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a BRD9 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a BRD9 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a BRD9 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000466684.5, premrna_ENST00000467963.6, premrna_ENST00000475706.5, premrna_ENST00000483173.5, premrna_ENST00000483234.5, premrna_ENST00000487688.1, premrna_ENST00000489093.1, premrna_ENST00000489816.5, premrna_ENST00000490814.6, premrna_ENST00000493082.5, premrna_ENST00000494422.1, premrna_ENST00000495265.5, premrna_ENST00000495794.5, premrna_ENST00000497410.5, premrna_ENST00000518250.5, premrna_ENST00000518251.1, premrna_ENST00000519112.5, premrna_ENST00000519838.5, and premrna_ENST00000523139.5. In some embodiments, the ASO targets a BRD9 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a BRD9 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a BRD9 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000466684.5, transcript_ENST00000467963.6, transcript_ENST00000475706.5, transcript_ENST00000483173.5, transcript_ENST00000483234.5, transcript_ENST00000487688.1, transcript_ENST00000489093.1, transcript_ENST00000489816.5, transcript_ENST00000490814.6, transcript_ENST00000493082.5, transcript_ENST00000494422.1, transcript_ENST00000495265.5, transcript_ENST00000495794.5, transcript_ENST00000497410.5, transcript_ENST00000518250.5, transcript_ENST00000518251.1, transcript_ENST00000519112.5, transcript_ENST00000519838.5, and transcript_ENST00000523139.5.

[0174] In some embodiments, the BRD9 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl 2020334067   16 Jul 2026 reference number ENSG00000028310.18 or a complement thereof. In some embodiments, the BRD9 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a BRD9 pre-mRNA transcript or a complement thereof described herein.

[0175] In some embodiments, the targeted portion of the BRD9 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000466684.5, premrna_ENST00000467963.6, premrna_ENST00000475706.5, premrna_ENST00000483173.5, premrna_ENST00000483234.5, premrna_ENST00000487688.1, premrna_ENST00000489093.1, premrna_ENST00000489816.5, premrna_ENST00000490814.6, premrna_ENST00000493082.5, premrna_ENST00000494422.1, premrna_ENST00000495265.5, premrna_ENST00000495794.5, premrna_ENST00000497410.5, premrna_ENST00000518250.5, premrna_ENST00000518251.1, premrna_ENST00000519112.5, premrna_ENST00000519838.5, premrna_ENST00000523139.5 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the BRD9 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 310 - SEQ ID NO. 313 or complements thereof. In some embodiments, the targeted portion of the BRD9 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0176] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a CALM3 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a CALM3 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a CALM3 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000291295.14, premrna_ENST00000391918.6, premrna_ENST00000477244.5, premrna_ENST00000482455.5, premrna_ENST00000486500.1, premrna_ENST00000594523.5, premrna_ENST00000595072.2, premrna_ENST00000596362.1, premrna_ENST00000597743.5, premrna_ENST00000597868.5, premrna_ENST00000598871.5, premrna_ENST00000599839.5, and premrna_ENST00000602169.2. In some embodiments, the ASO targets a CALM3 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a CALM3 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a CALM3 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000291295.14, transcript_ENST00000391918.6, transcript_ENST00000477244.5, transcript_ENST00000482455.5, transcript_ENST00000486500.1, transcript_ENST00000594523.5, transcript_ENST00000595072.2, transcript_ENST00000596362.1, transcript_ENST00000597743.5, transcript_ENST00000597868.5, transcript_ENST00000598871.5, transcript_ENST00000599839.5, and transcript_ENST00000602169.2. 2020334067   16 Jul 2026

[0177] In some embodiments, the CALM3 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000160014.17 or a complement thereof. In some embodiments, the CALM3 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a CALM3 pre-mRNA transcript or a complement thereof described herein.

[0178] In some embodiments, the targeted portion of the CALM3 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000291295.14, premrna_ENST00000391918.6, premrna_ENST00000477244.5, premrna_ENST00000482455.5, premrna_ENST00000486500.1, premrna_ENST00000594523.5, premrna_ENST00000595072.2, premrna_ENST00000596362.1, premrna_ENST00000597743.5, premrna_ENST00000597868.5, premrna_ENST00000598871.5, premrna_ENST00000599839.5, premrna_ENST00000602169.2 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the CALM3 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 314 - SEQ ID NO. 317 or complements thereof. In some embodiments, the targeted portion of the CALM3 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0179] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a CARS1 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a CARS1 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a CARS1 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000278224.13, premrna_ENST00000380525.8, premrna_ENST00000397111.9, premrna_ENST00000439280.6, premrna_ENST00000465207.5, premrna_ENST00000465240.1, premrna_ENST00000465331.1, premrna_ENST00000466442.6, premrna_ENST00000470221.6, premrna_ENST00000484484.5, premrna_ENST00000524825.5, premrna_ENST00000526890.5, premrna_ENST00000527330.2, premrna_ENST00000529772.5, premrna_ENST00000531387.5, and premrna_ENST00000639317.1. In some embodiments, the ASO targets a CARS1 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a CARS1 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a CARS1 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000278224.13, transcript_ENST00000380525.8, transcript_ENST00000397111.9, transcript_ENST00000439280.6, transcript_ENST00000465207.5, transcript_ENST00000465240.1, transcript_ENST00000465331.1, 2020334067   16 Jul 2026 transcript_ENST00000466442.6, transcript_ENST00000470221.6, transcript_ENST00000484484.5, transcript_ENST00000524825.5, transcript_ENST00000526890.5, transcript_ENST00000527330.2, transcript_ENST00000529772.5, transcript_ENST00000531387.5, and transcript_ENST00000639317.1.

[0180] In some embodiments, the CARS1 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000110619.17 or ENSG00000278191.4 or a complement thereof. In some embodiments, the CARS1 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a CARS1 pre-mRNA transcript or a complement thereof described herein.

[0181] In some embodiments, the targeted portion of the CARS1 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000278224.13, premrna_ENST00000380525.8, premrna_ENST00000397111.9, premrna_ENST00000439280.6, premrna_ENST00000465207.5, premrna_ENST00000465240.1, premrna_ENST00000465331.1, premrna_ENST00000466442.6, premrna_ENST00000470221.6, premrna_ENST00000484484.5, premrna_ENST00000524825.5, premrna_ENST00000526890.5, premrna_ENST00000527330.2, premrna_ENST00000529772.5, premrna_ENST00000531387.5, premrna_ENST00000639317.1, or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the CARS1 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 318 - SEQ ID NO. 321 or complements thereof. In some embodiments, the targeted portion of the CARS1 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0182] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a CASP9 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a CASP9 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a CASP9 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000333868.10, premrna_ENST00000348549.9, premrna_ENST00000375890.8, premrna_ENST00000400777.7, premrna_ENST00000424908.5, premrna_ENST00000440484.1, premrna_ENST00000447522.5, premrna_ENST00000469637.1, premrna_ENST00000474305.2, premrna_ENST00000546424.5, and premrna_ENST00000546969.1. In some embodiments, the ASO targets a CASP9 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a CASP9 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a CASP9 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of 2020334067   16 Jul 2026 transcript_ENST00000333868.10, transcript_ENST00000348549.9, transcript_ENST00000375890.8, transcript_ENST00000400777.7, transcript_ENST00000424908.5, transcript_ENST00000440484.1, transcript_ENST00000447522.5, transcript_ENST00000469637.1, transcript_ENST00000474305.2, transcript_ENST00000546424.5, and transcript_ENST00000546969.1.

[0183] In some embodiments, the CASP9 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000132906.18 or a complement thereof. In some embodiments, the CASP9 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a CASP9 pre-mRNA transcript or a complement thereof described herein.

[0184] In some embodiments, the targeted portion of the CASP9 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000333868.10, premrna_ENST00000348549.9, premrna_ENST00000375890.8, premrna_ENST00000400777.7, premrna_ENST00000424908.5, premrna_ENST00000440484.1, premrna_ENST00000447522.5, premrna_ENST00000469637.1, premrna_ENST00000474305.2, premrna_ENST00000546424.5, premrna_ENST00000546969.1 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the CASP9 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 322 - SEQ ID NO. 325 or complements thereof. In some embodiments, the targeted portion of the CASP9 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0185] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a CATSPER1 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a CATSPER1 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a CATSPER1 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000312106.6 and premrna_ENST00000529244.1. In some embodiments, the ASO targets a CATSPER1 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a CATSPER1 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a CATSPER1 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000312106.6 and transcript_ENST00000529244.1.

[0186] In some embodiments, the CATSPER1 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the 2020334067   16 Jul 2026 Ensembl reference number ENSG00000175294.6 or a complement thereof. In some embodiments, the CATSPER1 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a CATSPER1 pre-mRNA transcript or a complement thereof described herein.

[0187] In some embodiments, the targeted portion of the CATSPER1 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000312106.6, premrna_ENST00000529244.1, or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the CATSPER1 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 326 - SEQ ID NO. 329 or complements thereof. In some embodiments, the targeted portion of the CATSPER1 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0188] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a CCDC40 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a CCDC40 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a CCDC40 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000269318.9, premrna_ENST00000374876.4, premrna_ENST00000374877.7, premrna_ENST00000397545.9, premrna_ENST00000571028.1, premrna_ENST00000572083.5, premrna_ENST00000572253.5, premrna_ENST00000572270.1, premrna_ENST00000573474.5, premrna_ENST00000573903.1, premrna_ENST00000574099.1, premrna_ENST00000574799.5, premrna_ENST00000574933.1, premrna_ENST00000575431.1, premrna_ENST00000576033.5, and premrna_ENST00000576241.1. In some embodiments, the ASO targets a CCDC40 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a CCDC40 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a CCDC40 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000269318.9, transcript_ENST00000374876.4, transcript_ENST00000374877.7, transcript_ENST00000397545.9, transcript_ENST00000571028.1, transcript_ENST00000572083.5, transcript_ENST00000572253.5, transcript_ENST00000572270.1, transcript_ENST00000573474.5, transcript_ENST00000573903.1, transcript_ENST00000574099.1, transcript_ENST00000574799.5, transcript_ENST00000574933.1, transcript_ENST00000575431.1, transcript_ENST00000576033.5, and transcript_ENST00000576241.1.

[0189] In some embodiments, the CCDC40 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl 2020334067   16 Jul 2026 reference number ENSG00000141519.15 or a complement thereof. In some embodiments, the CCDC40 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a CCDC40 pre-mRNA transcript or a complement thereof described herein.

[0190] In some embodiments, the targeted portion of the CCDC40 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000269318.9, premrna_ENST00000374876.4, premrna_ENST00000374877.7, premrna_ENST00000397545.9, premrna_ENST00000571028.1, premrna_ENST00000572083.5, premrna_ENST00000572253.5, premrna_ENST00000572270.1, premrna_ENST00000573474.5, premrna_ENST00000573903.1, premrna_ENST00000574099.1, premrna_ENST00000574799.5, premrna_ENST00000574933.1, premrna_ENST00000575431.1, premrna_ENST00000576033.5, premrna_ENST00000576241.1, or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the CCDC40 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 330 - SEQ ID NO. 333 or complements thereof. In some embodiments, the targeted portion of the CCDC40 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0191] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a CCDC88B genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a CCDC88B genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a CCDC88B genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000301897.5, premrna_ENST00000356786.10, premrna_ENST00000359902.2, premrna_ENST00000463837.5, premrna_ENST00000472524.1, premrna_ENST00000473405.1, premrna_ENST00000479965.5, premrna_ENST00000492980.1, premrna_ENST00000494080.5, and premrna_ENST00000494566.5. In some embodiments, the ASO targets a CCDC88B pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a CCDC88B pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a CCDC88B pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000301897.5, transcript_ENST00000356786.10, transcript_ENST00000359902.2, transcript_ENST00000463837.5, transcript_ENST00000472524.1, transcript_ENST00000473405.1, transcript_ENST00000479965.5, transcript_ENST00000492980.1, transcript_ENST00000494080.5, and transcript_ENST00000494566.5. 2020334067   16 Jul 2026

[0192] In some embodiments, the CCDC88B pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000168071.22 or a complement thereof. In some embodiments, the CCDC88B pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a CCDC88B pre-mRNA transcript or a complement thereof described herein.

[0193] In some embodiments, the targeted portion of the CCDC88B pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000301897.5, premrna_ENST00000356786.10, premrna_ENST00000359902.2, premrna_ENST00000463837.5, premrna_ENST00000472524.1, premrna_ENST00000473405.1, premrna_ENST00000479965.5, premrna_ENST00000492980.1, premrna_ENST00000494080.5, premrna_ENST00000494566.5 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the CCDC88B pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 334 - SEQ ID NO. 337 or complements thereof. In some embodiments, the targeted portion of the CCDC88B pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0194] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a CD4 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a CD4 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a CD4 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000011653.9, premrna_ENST00000437800.6, premrna_ENST00000535466.5, premrna_ENST00000535707.5, premrna_ENST00000536563.1, premrna_ENST00000536590.1, premrna_ENST00000536610.5, premrna_ENST00000538827.5, premrna_ENST00000539492.1, premrna_ENST00000541982.5, premrna_ENST00000543755.1, and premrna_ENST00000544344.5. In some embodiments, the ASO targets a CD4 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a CD4 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a CD4 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000011653.9, transcript_ENST00000437800.6, transcript_ENST00000535466.5, transcript_ENST00000535707.5, transcript_ENST00000536563.1, transcript_ENST00000536590.1, transcript_ENST00000536610.5, transcript_ENST00000538827.5, transcript_ENST00000539492.1, transcript_ENST00000541982.5, transcript_ENST00000543755.1, and transcript_ENST00000544344.5. 2020334067   16 Jul 2026

[0195] In some embodiments, the CD4 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000010610.10 or a complement thereof. In some embodiments, the CD4 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a CD4 pre-mRNA transcript or a complement thereof described herein.

[0196] In some embodiments, the targeted portion of the CD4 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000011653.9, premrna_ENST00000437800.6, premrna_ENST00000535466.5, premrna_ENST00000535707.5, premrna_ENST00000536563.1, premrna_ENST00000536590.1, premrna_ENST00000536610.5, premrna_ENST00000538827.5, premrna_ENST00000539492.1, premrna_ENST00000541982.5, premrna_ENST00000543755.1, premrna_ENST00000544344.5 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the CD4 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 338 - SEQ ID NO. 341 or complements thereof. In some embodiments, the targeted portion of the CD4 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0197] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a CD58 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a CD58 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a CD58 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000369487.3, premrna_ENST00000369489.10, premrna_ENST00000457047.6, premrna_ENST00000464088.5, and premrna_ENST00000526981.1. In some embodiments, the ASO targets a CD58 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a CD58 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a CD58 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000369487.3, transcript_ENST00000369489.10, transcript_ENST00000457047.6, transcript_ENST00000464088.5, and transcript_ENST00000526981.1.

[0198] In some embodiments, the CD58 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000116815.16 or a complement thereof. In some embodiments, the CD58 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a CD58 pre-mRNA transcript or a complement thereof described herein. 2020334067   16 Jul 2026

[0199] In some embodiments, the targeted portion of the CD58 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000369487.3, premrna_ENST00000369489.10, premrna_ENST00000457047.6, premrna_ENST00000464088.5, premrna_ENST00000526981.1 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the CD58 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 342 - SEQ ID NO. 347 or complements thereof. In some embodiments, the targeted portion of the CD58 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0200] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a CES2 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a CES2 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a CES2 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000317091.10, premrna_ENST00000417689.6, premrna_ENST00000561697.5, premrna_ENST00000561843.1, premrna_ENST00000563988.1, premrna_ENST00000564420.1, premrna_ENST00000566182.1, premrna_ENST00000566359.1, premrna_ENST00000567128.1, premrna_ENST00000568347.1, premrna_ENST00000568470.6, premrna_ENST00000570032.2, premrna_ENST00000652196.1, and premrna_ENST00000652667.1.

[0201] In some embodiments, the ASO targets a CES2 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a CES2 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a CES2 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000317091.10, transcript_ENST00000417689.6, transcript_ENST00000561697.5, transcript_ENST00000561843.1, transcript_ENST00000563988.1, transcript_ENST00000564420.1, transcript_ENST00000566182.1, transcript_ENST00000566359.1, transcript_ENST00000567128.1, transcript_ENST00000568347.1, transcript_ENST00000568470.6, transcript_ENST00000570032.2, transcript_ENST00000652196.1, and transcript_ENST00000652667.1.

[0202] In some embodiments, the CES2 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000172831.14 or a complement thereof. In some embodiments, the CES2 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a CES2 pre-mRNA transcript or a complement thereof described herein.

[0203] In some embodiments, the targeted portion of the CES2 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous 2020334067   16 Jul 2026 nucleic acids of a sequence of premrna_ENST00000317091.10, premrna_ENST00000417689.6, premrna_ENST00000561697.5, premrna_ENST00000561843.1, premrna_ENST00000563988.1, premrna_ENST00000564420.1, premrna_ENST00000566182.1, premrna_ENST00000566359.1, premrna_ENST00000567128.1, premrna_ENST00000568347.1, premrna_ENST00000568470.6, premrna_ENST00000570032.2, premrna_ENST00000652196.1, premrna_ENST00000652667.1, or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the CES2 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 348 - SEQ ID NO. 359 or complements thereof. In some embodiments, the targeted portion of the CES2 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0204] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a CHFR genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a CHFR genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a CHFR genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000266880.11, premrna_ENST00000315585.11, premrna_ENST00000432561.6, premrna_ENST00000443047.6, premrna_ENST00000450056.6, premrna_ENST00000499045.2, premrna_ENST00000502279.2, premrna_ENST00000511001.2, premrna_ENST00000535181.5, premrna_ENST00000535527.5, premrna_ENST00000535897.1, premrna_ENST00000536196.1, premrna_ENST00000536843.5, premrna_ENST00000536932.5, premrna_ENST00000537551.5, premrna_ENST00000538235.2, premrna_ENST00000540537.5, premrna_ENST00000540963.1, premrna_ENST00000541341.5, premrna_ENST00000541817.5, premrna_ENST00000542714.5, premrna_ENST00000544093.5, premrna_ENST00000544268.5, and premrna_ENST00000545046.5. In some embodiments, the ASO targets a CHFR pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a CHFR pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a CHFR pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000266880.11, transcript_ENST00000315585.11, transcript_ENST00000432561.6, transcript_ENST00000443047.6, transcript_ENST00000450056.6, transcript_ENST00000499045.2, transcript_ENST00000502279.2, transcript_ENST00000511001.2, transcript_ENST00000535181.5, transcript_ENST00000535527.5, transcript_ENST00000535897.1, transcript_ENST00000536196.1, transcript_ENST00000536843.5, transcript_ENST00000536932.5, transcript_ENST00000537551.5, transcript_ENST00000538235.2, transcript_ENST00000540537.5, transcript_ENST00000540963.1, transcript_ENST00000541341.5, transcript_ENST00000541817.5, 2020334067   16 Jul 2026 transcript_ENST00000542714.5, transcript_ENST00000544093.5, transcript_ENST00000544268.5, and transcript_ENST00000545046.5.

[0205] In some embodiments, the CHFR pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000072609.17 or a complement thereof. In some embodiments, the CHFR pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a CHFR pre-mRNA transcript or a complement thereof described herein.

[0206] In some embodiments, the targeted portion of the CHFR pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000266880.11, premrna_ENST00000315585.11, premrna_ENST00000432561.6, premrna_ENST00000443047.6, premrna_ENST00000450056.6, premrna_ENST00000499045.2, premrna_ENST00000502279.2, premrna_ENST00000511001.2, premrna_ENST00000535181.5, premrna_ENST00000535527.5, premrna_ENST00000535897.1, premrna_ENST00000536196.1, premrna_ENST00000536843.5, premrna_ENST00000536932.5, premrna_ENST00000537551.5, premrna_ENST00000538235.2, premrna_ENST00000540537.5, premrna_ENST00000540963.1, premrna_ENST00000541341.5, premrna_ENST00000541817.5, premrna_ENST00000542714.5, premrna_ENST00000544093.5, premrna_ENST00000544268.5, premrna_ENST00000545046.5 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the CHFR pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 360 - SEQ ID NO. 363 or complements thereof. In some embodiments, the targeted portion of the CHFR pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0207] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a CLCN2 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a CLCN2 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a CLCN2 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000265593.9, premrna_ENST00000344937.11, premrna_ENST00000430397.5, premrna_ENST00000434054.6, premrna_ENST00000457512.1, premrna_ENST00000465231.1, premrna_ENST00000475279.2, premrna_ENST00000485667.1, premrna_ENST00000491162.1, premrna_ENST00000636180.1, premrna_ENST00000636241.1, premrna_ENST00000636419.1, premrna_ENST00000636492.1, premrna_ENST00000636658.1, premrna_ENST00000636661.1, premrna_ENST00000636830.1, premrna_ENST00000636860.1, premrna_ENST00000637258.1, premrna_ENST00000637392.1, premrna_ENST00000637538.1, premrna_ENST00000637909.1, and premrna_ENST00000638134.1. In some embodiments, the ASO targets a CLCN2 pre-mRNA sequence 2020334067   16 Jul 2026 comprising a NSAE exon. In some embodiments, the ASO targets a CLCN2 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a CLCN2 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000265593.9, transcript_ENST00000344937.11, transcript_ENST00000430397.5, transcript_ENST00000434054.6, transcript_ENST00000457512.1, transcript_ENST00000465231.1, transcript_ENST00000475279.2, transcript_ENST00000485667.1, transcript_ENST00000491162.1, transcript_ENST00000636180.1, transcript_ENST00000636241.1, transcript_ENST00000636419.1, transcript_ENST00000636492.1, transcript_ENST00000636658.1, transcript_ENST00000636661.1, transcript_ENST00000636830.1, transcript_ENST00000636860.1, transcript_ENST00000637258.1, transcript_ENST00000637392.1, transcript_ENST00000637538.1, transcript_ENST00000637909.1, and transcript_ENST00000638134.1.

[0208] In some embodiments, the CLCN2 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000114859.16 or a complement thereof. In some embodiments, the CLCN2 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a CLCN2 pre-mRNA transcript or a complement thereof described herein.

[0209] In some embodiments, the targeted portion of the CLCN2 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000265593.9, premrna_ENST00000344937.11, premrna_ENST00000430397.5, premrna_ENST00000434054.6, premrna_ENST00000457512.1, premrna_ENST00000465231.1, premrna_ENST00000475279.2, premrna_ENST00000485667.1, premrna_ENST00000491162.1, premrna_ENST00000636180.1, premrna_ENST00000636241.1, premrna_ENST00000636419.1, premrna_ENST00000636492.1, premrna_ENST00000636658.1, premrna_ENST00000636661.1, premrna_ENST00000636830.1, premrna_ENST00000636860.1, premrna_ENST00000637258.1, premrna_ENST00000637392.1, premrna_ENST00000637538.1, premrna_ENST00000637909.1, premrna_ENST00000638134.1 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the CLCN2 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 364 - SEQ ID NO. 369 or complements thereof. In some embodiments, the targeted portion of the CLCN2 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0210] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a CNOT3 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a CNOT3 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a CNOT3 genomic sequence comprising an intron flanking the 3’ splice site of 2020334067   16 Jul 2026 the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000221232.11, premrna_ENST00000358389.7, premrna_ENST00000440571.6, premrna_ENST00000447684.5, premrna_ENST00000457463.1, premrna_ENST00000471126.1, premrna_ENST00000496327.2, premrna_ENST00000613073.4, premrna_ENST00000617930.2, premrna_ENST00000618939.5, premrna_ENST00000642159.1, premrna_ENST00000644245.1, premrna_ENST00000644707.1, premrna_ENST00000646002.1, and premrna_ENST00000647082.1. In some embodiments, the ASO targets a CNOT3 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a CNOT3 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a CNOT3 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000221232.11, transcript_ENST00000358389.7, transcript_ENST00000440571.6, transcript_ENST00000447684.5, transcript_ENST00000457463.1, transcript_ENST00000471126.1, transcript_ENST00000496327.2, transcript_ENST00000613073.4, transcript_ENST00000617930.2, transcript_ENST00000618939.5, transcript_ENST00000642159.1, transcript_ENST00000644245.1, transcript_ENST00000644707.1, transcript_ENST00000646002.1, and transcript_ENST00000647082.1.

[0211] In some embodiments, the CNOT3 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000088038.19, ENSG00000273943.4, ENSG00000274176.4, ENSG00000274616.4, ENSG00000274941.4, ENSG00000275979.4, ENSG00000276082.4, ENSG00000277600.4, ENSG00000277114.4, or ENSG00000277615.4, or a complement thereof. In some embodiments, the CNOT3 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a CNOT3 pre-mRNA transcript or a complement thereof described herein.

[0212] In some embodiments, the targeted portion of the CNOT3 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000221232.11, premrna_ENST00000358389.7, premrna_ENST00000440571.6, premrna_ENST00000447684.5, premrna_ENST00000457463.1, premrna_ENST00000471126.1, premrna_ENST00000496327.2, premrna_ENST00000613073.4, premrna_ENST00000617930.2, premrna_ENST00000618939.5, premrna_ENST00000642159.1, premrna_ENST00000644245.1, premrna_ENST00000644707.1, premrna_ENST00000646002.1, premrna_ENST00000647082.1 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the CNOT3 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 370 - SEQ ID NO. 377 or complements thereof. In some embodiments, the targeted portion of the CNOT3 pre-mRNA 2020334067   16 Jul 2026 comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0213] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a CNTROB genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a CNTROB genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a CNTROB genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000380262.7, premrna_ENST00000563694.6, premrna_ENST00000565740.5, premrna_ENST00000570782.1, premrna_ENST00000570784.1, premrna_ENST00000571540.5, premrna_ENST00000571632.5, premrna_ENST00000573862.1, premrna_ENST00000574430.5, premrna_ENST00000575408.5, premrna_ENST00000576536.1, premrna_ENST00000576538.5, premrna_ENST00000576587.1, premrna_ENST00000576723.5, and premrna_ENST00000576922.5. In some embodiments, the ASO targets a CNTROB pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a CNTROB pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a CNTROB pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000380262.7, transcript_ENST00000563694.6, transcript_ENST00000565740.5, transcript_ENST00000570782.1, transcript_ENST00000570784.1, transcript_ENST00000571540.5, transcript_ENST00000571632.5, transcript_ENST00000573862.1, transcript_ENST00000574430.5, transcript_ENST00000575408.5, transcript_ENST00000576536.1, transcript_ENST00000576538.5, transcript_ENST00000576587.1, transcript_ENST00000576723.5, and transcript_ENST00000576922.5.

[0214] In some embodiments, the CNTROB pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000170037.14 or a complement thereof. In some embodiments, the CNTROB pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a CNTROB pre-mRNA transcript or a complement thereof described herein.

[0215] In some embodiments, the targeted portion of the CNTROB pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000380262.7, premrna_ENST00000563694.6, premrna_ENST00000565740.5, premrna_ENST00000570782.1, premrna_ENST00000570784.1, premrna_ENST00000571540.5, premrna_ENST00000571632.5, premrna_ENST00000573862.1, premrna_ENST00000574430.5, premrna_ENST00000575408.5, premrna_ENST00000576536.1, premrna_ENST00000576538.5, premrna_ENST00000576587.1, premrna_ENST00000576723.5, premrna_ENST00000576922.5 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the CNTROB pre-mRNA comprises a sequence 2020334067   16 Jul 2026 with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 378 - SEQ ID NO. 381 or complements thereof. In some embodiments, the targeted portion of the CNTROB pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0216] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a COL5A3 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a COL5A3 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a COL5A3 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000264828.4 and premrna_ENST00000461214.1. In some embodiments, the ASO targets a COL5A3 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a COL5A3 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a COL5A3 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000264828.4 and transcript_ENST00000461214.1.

[0217] In some embodiments, the COL5A3 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000080573.7 or a complement thereof. In some embodiments, the COL5A3 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a COL5A3 pre-mRNA transcript or a complement thereof described herein.

[0218] In some embodiments, the targeted portion of the COL5A3 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000264828.4, premrna_ENST00000461214.1, or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the COL5A3 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 382 - SEQ ID NO. 385 or complements thereof. In some embodiments, the targeted portion of the COL5A3 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0219] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a CPSF1 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a CPSF1 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a CPSF1 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO 2020334067   16 Jul 2026 targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000526271.2, premrna_ENST00000527827.1, premrna_ENST00000527916.1, premrna_ENST00000529288.1, premrna_ENST00000531042.5, premrna_ENST00000531480.2, premrna_ENST00000531727.5, premrna_ENST00000532560.5, premrna_ENST00000532725.1, premrna_ENST00000532935.5, premrna_ENST00000533492.1, premrna_ENST00000616140.2, premrna_ENST00000620219.4, and premrna_ENST00000622776.1. In some embodiments, the ASO targets a CPSF1 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a CPSF1 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a CPSF1 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000526271.2, transcript_ENST00000527827.1, transcript_ENST00000527916.1, transcript_ENST00000529288.1, transcript_ENST00000531042.5, transcript_ENST00000531480.2, transcript_ENST00000531727.5, transcript_ENST00000532560.5, transcript_ENST00000532725.1, transcript_ENST00000532935.5, transcript_ENST00000533492.1, transcript_ENST00000616140.2, transcript_ENST00000620219.4, and transcript_ENST00000622776.1.

[0220] In some embodiments, the CPSF1 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000071894.17 or ENSG00000285049.2 or a complement thereof. In some embodiments, the CPSF1 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a CPSF1 pre-mRNA transcript or a complement thereof described herein.

[0221] In some embodiments, the targeted portion of the CPSF1 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000526271.2, premrna_ENST00000527827.1, premrna_ENST00000527916.1, premrna_ENST00000529288.1, premrna_ENST00000531042.5, premrna_ENST00000531480.2, premrna_ENST00000531727.5, premrna_ENST00000532560.5, premrna_ENST00000532725.1, premrna_ENST00000532935.5, premrna_ENST00000533492.1, premrna_ENST00000616140.2, premrna_ENST00000620219.4, premrna_ENST00000622776.1, or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the CPSF1 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 386 - SEQ ID NO. 389 or complements thereof. In some embodiments, the targeted portion of the CPSF1 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0222] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a CSPP1 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a CSPP1 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre- 2020334067   16 Jul 2026 mRNA transcript from a CSPP1 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000262210.9, premrna_ENST00000519163.6, premrna_ENST00000519668.1, premrna_ENST00000519701.5, premrna_ENST00000521168.5, premrna_ENST00000521324.1, and premrna_ENST00000521919.5. In some embodiments, the ASO targets a CSPP1 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a CSPP1 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a CSPP1 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000262210.9, transcript_ENST00000519163.6, transcript_ENST00000519668.1, transcript_ENST00000519701.5, transcript_ENST00000521168.5, transcript_ENST00000521324.1, and transcript_ENST00000521919.5.

[0223] In some embodiments, the CSPP1 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000104218.14 or a complement thereof. In some embodiments, the CSPP1 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a CSPP1 pre-mRNA transcript or a complement thereof described herein.

[0224] In some embodiments, the targeted portion of the CSPP1 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000262210.9, premrna_ENST00000519163.6, premrna_ENST00000519668.1, premrna_ENST00000519701.5, premrna_ENST00000521168.5, premrna_ENST00000521324.1, and premrna_ENST00000521919.5, or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the CSPP1 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 390 - SEQ ID NO. 393 or complements thereof. In some embodiments, the targeted portion of the CSPP1 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0225] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a CTF1 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a CTF1 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a CTF1 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000279804.2, and premrna_ENST00000395019.3. In some embodiments, the ASO targets a CTF1 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a 2020334067   16 Jul 2026 CTF1 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a CTF1 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000279804.2, and transcript_ENST00000395019.3.

[0226] In some embodiments, the CTF1 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000150281.6 or a complement thereof. In some embodiments, the CTF1 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a CTF1 pre-mRNA transcript or a complement thereof described herein.

[0227] In some embodiments, the targeted portion of the CTF1 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000279804.2, premrna_ENST00000395019.3 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the CTF1 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 394 - SEQ ID NO. 399 or complements thereof. In some embodiments, the targeted portion of the CTF1 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0228] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a CTH genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a CTH genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a CTH genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000346806.2, premrna_ENST00000370938.8, premrna_ENST00000411986.6, premrna_ENST00000464926.1, and premrna_ENST00000482383.1. In some embodiments, the ASO targets a CTH pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a CTH pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a CTH pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000346806.2, transcript_ENST00000370938.8, transcript_ENST00000411986.6, transcript_ENST00000464926.1, and transcript_ENST00000482383.1.

[0229] In some embodiments, the CTH pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000116761.12 or a complement thereof. In some embodiments, the CTH pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a CTH pre-mRNA transcript or a complement thereof described herein. 2020334067   16 Jul 2026

[0230] In some embodiments, the targeted portion of the CTH pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000346806.2, premrna_ENST00000370938.8, premrna_ENST00000411986.6, premrna_ENST00000464926.1, premrna_ENST00000482383.1 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the CTH pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 400 - SEQ ID NO. 407 or complements thereof. In some embodiments, the targeted portion of the CTH pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0231] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a CYP3A5 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a CYP3A5 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a CYP3A5 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000222982.8, premrna_ENST00000339843.6, premrna_ENST00000439761.3, premrna_ENST00000456417.5, premrna_ENST00000461920.5, premrna_ENST00000463364.5, premrna_ENST00000463907.5, premrna_ENST00000466061.5, premrna_ENST00000469622.5, premrna_ENST00000469887.5, premrna_ENST00000473347.1, premrna_ENST00000480723.5, premrna_ENST00000481825.5, premrna_ENST00000488187.1, premrna_ENST00000489231.1, and premrna_ENST00000646887.1. In some embodiments, the ASO targets a CYP3A5 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a CYP3A5 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a CYP3A5 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000222982.8, transcript_ENST00000339843.6, transcript_ENST00000439761.3, transcript_ENST00000456417.5, transcript_ENST00000461920.5, transcript_ENST00000463364.5, transcript_ENST00000463907.5, transcript_ENST00000466061.5, transcript_ENST00000469622.5, transcript_ENST00000469887.5, transcript_ENST00000473347.1, transcript_ENST00000480723.5, transcript_ENST00000481825.5, transcript_ENST00000488187.1, transcript_ENST00000489231.1, and transcript_ENST00000646887.1.

[0232] In some embodiments, the CYP3A5 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000106258.15 or a complement thereof. In some embodiments, the CYP3A5 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 2020334067   16 Jul 2026 99% or 100% sequence identity to a CYP3A5 pre-mRNA transcript or a complement thereof described herein.

[0233] In some embodiments, the targeted portion of the CYP3A5 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000222982.8, premrna_ENST00000339843.6, premrna_ENST00000439761.3, premrna_ENST00000456417.5, premrna_ENST00000461920.5, premrna_ENST00000463364.5, premrna_ENST00000463907.5, premrna_ENST00000466061.5, premrna_ENST00000469622.5, premrna_ENST00000469887.5, premrna_ENST00000473347.1, premrna_ENST00000480723.5, premrna_ENST00000481825.5, premrna_ENST00000488187.1, premrna_ENST00000489231.1, premrna_ENST00000646887.1 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the CYP3A5 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 408 - SEQ ID NO. 411 or complements thereof. In some embodiments, the targeted portion of the CYP3A5 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0234] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a DAB2IP genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a DAB2IP genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a DAB2IP genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000259371.6, premrna_ENST00000309989.1, premrna_ENST00000373782.7, premrna_ENST00000394340.7, premrna_ENST00000408936.7, premrna_ENST00000436835.5, premrna_ENST00000459906.1, premrna_ENST00000465078.1, premrna_ENST00000487716.1, premrna_ENST00000489314.1, premrna_ENST00000648444.1, and premrna_ENST00000648693.1. In some embodiments, the ASO targets a DAB2IP pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a DAB2IP pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a DAB2IP pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000259371.6, transcript_ENST00000309989.1, transcript_ENST00000373782.7, transcript_ENST00000394340.7, transcript_ENST00000408936.7, transcript_ENST00000436835.5, transcript_ENST00000459906.1, transcript_ENST00000465078.1, transcript_ENST00000487716.1, transcript_ENST00000489314.1, transcript_ENST00000648444.1, and transcript_ENST00000648693.1.

[0235] In some embodiments, the DAB2IP pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl 2020334067   16 Jul 2026 reference number ENSG00000136848.17 or a complement thereof. In some embodiments, the DAB2IP pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a DAB2IP pre-mRNA transcript or a complement thereof described herein.

[0236] In some embodiments, the targeted portion of the DAB2IP pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000259371.6, premrna_ENST00000309989.1, premrna_ENST00000373782.7, premrna_ENST00000394340.7, premrna_ENST00000408936.7, premrna_ENST00000436835.5, premrna_ENST00000459906.1, premrna_ENST00000465078.1, premrna_ENST00000487716.1, premrna_ENST00000489314.1, premrna_ENST00000648444.1, premrna_ENST00000648693.1 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the DAB2IP pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 412 - SEQ ID NO. 415 or complements thereof. In some embodiments, the targeted portion of the DAB2IP pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0237] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a DBN1 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a DBN1 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a DBN1 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000292385.9, premrna_ENST00000309007.9, premrna_ENST00000393565.5, premrna_ENST00000467054.2, premrna_ENST00000471767.1, premrna_ENST00000472831.5, premrna_ENST00000477391.6, premrna_ENST00000505550.1, premrna_ENST00000506117.5, premrna_ENST00000512501.1, and premrna_ENST00000514833.1. In some embodiments, the ASO targets a DBN1 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a DBN1 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a DBN1 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000292385.9, transcript_ENST00000309007.9, transcript_ENST00000393565.5, transcript_ENST00000467054.2, transcript_ENST00000471767.1, transcript_ENST00000472831.5, transcript_ENST00000477391.6, transcript_ENST00000505550.1, transcript_ENST00000506117.5, transcript_ENST00000512501.1, and transcript_ENST00000514833.1.

[0238] In some embodiments, the DBN1 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000113758.13 or a complement thereof. In some embodiments, the DBN1 pre- 2020334067   16 Jul 2026 mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a DBN1 pre-mRNA transcript or a complement thereof described herein.

[0239] In some embodiments, the targeted portion of the DBN1 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000292385.9, premrna_ENST00000309007.9, premrna_ENST00000393565.5, premrna_ENST00000467054.2, premrna_ENST00000471767.1, premrna_ENST00000472831.5, premrna_ENST00000477391.6, premrna_ENST00000505550.1, premrna_ENST00000506117.5, premrna_ENST00000512501.1, premrna_ENST00000514833.1 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the DBN1 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 416 - SEQ ID NO. 424 or complements thereof. In some embodiments, the targeted portion of the DBN1 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0240] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a DDX51 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a DDX51 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a DDX51 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000329073.8, premrna_ENST00000397333.4, premrna_ENST00000462829.2, premrna_ENST00000541489.5, premrna_ENST00000545991.1, and premrna_ENST00000546058.1. In some embodiments, the ASO targets a DDX51 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a DDX51 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a DDX51 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000329073.8, transcript_ENST00000397333.4, transcript_ENST00000462829.2, transcript_ENST00000541489.5, transcript_ENST00000545991.1, and transcript_ENST00000546058.1.

[0241] In some embodiments, the DDX51 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000185163.10 or ENSG00000288503.1 or a complement thereof. In some embodiments, the DDX51 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a DDX51 pre-mRNA transcript or a complement thereof described herein.

[0242] In some embodiments, the targeted portion of the DDX51 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 2020334067   16 Jul 2026 contiguous nucleic acids of a sequence of premrna_ENST00000329073.8, premrna_ENST00000397333.4, premrna_ENST00000462829.2, premrna_ENST00000541489.5, premrna_ENST00000545991.1, premrna_ENST00000546058.1 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the DDX51 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 425 - SEQ ID NO. 428 or complements thereof. In some embodiments, the targeted portion of the DDX51 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0243] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a DEAF1 genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a DEAF1 genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a DEAF1 genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000382409.3, premrna_ENST00000524786.1, premrna_ENST00000525626.5, premrna_ENST00000525904.5, premrna_ENST00000526790.1, premrna_ENST00000526857.2, premrna_ENST00000527170.5, premrna_ENST00000527658.1, premrna_ENST00000528864.5, premrna_ENST00000529717.5, premrna_ENST00000529727.1, and premrna_ENST00000530813.1. In some embodiments, the ASO targets a DEAF1 pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a DEAF1 pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a DEAF1 pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000382409.3, transcript_ENST00000524786.1, transcript_ENST00000525626.5, transcript_ENST00000525904.5, transcript_ENST00000526790.1, transcript_ENST00000526857.2, transcript_ENST00000527170.5, transcript_ENST00000527658.1, transcript_ENST00000528864.5, transcript_ENST00000529717.5, transcript_ENST00000529727.1, and transcript_ENST00000530813.1.

[0244] In some embodiments, the DEAF1 pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000177030.17 or ENSG00000282712.1 a complement thereof. In some embodiments, the DEAF1 pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a DEAF1 pre-mRNA transcript or a complement thereof described herein.

[0245] In some embodiments, the targeted portion of the DEAF1 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence of premrna_ENST00000382409.3, premrna_ENST00000524786.1, premrna_ENST00000525626.5, premrna_ENST00000525904.5, 2020334067   16 Jul 2026 premrna_ENST00000526790.1, premrna_ENST00000526857.2, premrna_ENST00000527170.5, premrna_ENST00000527658.1, premrna_ENST00000528864.5, premrna_ENST00000529717.5, premrna_ENST00000529727.1, premrna_ENST00000530813.1 or a sequence of Table 3 or complements thereof. In some embodiments, the targeted portion of the DEAF1 pre-mRNA comprises a sequence with at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO. 429 - SEQ ID NO. 432 or complements thereof. In some embodiments, the targeted portion of the DEAF1 pre-mRNA comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence of Table 6A or Table 6B or a complement thereof.

[0246] In some embodiments, the ASOs disclosed herein target a NSAE pre-mRNA transcribed from a DGKE genomic sequence. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a DGKE genomic sequence comprising a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript from a DGKE genomic sequence comprising an intron flanking the 3’ splice site of the NSAE exon and an intron flanking the 5’ splice site of a NSAE exon. In some embodiments, the ASO targets a NSAE pre-mRNA transcript comprising a sequence selected from the group consisting of premrna_ENST00000284061.8, premrna_ENST00000570738.1, premrna_ENST00000571084.1, premrna_ENST00000572810.1, premrna_ENST00000572944.1, and premrna_ENST00000576869.5. In some embodiments, the ASO targets a DGKE pre-mRNA sequence comprising a NSAE exon. In some embodiments, the ASO targets a DGKE pre-mRNA sequence comprising an intron flanking the 3’ splice site of the NSAE exon. In some embodiments, the ASO targets a DGKE pre-mRNA sequence comprising an intron flanking the 5’ splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000284061.8, transcript_ENST00000570738.1, transcript_ENST00000571084.1, transcript_ENST00000572810.1, transcript_ENST00000572944.1, and transcript_ENST00000576869.5.

[0247] In some embodiments, the DGKE pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the Ensembl reference number ENSG00000153933.10 or a complement thereof. In some embodiments, the DGKE pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a DGKE pre-mRNA transcript or a complement thereof described herein.

[0248] In some embodi...

Claims

1. A composition comprising a non-sense mediated RNA decay alternative exon (NSAE)-modulating agent that interacts with a target motif within a pre-processed mRNA transcript that encodes a target protein to modulate splicing at an alternative 3’ splice site of an intron in the pre-processed mRNA transcript, thereby promoting inclusion of a canonical exon in a processed mRNA transcript that is processed from the pre-processed mRNA transcript, and promoting exclusion of an alternative exon from the pre-processed mRNA transcript;wherein the NSAE modulating agent is an antisense oligomer (ASO) comprising between 12 and 50 nucleobases and at least one modified sugar moiety;wherein the alternative exon comprises the canonical exon and at least a portion of a canonical intron adjacent to the canonical exon;wherein the target protein is SYNGAP1;wherein the target motif comprises a sequence with at least 90% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NOs: 166-169 and 980-983; andwherein the ASO comprises at least 12 contiguous bases that are complementary to a sequence of the target motif that is (i) from 4 to 300 nucleotides upstream of the alternative 3’ splice site or (ii) from 4 to 300 nucleotides downstream of the alternative 3’ splice site.

2. The composition of claim 1, wherein the NSAE-modulating agent increases expression of the target protein in a cell containing the pre-processed mRNA transcript.

3. The composition of claim 1 or 2, wherein the alternative 3’ splice site flanks the alternative exon, is downstream of a 3’ splice site flanking the canonical exon, and is within the canonical exon.

4. The composition of claim 1 or 2, wherein the alternative 3’ splice site flanks the alternative exon, is upstream of a 3’ splice site flanking the canonical exon, and is within the canonical intron immediately preceding the canonical exon.

5. The composition of any one of claims 1 to 4, wherein each nucleotide of the antisense oligomer independently comprises a 2’-O-methyl moiety, a 2’-methoxyethyl moiety, or a 2’-fluoro moiety.2020334067   02 Oct 20266. The composition of any one of claims 1 to 4, wherein the antisense oligomer comprises a phosphorodiamidate morpholino, a locked nucleic acid, or a peptide nucleic acid.

7. The composition of claim 5 or 6, wherein the antisense oligomer comprises a backbone modification.

8. The composition of claim 7, wherein the backbone modification comprises a phosphorothioate linkage or a phosphorodiamidate linkage.

9. The composition of any one of claims 5 to 8, wherein the antisense oligomer comprises a 2’-O-methoxyethyl moiety.

10. The composition of any one of claims 5 and 7 to 9, wherein each nucleotide of the antisense oligomer comprises a 2’-O-methoxyethyl moiety.

11. The composition of any one of claims 5 to 10, wherein the antisense oligomer is at least 95% complementary to the target motif of the pre-processed mRNA encoding the target protein.

12. The composition of any one of claims 1 to 11, wherein the target protein is SYNGAP1 protein, and wherein the pre-processed mRNA comprises a sequence selected from the group consisting of premrna_ENST00000293748.9, premrna_ENST00000418600.7, premrna_ENST00000428982.4, premrna_ENST00000449372.7, premrna_ENST00000470232.1, premrna_ENST00000479510.2, premrna_ENST00000628646.2, premrna_ENST00000629380.3, premrna_ENST00000635885.1, premrna_ENST00000636075.1, premrna_ENST00000636116.1, premrna_ENST00000636146.1, premrna_ENST00000636193.1, premrna_ENST00000636436.1, premrna_ENST00000636443.1, premrna_ENST00000636640.1, premrna_ENST00000636731.1, premrna_ENST00000636905.1, premrna_ENST00000637052.1, premrna_ENST00000637194.1, premrna_ENST00000637490.1, premrna_ENST00000637587.1, premrna_ENST00000637671.1, premrna_ENST00000637721.1, premrna_ENST00000637911.1, premrna_ENST00000638127.1, premrna_ENST00000638142.2, premrna_ENST00000644458.1, premrna_ENST00000645250.1, and premrna_ENST00000646630.1.

13. The composition of any one of claims 1 to 12, wherein target protein is SYNGAP1 protein, and wherein target motif comprises a sequence that is complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NOs: 1-165 and 4300-4352, and a complement thereof.2020334067   02 Oct 202614. The composition of any one of claims 1 to 13, wherein the NSAE-modulating agent comprises a sequence that comprises at least about 80% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 1-165 and 4300-4352.

15. A pharmaceutical composition comprising the composition of any one of claims 1 to 14 and a pharmaceutically acceptable excipient and / or carrier.

16. A method of modulating expression of a target protein in a cell, comprising contacting a nonsense mediated RNA decay alternative exon (NSAE)-modulating agent with the cell,wherein the NSAE-modulating agent is an antisense oligomer (ASO) comprising between 12 and 50 nucleobases and at least one modified sugar moiety;wherein the NSAE-modulating agent interacts with a target motif within a preprocessed mRNA transcript that encodes the target protein to modulate splicing at an alternative 3’ splice site of the pre-processed mRNA transcript, thereby promoting inclusion of a canonical exon in a processed mRNA transcript that is processed from the pre-processed mRNA transcript, and promoting exclusion of an alternative exon from the pre-processed mRNA transcript,wherein the alternative exon comprises the canonical exon and at least a portion of a canonical intron upstream of the canonical exon and adjacent to the canonical exon;wherein the target protein is SYNGAP1;wherein the target motif comprises a sequence with at least 90% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NOs: 166-169 and 980-983; andwherein the ASO comprises at least 12 contiguous bases that are complementary to a sequence of the target motif that is (i) from 4 to 300 nucleotides upstream of the alternative 3’ splice site or (ii) from 4 to 300 nucleotides downstream of the alternative 3’ splice site.

17. The method of claim 16, wherein modulation of splicing of the pre-processed mRNA increases the expression of the target protein.

18. The method of claim 17, wherein the expression of the target protein in the cell is increased about 1.1 to about 10-fold, compared to the level of processed mRNA encoding the target protein in a control cell.

19. The method of any one of claims 16 to 18, wherein modulation of splicing of the preprocessed mRNA increases the level of the processed mRNA encoding the target protein.2020334067   02 Oct 202620. The method of claim 19, wherein the level of processed mRNA encoding the target protein in the cell is increased about 1.1 to about 10-fold, compared to the level of processed mRNA encoding the target protein in a control cell.

21. The method of any one of claims 16 to 20, wherein the target protein is the canonical isoform of the protein.

22. A method of treating or preventing a disease or condition in a subject in need thereof, the method comprising: administering to the subject a pharmaceutical composition comprising:(a) a non-sense mediated RNA decay alternative exon (NSAE)-modulating agent, wherein the NSAE-modulating agent is an antisense oligomer (ASO) comprising between 12 and 50 nucleobases and at least one modified sugar moiety, and wherein the antisense oligomer interacts with a target motif within a pre-processed mRNA transcript that encodes a target protein to modulate splicing at an alternative 3’ splice site of the preprocessed mRNA transcript, thereby promoting inclusion of a canonical exon in a processed mRNA transcript that is processed from the pre-processed mRNA transcript, and promoting exclusion of an alternative exon from the pre-processed mRNA transcript, wherein the alternative exon comprises the canonical exon and at least a portion of a canonical intron upstream of the canonical exon and adjacent to the canonical exon, wherein the target protein is SYNGAP1,wherein the target motif comprises a sequence with at least 90% sequence identity to a region comprising at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO: 166-169 and 980-983, andwherein the ASO comprises at least 12 contiguous bases that are complementary to a sequence of the target motif that is (i) from 4 to 300 nucleotides upstream of the alternative 3’ splice site or (ii) from 4 to 300 nucleotides downstream of the alternative 3’ splice site; and(b) a pharmaceutically acceptable excipient and / or a delivery vehicle, and wherein the disease or condition is treated or prevented in the subject by the administration of the NSAE-modulating agent to modulate expression of the target protein.

23. The method of claim 22, wherein the disease is autosomal dominant mental retardation, epileptic encephalopathy, or autism.2020334067   02 Oct 202624. The method of claim 22, wherein the disease or the condition is caused by a deficient amount or activity of the target protein.

25. The method of any one of claims 22 to 24, wherein the subject is a human or non-human animal.

26. The method of any one of claims 22 to 25, wherein the subject is a child.

27. The method of any one of claims 16 to 21, wherein the cell is ex vivo, in a tissue ex vivo, or in an organ ex vivo.

28. A pharmaceutical composition of claim 15 for use in the treatment of a disease.

29. Use of a composition of any one of claims 1 to 14 for manufacturing a medicament for the treatment of a disease.

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