Compositions and methods for regulating splicing and protein expression

Abstract

The present invention provides a therapeutic agent that can target alternative splicing events in genes, thereby regulating the expression levels of functional proteins and / or inhibiting abnormal protein expression in affected patients. [Solution] A composition is provided comprising an NSAE regulator that interacts with a target motif in a preprocessed mRNA transcript to regulate the exclusion of nonsense mutation-dependent RNA degradation mechanism selective exons (NSAEs) from the processed mRNA transcript and to regulate the inclusion of canonical exons in the processed mRNA transcript.

Description

Technical Field

[0001] Cross-reference

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

[0002] Reference to Sequence Listing

[0002] This application includes a sequence listing submitted electronically in ASCII format, which is incorporated herein by reference in its entirety. The ASCII copy was created on August 19, 2020, has the name 47991-727_601_SL.txt, and is 17,694,293 bytes in size.

Background Art

[0003]

[0003] Alternative splicing events in genes can lead to non-productive or poorly productive mRNA transcripts, and therapeutic agents that can target alternative splicing events in genes can regulate the expression levels of functional proteins in patients and / or inhibit abnormal protein expression. Such therapeutic agents can be used to treat conditions or diseases caused by protein deficiency.

Summary of the Invention

Means for Solving the Problems

[0004]

[0004] In some embodiments, compositions comprising an NSAE modulator that interacts with a target motif in a preprocessed mRNA transcript to modulate the exclusion of a nonsense mutation-dependent RNA degradation mechanism selective exon (NSAE) from the processed mRNA transcript and to modulate the inclusion of a canonical exon in the processed mRNA transcript, wherein the target motif is located (i) within an intron region between two canonical exons, (ii) within one of the two canonical exons, or (iii) within a region spanning both an intron and a canonical exon, and the NSAE comprises (i) only a portion of a canonical exon, or (ii) at least a portion of a canonical exon and an intron adjacent to a canonical exon, and the NSAE modulator modulates the exclusion of the NSAE from the processed mRNA transcript and to modulate the inclusion of a canonical exon in the processed mRNA transcript are provided herein.

[0005]

[0005] In some embodiments, compositions are provided herein that modulate the expression of a target protein in a cell containing a nonsense mutation-dependent RNA degradation mechanism alternative exon (NSAE) modulator, the NSAE modulator modulates the processing of the mRNA transcript from the preprocessed mRNA transcript by modulating the splicing of the premRNA at the 5' alternative splice site, and the splicing of the premRNA at the 5' alternative splice site modulates the expression of the target protein in a cell containing a preprocessed mRNA transcript (premRNA) which encodes a target protein and includes an alternative 5' splice site downstream of the 5' splice site of the canonical exon and inside the canonical exon, or upstream of the 5' splice site of the canonical exon and inside the intron, wherein the NSAE modulator modulates the processing of the mRNA transcript from the preprocessed mRNA transcript by modulating the splicing of the premRNA at the 5' alternative splice site, and the splicing of the premRNA at the 5' alternative splice site modulates the expression of the target protein in the cell.

[0006]

[0006] In some embodiments, the target protein is encoded and the 3' sprue of the canonical exon is located. A composition comprising a nonsense mutation-dependent RNA degradation mechanism alternative exon (NSAE) modulator that modulates the expression of a target protein in a cell containing a preprocessed mRNA transcript (premRNA) comprising an alternative nonsense mutation-dependent RNA degradation mechanism induction (NMD) exon, which includes an alternative 3' splice site upstream of the chair site and inside the canonical exon, or downstream of the 3' splice site of the canonical exon and inside the intron, wherein the NSAE modulator modulates the processing of mRNA transcript from the preprocessed mRNA transcript by modulating the splicing of premRNA at the 3' alternative splice site, and the splicing of premRNA at the 3' alternative splice site modulates the expression of a target protein in the cell is provided herein.

[0007]

[0007] In some embodiments, a composition comprising a nonsense mutation-dependent RNA degradation mechanism alternative 5' or 3' splice site (NSASS) modifier that interacts with a target motif in a preprocessed mRNA transcript to modulate splicing at an alternative 5' or 3' splice site of the preprocessed mRNA transcript and modulates the inclusion of canonical exons in a processed mRNA transcript processed from the preprocessed mRNA transcript, wherein the target motif is located within an intron region between two canonical exons, within one of the two canonical exons, or between an intron and A composition is provided herein, wherein the modification of splicing at the alternative 5' or 3' splice site of the preprocessed mRNA transcript, located within a region spanning both canonical exons, modulates the exclusion of the alternative exon from the processed mRNA transcript, and the alternative exon comprises only a portion of the canonical exon, or at least a portion of the canonical exon and an intron adjacent to the canonical exon, and the NSASS modulator modulates the exclusion of the alternative exon from the processed mRNA transcript and modulates the inclusion of the canonical exon in the processed mRNA transcript.

[0008]

[0008] In some embodiments, compositions comprising a nonsense mutation-dependent RNA degradation mechanism alternative 5' or 3' splice site (NSASS) modifier for regulating the expression of a target protein in cells comprising a preprocessed mRNA transcript (premRNA) encoding a target protein, wherein the premRNA comprises an alternative exon containing 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 a canonical exon and within an intron, and the NSASS modifier regulates the processing of the mRNA transcript from the preprocessed mRNA transcript by regulating the splicing of the premRNA at the 5' alternative splice site, and the splicing of the premRNA at the 5' alternative splice site regulates the expression of a target protein in cells, are provided herein.

[0009]

[0009] In some embodiments, compositions comprising a nonsense mutation-dependent RNA degradation mechanism selective exon (NSASS) modulator for regulating the expression of a target protein in cells containing a preprocessed mRNA transcript (premRNA) encoding a target protein, wherein the premRNA comprises an alternative exon containing an alternative 3' splice site upstream of the 3' splice site of the canonical exon and inside the canonical exon, or downstream of the 3' splice site of the canonical exon and inside an intron, and the NSASS modulator regulates the processing of the mRNA transcript from the preprocessed mRNA transcript by regulating the splicing of the premRNA at the 3' alternative splice site, and the splicing of the premRNA at the 3' alternative splice site regulates the expression of a target protein in cells, are provided herein.

[0010]

[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 Morphologically, 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 conjugated or complexed with one or more nucleic acid molecules. In some embodiments, the agent is an antisense oligomer (ASO) complementary to the targeting region of the premRNA. 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 targeting region of the premRNA encoding the target protein. In some embodiments, the agent is an antisense oligomer and the agent includes a skeletal modification containing a phosphorothioate bond or a phosphorodiamidate bond. In some embodiments, the agent is an antisense oligomer and the agent includes a phosphorodiamidate morpholino. In some embodiments, the agent is an antisense oligomer and the agent includes a locked nucleic acid. In some embodiments, the agent is an antisense oligomer and the agent includes a peptide nucleic acid. In some embodiments, the agent is an antisense oligomer and the agent contains 2'-O-methyl. In some embodiments, the agent is an antisense oligomer and the agent contains a 2'-fluoro or 2'-O-methoxyethyl moiety. In some embodiments, the agent is an antisense oligomer and the agent contains 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 the agent is composed of 8-50 nucleic acid bases, 8-40 nucleic acid bases, 8-35 nucleic acid bases, 8-30 nucleic acid bases, 8-25 nucleic acid bases, 8-20 nucleic acid bases, 8-15 nucleic acid bases, 9-50 nucleic acid bases, 9-40 nucleic acid bases, 9-35 nucleic acid bases, 9-30 nucleic acid bases, 9-25 nucleic acid bases, 9-20 nucleic acid bases, 9-15 nucleic acid bases, 10-50 nucleic acid bases, 10-40 nucleic acid bases, 10-35 nucleic acid bases, 1 The nucleic acid molecules consist of 0 to 30 nucleic acid bases, 10 to 25 nucleic acid bases, 10 to 20 nucleic acid bases, 10 to 15 nucleic acid bases, 11 to 50 nucleic acid bases, 11 to 40 nucleic acid bases, 11 to 35 nucleic acid bases, 11 to 30 nucleic acid bases, 11 to 25 nucleic acid bases, 11 to 20 nucleic acid bases, 11 to 15 nucleic acid bases, 12 to 50 nucleic acid bases, 12 to 40 nucleic acid bases, 12 to 35 nucleic acid bases, 12 to 30 nucleic acid bases, 12 to 25 nucleic acid bases, 12 to 20 nucleic acid bases, or 12 to 15 nucleic acid bases. In some embodiments, compositions of nucleic acid molecules encoding NSAE modifiers are described herein. In some embodiments, the nucleic acid molecules are incorporated into a virus delivery system. In some embodiments, the virus delivery system is an adenovirus-associated vector.

[0011]

[0011] In some embodiments, a method for regulating protein expression, comprising the steps of (a) contacting a nonsense mutation-dependent RNA degradation mechanism selective exon (NSAE) modulator with a target motif in a preprocessed mRNA transcript, wherein the NSAE comprises (i) only a portion of a canonical exon, or (ii) at least a portion of the canonical exon and an intron adjacent to the canonical exon; and (b) processing the mRNA transcript from the preprocessed mRNA transcript, thereby processing the mRNA transcript. A method is provided herein that includes (c) forming an RNA transcript, wherein an NSAE modulator modulates the exclusion of NSAE from the processed mRNA transcript and the inclusion of a canonical exon in the processed mRNA transcript; and (a) translating the processed mRNA transcript, wherein the exclusion of NSAE and the inclusion of a canonical exon modulate protein expression compared to protein expression of an equivalent mRNA transcript containing NSAE instead of a canonical exon. In some embodiments, the target motif is located within an intron region between two canonical exons. In some embodiments, the target motif is located within one of the two canonical exons. In some embodiments, the target motif is located within a region spanning both an intron and a canonical exon.

[0012]

[0012] In some embodiments, the target protein is encoded and the 3' of the canonical exon is A method for regulating the expression of a target protein by a cell having a preprocessed mRNA transcript (premRNA) containing an alternative nonsense mutation-dependent RNA degradation mechanism (NMD) exon, which includes an alternative 3' splice site upstream of a splice site and inside a canonical exon, or downstream of a 3' splice site of a canonical exon and inside an intron, the method comprising the steps of contacting the cell with a nonsense mutation-dependent RNA degradation mechanism alternative exon (NSAE) modulator, wherein the nonsense mutation-dependent RNA degradation mechanism alternative exon (NSAE) modulator modulates the processing of the mRNA transcript from the preprocessed mRNA transcript by modulating the splicing of the premRNA at the 3' alternative splice site, and the splicing of the premRNA at the 3' alternative splice site modulates the expression of the target protein.

[0013]

[0013] In some embodiments, a method is provided herein for regulating the expression of a target protein by a cell having a preprocessed mRNA transcript (premRNA) that encodes a target protein and includes an alternative nonsense mutation-dependent RNA degradation mechanism-inducing (NMD) exon, which includes an alternative 5' splice site downstream of the 5' splice site of the canonical exon and inside the canonical exon, or upstream of the 5' splice site of the canonical exon and inside the intron, the method comprising the steps of contacting the cell with a nonsense mutation-dependent RNA degradation mechanism alternative exon (NSAE) modulator, the nonsense mutation-dependent RNA degradation mechanism alternative exon (NSAE) modulator regulating the processing of the mRNA transcript from the preprocessed mRNA transcript by regulating the splicing of the premRNA at the 5' alternative splice site, and the splicing of the premRNA at the 5' alternative splice site regulating the expression of the target protein.

[0014]

[0014] In some embodiments, the nonsense mutation-dependent RNA degradation mechanism selective exon (NSAE) modulator binds to the targeted region of the preprocessed mRNA transcript. In some embodiments, the nonsense mutation-dependent RNA degradation mechanism selective exon (NSAE) modulator binds to factors involved in splicing NSAEs or NMD exons. In some embodiments, the nonsense mutation-dependent RNA degradation mechanism selective exon (NSAE) modulator inhibits the activity of factors involved in splicing NMD exons. In some embodiments, the nonsense mutation-dependent RNA degradation mechanism selective exon (NSAE) modulator binds to the region of the targeted region of the preprocessed mRNA transcript where factors involved in splicing NMD exons are involved. In some embodiments, the regulation of premRNA splicing increases the expression of the target protein. In some embodiments, the level of the target protein in cells is approximately 1.1 to 10 times, 1.5 to 10 times, 2 to 10 times, 3 to 10 times, 4 to 10 times, 1.1 to 5 times, 1.1 to 6 times, 1.1 to 7 times, 1.1 to 8 times, 1.1 to 9 times, 2 to 5 times, and 2 times higher compared to the level of processed mRNA encoding the target protein in control cells. The production increases by approximately 6 times, 2 to 7 times, 2 to 8 times, 2 to 9 times, 3 to 6 times, 3 to 7 times, 3 to 8 times, 3 to 9 times, 4 to 7 times, 4 to 8 times, 4 to 9 times, at least 1.1 times, at least 1.5 times, at least 2 times, at least 2.5 times, at least 3 times, at least 3.5 times, at least 4 times, at least 5 times, or at least 10 times. In some embodiments, regulation of premRNA splicing increases the production of processed mRNA encoding the target protein.In some embodiments, the level of processed mRNA encoding the target protein in cells contacted with the therapeutic agent is approximately 1.1 to 10 times, 1.5 to 10 times, 2 to 10 times, 3 to 10 times, 4 to 10 times, 1.1 to 5 times, 1.1 to 6 times, 1.1 to 7 times, 1.1 to 8 times, and approximately, compared to the level of processed mRNA encoding the target protein in control cells. The increase is approximately 1.1 to 9 times, approximately 2 to 5 times, approximately 2 to 6 times, approximately 2 to 7 times, approximately 2 to 8 times, approximately 2 to 9 times, approximately 3 to 6 times, approximately 3 to 7 times, approximately 3 to 8 times, approximately 3 to 9 times, approximately 4 to 7 times, approximately 4 to 8 times, approximately 4 to 9 times, at least approximately 1.1 times, at least approximately 1.5 times, at least approximately 2 times, at least approximately 2.5 times, at least approximately 3 times, at least approximately 3.5 times, at least approximately 4 times, at least approximately 5 times, or at least approximately 10 times. In some embodiments, the target protein is a canonical isoform of a protein. In some embodiments, the target protein is SynGAP1. In some embodiments, the target proteins are 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, C OL5A3, 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, GG A1, GGA3, GGT1, GLMN, GON4L, GRB14, HDAC3, HELQ, HP1BP3, HPS1, HPS4, IDUA, IFT122, IL17RC, IMPDH1, INVS, IR F3, KCTD3, KLKB1, KYAT1, LAMC3, LDAH, LIMS2, MALT1, MAP3K7, MAPK13, MCAT, MCEE, MPI, MSTO1, NBEAL2, NLE1, N LRC5, 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, SE MA3F, SH2D3A, SIK3, SIRT3, SKIV2L, SLC2A13, SLC12A7, SLC22A3, SLC25A13, SLC25A37, SLC27A5, SLC30A9, SLC30A10, SMPD1, SMTN, S It is one selected from the group consisting of NRPB, 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 nonsense mutation-dependent RNA degradation mechanism selective exon (NSAE) modulator is a composition described herein.

[0015]

[0015] In some embodiments, therapeutic agents comprising compositions described herein, as well as pharmaceutical compositions comprising pharmaceutically acceptable excipients and / or delivery media, are provided herein.

[0016]

[0016] In some embodiments, methods for treating or preventing a disease or condition in a subject requiring treatment or prevention of a disease or condition are provided herein, the methods comprising the step of administering a pharmaceutical composition described herein to the subject.

[0017]

[0017] In some embodiments, a method for treating or preventing a disease or condition in an object requiring treatment or prevention of a disease or condition, comprising (a) interacting with a target motif in a preprocessed mRNA transcript and N from the processed mRNA transcript Provided herein is a method for treating or preventing a disease or condition in a subject by the administration of the NSAE modulator, which modulates the exclusion of a SAE and modulates the inclusion of a canonical exon in a 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 delivery medium, wherein the disease or condition is treated or prevented in the subject by the administration of the NSAE modulator, by modulation of the expression of a protein translated from the processed mRNA transcript.

[0018]

[0018] In some embodiments, methods are provided herein for treating a disease or condition in a subject requiring treatment of the disease or condition by regulating the expression of a target protein in cells of the subject, wherein the cells of the subject have a preprocessed mRNA transcript (premRNA) encoding the target protein and comprising an alternative nonsense mutation-dependent RNA degradation mechanism-inducing (NMD) exon which (a) an exon followed by an intron adjacent to the 3' splice site of the exon, and (b) an alternative 3' splice site upstream of the 3' splice site of the exon and inside the exon, or downstream of the 3' splice site of the exon and inside the intron, and a therapeutic agent is brought into contact with the cells, wherein the therapeutic agent regulates the processing of the mRNA transcript from the preprocessed mRNA transcript by regulating the splicing of the premRNA at the 3' alternative splice site, and the splicing of the premRNA at the 3' alternative splice site regulates the expression of the target protein in cells of the subject.

[0019]

[0019] In some embodiments, methods are provided herein for treating a disease or condition in a subject requiring treatment of the disease or condition by regulating the expression of a target protein in cells of the subject, wherein the cells of the subject have a preprocessed mRNA transcript (premRNA) encoding the target protein and comprising an exon preceded by (a) an intron adjacent to the 5' splice site of the exon, and (b) an alternative nonsense mutation-dependent RNA degradation mechanism-inducing (NMD) exon, which comprises an alternative 5' splice site downstream of the 5' splice site of the exon and inside the exon, or upstream of the 5' splice site of the exon and inside the intron, and the step of contacting the cells with a therapeutic agent, wherein the processing of the mRNA transcript from the therapeutic agent preprocessed mRNA transcript is regulated by regulating the splicing of the premRNA at the 5' alternative splice site, the splicing of the premRNA at the 5' alternative splice site regulating the expression of the target protein in cells of the subject.

[0020]

[0020] In some embodiments, the disease is autosomal dominant intellectual disability, epileptic encephalopathy, or autism. In some embodiments, the disease or condition is caused by a deficiency in the amount or activity of a target protein. In some embodiments, the therapeutic agent increases the level of processed mRNA encoding the target protein in cells. In some embodiments, the therapeutic agent increases the expression of the target protein in cells. In some embodiments, the level of processed mRNA encoding the target protein in cells exposed to the therapeutic agent is about 1.1 to about 10 times, about 1.5 to about 10 times, about 2 to about 10 times, about 3 to about 10 times, about 4 to about 10 times, about 1.1 to about 5 times, about 1.1 to about 6 times, about 1.1 to about 7 times, and about 1. 1 to approximately 8 times, approximately 1.1 to approximately 9 times, approximately 2 to approximately 5 times, approximately 2 to approximately 6 times, approximately 2 to approximately 7 times, approximately 2 to approximately 8 times, approximately 2 to approximately 9 times, approximately 3 to approximately 6 times, approximately 3 to approximately 7 times, approximately 3 to approximately 8 times, approximately 3 to approximately 9 times, approximately 4 to approximately 7 times, approximately 4 to approximately 8 times, approximately 4 to approximately 9 times, at least approximately 1.1 times, at least approximately 1.5 times, at least approximately 2 times, at least approximately 2.5 times, at least approximately 3 times, at least approximately 3.5 times, at least approximately 4 times, The levels of the target protein in cells increase by at least approximately 5 times, or at least approximately 10 times, compared to the levels of processed mRNA encoding the target protein in control cells. The levels increase by approximately 6 times, 2 to 7 times, 2 to 8 times, 2 to 9 times, 3 to 6 times, 3 to 7 times, 3 to 8 times, 3 to 9 times, 4 to 7 times, 4 to 8 times, 4 to 9 times, at least 1.1 times, at least 1.5 times, at least 2 times, at least 2.5 times, at least 3 times, at least 3.5 times, at least 4 times, at least 5 times, or at least 10 times. In some embodiments, the method further includes a step of evaluating the mRNA level or expression level of the target protein. In some embodiments, the method further includes a step of evaluating the genome in question with respect to at least one gene mutation associated with the disease.

[0021]

[0021] In some embodiments, the disease or condition is caused by an excess amount or activity of the target protein. In some embodiments, the therapeutic agent reduces the level of processed mRNA encoding the target protein in cells. In some embodiments, the therapeutic agent reduces the expression of the target protein in cells. In some embodiments, the level of processed mRNA encoding the target protein in cells exposed to the therapeutic agent is about 1 / 1 to 1 / 10, about 1 / 1.5 to 1 / 10, about 1 / 2 to 1 / 10, about 1 / 3 to 1 / 10, about 1 / 4 to 1 / 10, about 1 / 1 to 1 / 5, about 1 / 1 to 1 / 6, about 1 / 1 to 1 / 7, about 1 / 1 to 1 / 8, about 1 / 1 to 9 It decreases to 1 / 2 to 1 / 5, 1 / 2 to 1 / 6, 1 / 2 to 1 / 7, 1 / 2 to 1 / 8, 1 / 2 to 1 / 9, 1 / 3 to 1 / 6, 1 / 3 to 1 / 7, 1 / 3 to 1 / 8, 1 / 3 to 1 / 9, 1 / 4 to 1 / 7, 1 / 4 to 1 / 8, 1 / 4 to 1 / 9, 1 / 1.1 or less, 1 / 1.5 or less, 1 / 2 or less, 1 / 2.5 or less, 1 / 3 or less, 1 / 3.5 or less, 1 / 4 or less, 1 / 5 or less, or 1 / 10 or less.In some embodiments, the level of the target protein in cells is approximately 1 / 1.1 to 1 / 10, 1 / 1.5 to 1 / 10, 1 / 2 to 1 / 10, 1 / 3 to 1 / 10, 1 / 4 to 1 / 10, 1 / 1.1 to 1 / 5, 1 / 1.1 to 1 / 6, 1 / 1.1 to 1 / 7, 1 / 1.1 to 1 / 8, 1 / 1.1 to 1 / 9, and 1 / 2 to 1 / 5 compared to the level of processed mRNA encoding the target protein in control cells. 1. It decreases to approximately 1 / 2 to 1 / 6, 1 / 2 to 1 / 7, 1 / 2 to 1 / 8, 1 / 2 to 1 / 9, 1 / 3 to 1 / 6, 1 / 3 to 1 / 7, 1 / 3 to 1 / 8, 1 / 3 to 1 / 9, 1 / 4 to 1 / 7, 1 / 4 to 1 / 8, 1 / 4 to 1 / 9, 1 / 1.1 or less, 1 / 1.5 or less, 1 / 2 or less, 1 / 2.5 or less, 1 / 3 or less, 1 / 3.5 or less, 1 / 4 or less, 1 / 5 or less, or 1 / 10 or less.

[0022]

[0022] In some embodiments, at least one gene mutation is located within a locus of a disease-related gene. In some embodiments, at least one gene mutation is located within a locus associated with the expression of a disease-related gene. In some embodiments, at least one gene mutation is located within the SYNGAP1 gene locus. In some embodiments, at least one gene mutation is located within a locus associated with the expression of the SYNGAP1 gene. In some embodiments, at least one gene mutation is located within a target gene locus, where the target gene locus is ABCA5, ABCA7, ABCC3, ABCC5, AB CC8、ABCD1、ABR、ACAD9、ACAP1、ACOX2、ACSF3、ACTN4、ADAM17、ADAMTS13、AK R1E2、ALAD、ALG3、ANKRD29、ANKS3、ANO4、AP3B2、AP3M1、AP5Z1、ARNTL、ASAP 3、ATRX、BBS2、BBS4、BRD9、CALM3、CARS1、CASP9、CATSPER1、CCDC40、CCDC88 B、CD4、CD58、CES2、CHFR、CLCN2、CNOT3、CNTROB、COL5A3、CPSF1、CSPP1、CTF 1、CTH、CYP3A5、DAB2IP、DBN1、DDX51、DEAF1、DGKE、DHDDS、DMKN、DNHD1、DOC K8、DOK5、EIF2B5、ELAC2、ELP1、ENTPD4、ESRRA、ESS2、ETAA1、ETHE1、FANCA、 FASTK、FASTKD3、FPGS、FREM1、GAS8、GCK、GGA1、GGA3、GGT1、GLMN、GON4L、GR B14、HDAC3、HELQ、HP1BP3、HPS1、HPS4、IDUA、IFT122、IL17RC、IMPDH1、INVS、 IRF3、KCTD3、KLKB1、KYAT1、LAMC3、LDAH、LIMS2、MALT1、MAP3K7、MAPK13、MC AT、MCEE、MPI、MSTO1、NBEAL2、NLE1、NLRC5、NOM1、NOP58、NPHP1、NPR1、NUP1 88、OSGEP、PABPC4、PCOLCE、PHKA2、PIDD1、PKD1、PLA2G6、PLD2、PLEKHG5、PN PO、POLE、PON2、PRMT7、PRODH、PRPF3、PRPF4、PYCR1、RAD52、REXO1、RFX5、RHB DF2, 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、SY NGAP1、SYNJ2、TAZ、TBL2、TDRD7、TECPR2、TFB1M、TM6SF1、TNK2、TOE1、TOR1B、The target gene is selected from the group consisting of TRAPPC6B, TRIP4, TRMT2A, TRMU, TRPV4, TTC19, TYMP, UMPS, UROD, WDR11, WDR62, WIPI1, WRAP53, XPO1, YY1AP1, and ZC3H14 gene loci. In some embodiments, at least one gene mutation is located within a locus associated with target gene expression, and the target gene is 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, PLEKHG 5, PNPO, POLE, PON2, PRMT7, PRODH, PRPF3, PRPF4, PYCR1, RAD52, REXO1, RFX5, RHBDF2, RMND1, ROBO3, RPGRIP1, RTTN, RUFY3, SEMA3B,SEMA3F, SH, Any one selected from the group consisting of 2D3A, 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 the ZC3H14 gene. In some embodiments, the subject is human. In some embodiments, the subject is a non-human animal. In some embodiments, the subject is a fetus, embryo, or infant. In some embodiments, one or more cells are ex vivo, or in a tissue, or in an ex vivo organ. In some embodiments, the therapeutic agent is administered to the subject by intracerebroventricular injection, intraperitoneal injection, intramuscular injection, intrathecal injection, subcutaneous injection, oral administration, bursa injection, intravitreal administration, subretinal injection, topical application, implantation, or intravenous injection.

[0023]

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

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

[0024]

[0025] In some aspects, a method of treating a subject in need of treatment, comprising administering to the subject the pharmaceutical composition described herein by intracerebroventricular injection, intraperitoneal injection, intramuscular injection, intrathecal injection, subcutaneous injection, oral administration, bursa injection, intravitreal administration, subretinal injection, topical application, implantation, or intravenous injection. The method is provided herein.

Brief Description of the Drawings

[0025] [Figure 1A]

[0026] Figure 1A is a schematic diagram illustrating a wild-type cell expressing pre-mRNA that undergoes alternative splicing to produce productive and non-productive mRNA. Non-productive mRNA is degraded by NMD, while productive mRNA is translated at normal protein levels. [Figure 1B]

[0027] Figure 1B is a schematic diagram illustrating wild-type cells treated with TANGO (Targeted Augmentation of Nuclear Gene Output) ASO, which targets unproductive AS events (e.g., exon inclusion) that inhibit the inclusion of unproductive exons, leading to an increase in productive mRNA. The increase in productive mRNA levels results in an increase in protein levels exceeding 100%. [Figure 1C]

[0028] Figure 1C is an illustrative schematic diagram showing an example of haploinsufficient cells containing a wild-type allele (orange) and a mutant allele (red). Both alleles express premRNA, which undergoes alternative splicing to produce productive and non-productive mRNA. While the non-productive mRNA is degraded by NMD, the productive mRNA from the wild-type allele produces 50% of the normal protein level that leads to disease. [Figure 1D]

[0029] Figure 1D is an illustrative schematic diagram showing an example of haploinsufficient cells treated with TANGO ASO, which targets unproductive AS events (e.g., exon inclusion) that block the inclusion of unproductive exons, leading to an increase in productive mRNA from both alleles. Although mutant mRNA does not produce functional protein, the increase in wild-type productive mRNA levels restores protein levels to normal. [Figure 1E]

[0030] Figure 1E is a schematic diagram illustrating a selective 5'ss of an exon (exon B) (corresponding to a selective 3'ss of the preceding intron (intron A)). In this example, the selective exon is longer than its corresponding canonical exon, and the selective intron is shorter than its corresponding canonical intron. [Figure 1F]

[0031] Figure 1F is a schematic diagram illustrating the selective 5'ss of an exon (exon B) (corresponding to the selective 3'ss of the preceding intron (intron A)). In this example, the selective exon is shorter than the corresponding canonical exon, and the selective intron is longer than the corresponding canonical intron. [Figure 1G]

[0032] Figure 1G is an exemplary schematic diagram illustrating the selective 3'ss of an exon (exon B) (corresponding to the selective 5'ss of the intron (intron B) that follows the exon). In this example, the selective exon is longer than the corresponding canonical exon, and the selective intron is shorter than the corresponding canonical intron. [Figure 1H]

[0033] Figure 1H is an exemplary schematic diagram illustrating the selective 3'ss of an exon (exon B) (corresponding to the selective 5'ss of the intron (intron B) that follows the exon). In this example, the selective exon is shorter than the corresponding canonical exon, and the selective intron is longer than the corresponding canonical intron. [Figure 2]

[0034] Figure 2 shows an example of an unproductive alternative splicing event that is expected to lead to an immature stop codon and subsequent nonsense mutation-dependent degradation of the processed mRNA transcript. The left panel shows the types of alternative splicing events (cassette exons, alternative splice sites, and alternative introns) that are expected to lead to the introduction of an immature stop codon (PTC) and the degradation of the transcript. The horizontal bar graphs provide an overview of the number of protein-coding genes containing each type of unproductive alternative splicing event. Non-disease-related genes are depicted by the upper bars, and disease-related genes are depicted by the lower bars (based on the Orphanet disease database). Exons are represented by rectangles, and introns by lines. Dark gray rectangles or lines represent unproductive alternative splicing regions. [Figure 3]

[0035] Figure 3 is an illustrative schematic diagram of an NMD-inducible alternative 3' splice site in a SYNGAP1 intron (corresponding to the alternative 5'ss of the exon downstream of the alternative intron). NMD-inducible alt 3'ss event: UCSC Genome Browser snapshot of a region within the SYNGAP1 gene (chr6 33440553 33440728) containing an NMD-inducible alternative 3' splice site event, depicted by the shaded area and the black bar at the top (exons are squares and introns are lines with arrowheads). RNA sequencing traces from human middle frontal gyrus samples from individuals of various ages, and from proliferating or differentiated RenCellVM cells treated with cycloheximide (CHX) or DMSO controls are shown. [Figure 4]

[0036] Figure 4 shows an exemplary ASO walk design. The shaded nucleotides correspond to the expanded exon 11 of SYNGAP1, derived from the selection of the displayed Alt 3'ss of the intron (corresponding to the selective 5'ss of the exon downstream of the selective intron). The figure discloses each of sequence numbers 10226–10228 in order of appearance. [Figure 5]

[0037] Figures 5A-5C are graphs illustrating exemplary ASO walks using Taqman qPCR, such as the results of ASO screening by Taqman qPCR.

[0038] Figure 5A shows exemplary Taqman qPCR results using RNA from HEK293 cells transfected for 24 hours with 80 nM ASO from region 1 depicted in Figure 4. The exemplary Taqman probe spans the junction of exons 10 and 11 to measure productive mRNA.

[0039] Figure 5B shows exemplary Taqman qPCR results using RNA from HEK293 cells transfected for 24 hours with 80 nM ASO from region 2 depicted in Figure 4. The exemplary Taqman probe spans the junction of exons 10 and 11 to measure productive mRNA.

[0040] Figure 5C shows exemplary Taqman qPCR results using RNA from HEK293 cells transfected for 24 hours with 80 nM ASO from region 3 depicted in Figure 4. The exemplary Taqman probe spans the junction of exons 10 and 11 to measure productive mRNA. [Figure 6]

[0041] Figure 6 illustrates the use of antisense oligomers to modulate unproductive alternative splicing events and increase mRNA and protein levels in a dose-dependent manner in vitro. Selected SYNGAP1 ASOs targeting alternative 3' splice site events were transfected into HEK293 (human embryonic kidney cells) cells at increasing concentrations for 24 hours, followed by RT-PCR (reverse transcription polymerase chain reaction) and TaqMan qPCR (quantitative polymerase chain reaction). The bar graph on the left shows a dose-dependent decrease in unproductive mRNA, and the bar graph on the right shows a dose-dependent increase in productive mRNA. Western blots and protein quantifications for SynGAP from HEK293 cells treated with each selected ASO at increasing concentrations for 48 hours are shown on the right. Equal protein loading was confirmed by Ponceau staining. Fc = change factor relative to control. [Figure 7]

[0042] Figure 7 shows exemplary RT-PCR and RT-PCR concentration quantification validation for SYNGAP1 in cells treated with 50 μg / mL cycloheximide (CHX) or an equivalent volume of DMSO (dimethyl sulfoxide) for 3 hours. [Figure 8]

[0043] Figure 8 shows the dose-dependent effect of antisense oligomers on modulating unproductive alternative splicing events. Representative RT-PCR PAGE (polyacrylamide gel electrophoresis) of cells transfected with selected antisense oligomers at increasingly increasing concentrations targeting alternative 3'ss in SYNGAP1 is shown. [Figure 9]

[0044] Figure 9 shows an exemplary Western blot of SynGAP in HEK293 cells after 48 hours of treatment with 100 nM siRNA against SYNGAP1. [Figure 10A]

[0045] Figures 10A–10D are illustrative diagrams, photographs, and graphs illustrating the validation of alternative 3' splice site events in an intron (intron 10) (corresponding to alternative 5'ss in the downstream exon (exon 11) of the alternative intron). *Mouse events have a different size than human events.

[0046] Figure 10A is a schematic diagram illustrating an example of an intron (intron 10) alternative 3' splice site (Alt 3'ss) event in SYNGAP1 (corresponding to the alternative 5'ss of the downstream exon (exon 11) of the alternative intron). [Figure 10B]

[0047] Figure 10B shows exemplary results of RT-PCR against SYNGAP1 using RNA from RenCellsVM (neural progenitor cells) or Neuro 2A (mouse neuroblastoma cells) treated with either DMSO(-) or cycloheximide (CHX)(+). Primers were placed at exons 10 and 11. [Figure 10C]

[0048] Figure 10C shows exemplary results of RT-PCR against SYNGAP1 using RNA from the whole mouse brain. Primers were placed in exons 10 and 11. [Figure 10D]

[0049] Figure 10D shows an exemplary quantification of RT-PCR SYNGAP1 products using RNA from various non-human primate brain regions, plotted as the 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). [Figure 11]

[0050] Figures 11A–11C show graphs and photographs demonstrating that exemplary ASOs inhibit Alt 3'ss selection and increase SYNGAP1 mRNA and protein.

[0051] Figures 11A and 11B show exemplary RT-PCR results demonstrating a decrease in the SYNGAP1 Alt 3'ss isoform and exemplary Taqman qPCR results demonstrating an increase in productive mRNA, respectively.

[0052] Figure 11A shows the quantification of RT-PCR products using RNA from HEK293 cells transfected for 24 hours 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 placed at exons 10 and 11. N=2. NT = untargeted ASO control.

[0053] Figure 11B shows the results of Taqman qPCR using a probe spanning the junction of exons 10–11 to measure productive mRNA, plotted as a change factor against an ASO-free control (-) using the same sample as in Figure 11A. N=2. NT=untargeted ASO control.

[0054] Figure 11C shows exemplary Western blot results demonstrating an increase in SynGAP protein. Figure 11C shows Western blot analysis using whole cell lysates from HEK293 cells transfected with selected ASO for 48 hours. Quantification of the band corresponding to SynGAP is standardized against a Ponceau loading control, and the change factor (fc) relative to the control (-) is shown below the gel. [Figure 12-1]

[0055] Figures 12A–12E are photographs and graphs showing that exemplary selected MOE(2-methoxyethyl)) lengthmers and PMO(phosphodiamidate morpholino) inhibit Alt intron 3'ss selection (Alt downstream exon 5'ss selection) and increase SYNGAP1 mRNA and protein.

[0056] Figures 12A and 12B show exemplary RT-PCR results demonstrating a reduction in the SYNGAP1 Alt intron 3'ss isoform (Alt downstream exon 5'ss isoform).

[0057] Figure 12A shows the results of RT-PCR using selected MOE #5 from region 1, as well as RNA from MEF (mouse embryonic fibroblast) cells nucleofected for 24 hours with derivative MOE lengthmers and PMO. Primers were placed at exons 10 and 11.

[0058] Figure 12B shows the quantification of the RT-PCR products shown in Figure 12A, plotted as the 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. -=Control without ASO. [Figure 12-2]

[0059] Figure 12C shows exemplary Taqman qPCR results demonstrating an increase in productive mRNA. Figure 12C shows Taqman qPCR results using a probe spanning the exon 10-11 junction to measure productive mRNA, plotted as a change factor against an ASO-free control (-) using the same sample as in Figure 12A. N=2. -=ASO-free control.

[0060] Figures 12D and 12E show exemplary Western blot results demonstrating an increase in SynGAP protein.

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

[0062] Figure 12E shows the quantification of the band corresponding to SynGAP, standardized against the Ponceau loading control and plotted as a change factor (fc) relative to the control (-). N=2. -=Control without ASO. [Modes for carrying out the invention]

[0026]

[0063] Certain details in this specification are provided to provide a full understanding of the various embodiments. However, those skilled in the art will understand that this disclosure can be carried out without these details. In other cases, well-known structures are not shown or described in detail to avoid unnecessarily obscuring the description of embodiments. Unless otherwise required by the context, the word “comprise,” and its variations, e.g., “comprises” and “comprising,” throughout this specification and the subsequent claims should be interpreted as having an open and comprehensive meaning, i.e., “including, but not limited to.” Furthermore, the headings provided herein are for convenience only and do not describe the scope and meaning of the claimed disclosure.

[0027]

[0064] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include multiple references unless the context clearly indicates otherwise. It should also be noted that the term “or” is generally used to include “and / or” unless the context clearly indicates otherwise.

[0028]

[0065] As used herein, coordinates refer to the coordinates of the genome reference assembly GRCh38 (Genome Research Consortium human build 38), also known as Hg38 (Human Genome Build 38).

[0029]

[0066] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which this disclosure belongs. Similar or equivalent methods and materials may be used in the implementation or testing of this disclosure, but suitable methods and materials are described below.

[0030]

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

[0031] Autosomal dominant intellectual disability and the SYNGAP1 gene

[0069] Autosomal dominant intellectual disability is an autosomal dominant neurodevelopmental disorder characterized by marked impairment of intellectual function and adaptive behavior, one of which is haploinsufficient expression of the SYNGAP1 gene. SYNGAP1 encodes the SYNGAP1 protein, a ras GTPase-activating protein involved in cognitive development and proper synaptic function between neurons. SYNGAP1 is known to be involved in synaptic plasticity, axon formation, and AMPA receptor transport. Generally speaking, SYNGAP1 activity is essential for development and survival. SYNGAP1 deficiency can be caused by sporadic mutations or alternative splicing events. Deficiency in SYNGAP1 activity can lead to intellectual disability, i.e., intellectual impairment, epileptic encephalopathy, or autism.

[0032]

[0070] This disclosure provides compositions and methods for modulating alternative splicing of SYNGAP1 to regulate the production of mature mRNA encoding a functional protein, and therefore, the translated functional SYNGAP1 protein. These compositions and methods include antisense oligomers (ASOs) that can promote canonical splicing of SYNGAP1 premRNA. In various embodiments, the methods of this disclosure can be used to increase functional SYNGAP1 protein to treat conditions caused by SYNGAP1 protein deficiency. In some embodiments, the condition is autosomal dominant intellectual disability. In other embodiments, the condition is epileptic encephalopathy or autism.

[0033]

[0071] In some embodiments, the method of the present invention is used to increase the production of functional SYNGAP1 protein to treat a condition in subjects requiring treatment of the condition. In some embodiments, the subjects have a condition in which SYNGAP1 is not necessarily deficient compared to the wild type, but an increase in SYNGAP1 still alleviates the condition. In some embodiments, the condition is caused by a sporadic mutation. In some embodiments, the method of the present invention is used to decrease functional SYNGAP1 to treat a condition in subjects requiring treatment of the protein-producing condition. In some embodiments, the method of the present invention is used to regulate the production of functional SYNGAP1 protein to treat a condition in subjects requiring treatment of the condition.

[0034] target genes

[0072] This disclosure provides compositions and methods for modulating alternative splicing of targets in order to regulate the production of mature mRNA encoding functional proteins and, therefore, the translated functional target proteins, wherein the targets are ABCA5, ABCA7, ABCC3, ABCC5, ABCC8, ABCD1, ABR, ACAD9, ACAP1, ACOX2, ACSF3, ACTN4, ADAM17, ADAMTS13, AKR1E2, ALAD, ALG3, ANKRD29, ANKS3, ANO4, AP3B2, AP3M1, AP5Z1, ARNTL, A SAP3, ATRX, BBS2, BBS4, BRD9, CALM3, CARS1, CASP9, CATSPER1, CCDC40, CCDC88B, CD4, CD58, CES2, CHFR, CLCN2, CNOT3, CNTROB, COL5A3, CPSF1, CSPP1, C TF1, 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, INV S, IRF3, KCTD3, KLKB1, KYAT1, LAMC3, LDAH, LIMS2, MALT1, MAP3K7, MAPK13, MCAT, MCEE, MPI, MSTO1, NBEAL2, NLE1, NLRC5, NOM1, NOP58, NPHP1, NPR1, NUP 188, OSGEP, PABPC4, PCOLCE, PHKA2, PIDD1, PKD1, PLA2G6, PLD2, PLEKHG5, PNPO, POLE, PON2, PRMT7, PRODH, PRPF3, PRPF4, PYCR1, RAD52, REXO1, RFX5, RH BDF2, RMND1, ROBO3, RPGRIP1, RTTN, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIK3, SIRT3, SKIV2L, SLC2A13, SLC12A7, SLC22A3, SLC25A13, SLC25A37, SLC27A5,It is one of the following selected from the group consisting of 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 target premRNAs, wherein the targets are 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, CS PP1, 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, GGA 1, GGA3, GGT1, GLMN, GON4L, GRB14, HDAC3, HELQ, HP1BP3, HPS1, HPS4, IDUA, IFT122, IL17RC, IMPDH1, I NVS, 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, PRPF 3, PRPF4, PYCR1, RAD52, REXO1, RFX5, RHBDF2, RMND1, ROBO3, RPGRIP1, RTTN, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIK3, SIRT3, SKIV2L, SLC2A13, SLC12A7, SLC22A3, SLC It is one of the following selected from the group consisting of 25A13, 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, the methods of the present disclosure can be used to increase the functional target protein in order to treat a condition caused by a target protein deficiency, wherein the target is 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, C PSF1, 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, H ELQ, HP1BP3, HPS1, HPS4, IDUA, IFT122, IL17RC, IMPDH1, INVS, IRF3, KCTD3, KLKB1, KYAT1, LAMC3, LDAH, LIMS2, MALT 1, 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, R EXO1, RFX5, RHBDF2, RMND1, ROBO3, RPGRIP1, RTTN, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIK3, SIRT3, SKIV2L, SLC2A13, S LC12A7, SLC22A3, SLC25A13, SLC25A37, SLC27A5, SLC30A9, SLC30A10, SMPD1, SMTN, SNRPB, SP140, STAMBP, STXBP2, S The condition is selected from the group consisting of ULF2, 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 intellectual disability. In other embodiments, the condition is epileptic encephalopathy or autism.

[0035]

[0073] In some embodiments, the method of the present invention is used to increase the production of functional target proteins in order to treat a condition in an object requiring treatment of the condition, where the target is 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、EIF2 B5、ELAC2、ELP1、ENTPD4、ESRRA、ESS2、ETAA1、ETHE1、FANCA、FASTK、FASTKD3 FPGS, FREM1, GAS8, GKK, GGA1, GGA3, GGT1, GLMN, GON4L, GRB14, HDAC3, HELQ, HP1BP3, HPS1, HPS4, IDUA, IFT122, IL17RC, IMPDH1, INVS, IRF3, KCTD3, KL KB1、KYAT1、LAMC3、LDAH、LIMS2、MALT1、MAP3K7、MAPK13、MCAT、MCEE、MPI、M STO1、NBEAL2、NLE1、NLRC5、NOM1、NOP58、NPHP1、NPR1、NUP188、OSGEP、PABPC 4、PCOLCE、PHKA2、PIDD1、PKD1、PLA2G6、PLD2、PLEKHG5、PNPO、POLE、PON2、P RMT7、PRODH、PRPF3、PRPF4、PYCR1、RAD52、REXO1、RFX5、RHBDF2、RMND1、ROBO 3, RPGRIP1, RTTN, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIK3, SIRT3, SKIV2L, SLC2A13, SLC12A7, SLC22A3, SLC25A13, SLC25A37, SLC27A5, SLC30A9, SLC30A1 0、SMPD1、SMTN、SNRPB、SP140、STAMBP、STXBP2、SULF2、SYNGAP1、SYNJ2、TAZ 、TBL2、TDRD7、TECPR2、TFB1M、TM6SF1、TNK2、TOE1、TOR1B、TRAPPC6B、TRIP4、The target is selected from the group consisting of 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 compared to the wild type, but an increase in the target protein still alleviates the condition, where the target is 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, COL5A 3, 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, HP1BP 3, 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, PLEKH G5, PNPO, POLE, PON2, PRMT7, PRODH, PRPF3, PRPF4, PYCR1, RAD52, REXO1, RFX5, RHBDF2, RMND1, ROBO3, RPGRIP1, RTTN, RUFY3, SEMA3B, S,It is one of the following selected from the group consisting of EMA3F, 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 mutations. In some embodiments, the methods of the present invention are used to reduce the production of functional target proteins in order to treat the condition in subjects requiring treatment of the condition, where the targets are 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, HP 1BP3, 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, PLEK HG5, PNPO, POLE, PON2, PRMT7, PRODH, PRPF3, PRPF4, PYCR1, RAD52, REXO1, RFX5, RHBDF2, RMND1, ROBO3, RPGRIP1, RTTN, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIK3, SIRT3, SKIV2L, SLC2 It is one of the following selected from the group consisting of A13, 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 present invention are used to regulate the production of functional target proteins to treat a condition in an object requiring treatment of the condition, where the target is 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, CH FR, CLCN2, CNOT3, CNTROB, COL5A3, CPSF1, CSPP1, CTF1, CTH, CYP3A5, DAB2IP, DBN1, DDX51, DEAF1, DGKE, DHDDS, DMKN, DNHD1,DOC, K8, 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, KLK B1, 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, S KIV2L, SLC2A13, SLC12A7, SLC22A3, SLC25A13, SLC25A37, SLC27A5, SLC30A9, SLC30A10, SMPD1, SMTN, SNRPB, SP140, STAMB It is one of the following selected from the group consisting of P, 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.

[0036] Splicing

[0074] Intervening sequences or introns are removed by large, highly dynamic RNA-protein complexes called spliceosomes, which regulate the complex interactions between primary transcripts, nuclear small RNAs (snRNAs), and numerous proteins. Spliceosomes are constructed on each intron in an ordered manner, starting with the recognition of the 5' splice site (5'ss) by U1 snRNA, or the recognition of the 3' splice site (3'ss) with the binding of the U2 cofactor (U2AF) to the 3'ss region, facilitating the binding of U2 snRNA to branch point sequences (BPS). U2AF is a stable heterodimer consisting of a 65kD subunit (U2AF65) encoded by U2AF2 that binds to polypyrimidine tract (PPT), and a 35kD subunit (U2AF35) encoded by U2AF1 that interacts with the highly conserved AG dinucleotide at 3'ss to stabilize U2AF65 binding. Accurate splicing requires not only BPS / PPT units and 3'ss / 5'ss sequences, but also auxiliary sequences or structures known as intronic or exonic splicing enhancers or splicing silencers that activate or suppress splice site recognition. These elements enable true splice sites to be recognized from among a vast excess of latent or pseudo-sequences in higher eukaryotic genomes, which have the same sequence but are an order of magnitude more numerous than true sites. While these often have regulatory functions, the precise mechanisms of their activation or suppression are largely unknown.

[0037]

[0075] The decision of whether or not splicing occurs can typically be modeled as a probabilistic rather than deterministic process, and therefore, even the clearest splicing signals can sometimes lead to inaccurate splicing. However, under normal conditions, premRNA splicing proceeds with surprisingly high precision. This is thought to be partly due to the activity of adjacent cis-acting auxiliary exon splicing regulatory elements and intron splicing regulatory elements (ESRs or ISRs). Typically, these functional elements act as exon or intron splicing enhancers, respectively, based on their ability to stimulate or inhibit splicing. They are classified as either esplicosomes (ESE or ISE) or splicing silencers (ESS or ISS). Currently, there is evidence suggesting that some auxiliary cis-acting elements may act by influencing the dynamics of spliceosome construction, for example, the arrangement of the complex between U1 snRNP and 5'ss, but it is highly probable that multiple elements function in a coordinated manner with trans-acting RNA-binding proteins (RBPs). For example, the serine-rich and arginine-rich families of RBPs (SR proteins) are a conserved family of proteins that play a crucial role in exon determination. SR proteins promote exon recognition by recruiting components of the press spliceosome to adjacent splice sites or by antagonizing the effects of ESS in their vicinity. The repressive effects of ESS and ISS can be mediated by members of the heteronuclear ribonucleoprotein (hnRNP) family, which can alter the recruitment of core splicing factors to adjacent splice sites. In addition to their role in splicing control, silencer elements have been suggested to also play a role in suppressing pseudoexons, which are sets of decoy intron splice sites that have typical exon spacing but lack a functional open reading frame. ISEs, ISSs, ESEs, and ESSs, in conjunction with their associated transactive RBPs, are key components in a set of splicing controls that determine how, where, and when mRNA is constructed from its precursor.

[0038]

[0076] The sequences that form the exon-intron boundaries are degenerate signals of varying intensities that can occur frequently within human genes. In polyexon genes, various pairs of splice sites can link to each other in many different combinations, allowing a wide variety of transcripts to be produced from a single gene. This is generally called alternative premRNA splicing. Most mRNA isoforms produced by alternative splicing are exported from the nucleus and translated into functional polypeptides, but different mRNA isoforms originating from a single gene can exhibit significant variability in their translation efficiency. mRNA isoforms with an immature stop codon (PTC) at least 50 bp upstream of the exon junction complex are likely to be targeted for degradation by the nonsense mutation-dependent mRNA degradation (NMD) pathway. These mRNA isoforms contain nonsense mutation-dependent mRNA degradation alternative exons (NSAEs), which are exons that have undergone alternative splicing leading to NMD. Mutations in conventional (BPS / PPT / 3'ss / 5'ss) and auxiliary splicing motifs can lead to abnormal splicing, such as exon skipping, latent (or false) exon inclusion, or splice site activation, which can significantly contribute to human morbidity and mortality. Both abnormal and alternative splicing patterns can be influenced by native DNA variants in exons and introns.

[0039] Target transcript

[0077] In some embodiments, the method of the disclosure utilizes the presence of nonsense mutation-dependent RNA degradation mechanism selective exon-containing premRNA (NSAE premRNA) transcribed from a certain gene. In some embodiments, the method of the disclosure utilizes the presence of nonsense mutation-dependent RNA degradation mechanism selective exon-containing premRNA (NSAE premRNA) transcribed from the SYNGAP1 gene. Canonical splicing of an identified SYNGAP1 NSAE premRNA transcript that produces functional mature SYNGAP1 mRNA can be induced using a therapeutic agent, such as an ASO, that promotes constitutive splicing of SYNGAP1 NSAE premRNA at the canonical splice site. In some embodiments, the resulting functional mature SYNGAP1 mRNA is successfully translated, thereby increasing the amount of functional SYNGAP1 protein in the patient's cells and preventing symptoms of SYNGAP1-related disease. In some embodiments, the identified SYNGAP1 NSAE premRNA transcript that produces functional mature SYNGAP1 mRNA Canonical splicing of transcripts can be reduced using therapeutic agents that inhibit constitutive splicing of SYNGAP1 NSAE premRNA at the canonical splice site, such as ASOs. In some embodiments, the resulting functionally matured SYNGAP1 mRNA is abnormally translated, thereby reducing the amount of functional SYNGAP1 protein in the patient's cells and preventing the symptoms of SYNGAP1-related disease.

[0040]

[0078] In some embodiments, the methods of the present disclosure utilize the presence of nonsense mutation-dependent RNA degradation mechanism selective exon-containing premRNA (NSAE premRNA) transcribed from target genes, where the targets are 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, KLK B1, 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,The selected agent is one of the following: 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 premRNA transcript, which produces a functionally matured target mRNA, can be induced using a therapeutic agent that promotes constitutive splicing of the target NSAE premRNA at the canonical splice site, such as ASO. In some embodiments, the resulting functionally matured target mRNA is normally translatable and can increase the amount of functional target protein in the patient's cells, thereby preventing the symptoms of target-related disease. In some embodiments, canonical splicing of the identified target NSAE premRNA transcript that produces functionally matured target mRNA can be reduced using therapeutic agents that inhibit constitutive splicing of the target NSAE premRNA at the canonical splice site, such as ASOs. In some embodiments, the resulting functionally matured target mRNA is abnormally translated, thereby reducing the amount of functional target protein in the patient's cells, and preventing the symptoms of target-related disease.

[0041]

[0079] In various embodiments, the disclosure provides therapeutic agents that can target SYNGAP1 premRNA to modulate splicing or protein expression levels. The therapeutic agent may be a small molecule, a nucleic acid oligomer, or a polypeptide. In some embodiments, the therapeutic agent is an ASO. Various regions or sequences on SYNGAP1 premRNA can be targeted by the therapeutic agent, e.g., the ASO. In some embodiments, the ASO targets SYNGAP1 NSAE premRNA transcribed from the SYNGAP1 gene. In some embodiments, the ASO targets SYNGAP1 NSAE premRNA transcribed from the SYNGAP1 gene, including a nonsense mutation-dependent RNA degradation mechanism selective exon (NSAE). In some embodiments, the NSAE includes a portion or the entirety of canonical exon 11 of the SYNGAP1 premRNA transcript. In some embodiments, the NSAE comprises only a portion of canonical exon 11 of the SYNGAP1 premRNA transcript, or canonical exon 11 of the SYNGAP1 premRNA transcript and at least a portion of the intron upstream of exon 11 of the SYNGAP1 premRNA transcript. In some embodiments, the NSAE is incorporated into the SYNGAP1 premRNA 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 target sequence within the NSAE of the SYNGAP1 premRNA transcript. In some embodiments, the NSAE comprises a portion of canonical exon 11 of the SYNGAP1 premRNA transcript or the entire canonical exon 11. In some embodiments, the ASO targets a sequence within exon 10 or 11 of the SYNGAP1 premRNA transcript. In some embodiments, the ASO targets an exon sequence upstream (or 5') of the 5' splice site of exon 11 of the SYNGAP1 premRNA transcript.In some embodiments, the ASO targets an exon sequence downstream (or 3') of the 3' splice site of exon 11 of the SYNGAP1 premRNA transcript. In some embodiments, the ASO targets a sequence inside the intron adjacent to the 3' splice site of the NSAE of the SYNGAP1 premRNA transcript. In some embodiments, the ASO targets a sequence inside intron 10 or 11 of the SYNGAP1 premRNA transcript. In some embodiments, the ASO targets an intron sequence upstream (or 5') of the 3' splice site of intron 10 or 11 of the SYNGAP1 premRNA transcript. In some embodiments, the ASO targets an intron sequence downstream (or 3') of the 5' splice site of intron 10 or 11 of the SYNGAP1 premRNA transcript. In some embodiments, the ASO targets a sequence inside the intron adjacent to the 5' splice site of the NSAE of the SYNGAP1 premRNA transcript. In some embodiments, the ASO targets a sequence within intron 10 of the SYNGAP1 premRNA transcript. In some embodiments, the ASO targets a sequence within intron 11 of the SYNGAP1 premRNA transcript. In some embodiments, the ASO targets an intron sequence upstream (or 5') of the 3' splice site of intron 10 or 11 of the SYNGAP1 premRNA transcript. In some embodiments, the ASO targets an intron sequence downstream (or 3') of the 5' splice site of intron 10 or 11 of the SYNGAP1 premRNA transcript. In some embodiments, the ASO targets a sequence containing the exon-intron boundary of the SYNGAP1 premRNA transcript. In some embodiments, the exon is an NSAE. The exon-intron boundary can refer to the junction between the exon sequence and the intron sequence. In some embodiments, the intron sequence may be adjacent to the 5' end of the NSAE or the 3' end of the exon. In some embodiments, the ASO targets a sequence containing the exon 10-intron 11 boundary of the SYNGAP1 premRNA transcript. In some embodiments, the ASO targets a sequence containing the intron 10-exon 11 boundary of the SYNGAP1 NSAE premRNA transcript.In some embodiments, the ASO targets a sequence that includes both a portion of an intron and a portion of an exon.

[0042]

[0080] In various embodiments, the present disclosure provides therapeutic agents that can modulate the level of splicing or protein expression by targeting a target premRNA, wherein the target is 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, C ALM3, 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, LA MC3, LDAH, LIMS2, MALT1, MAP3K7, MAPK13, MCAT, MCEE, MPI, MSTO1, NBEAL2, NLE1, NLRC5, NOM1, NOP58, NPHP1, NPR1, NUP188, OSGEP, PABPC4, PCOLCE, PHK A2, PIDD1, PKD1, PLA2G6, PLD2, PLEKHG5, PNPO, POLE, PON2, PRMT7, PRODH, PRPF3, PRPF4, PYCR1, RAD52, REXO1, RFX5, RHBDF2, RMND1, ROBO3, RPGRIP1, RT TN, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIK3, SIRT3, SKIV2L, SLC2A13, SLC12A7, SLC22A3, SLC25A13, SLC25A37, SLC27A5, SLC30A9, SLC30A10, SMPD1, SMTN,The therapeutic agent is selected from the group consisting of 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 may be a small molecule, a nucleic acid oligomer, or a polypeptide. In some embodiments, the therapeutic agent is an ASO. Various regions or sequences on the target premRNA can be targeted by the therapeutic agent, e.g., the ASO. In some embodiments, the ASO targets a target NSAE premRNA transcribed from the target gene. In some embodiments, the ASO targets a target NSAE premRNA transcribed from a target gene, which includes a nonsense mutation-dependent RNA degradation mechanism selective exon (NSAE). In some embodiments, the NSAE includes a portion of the canonical exon or the entire canonical exon of the target premRNA transcript. In some embodiments, the NSAE includes only a portion of the canonical exon of the target premRNA transcript, or the canonical exon of the target premRNA transcript and at least a portion of the intron upstream of the exon of the target premRNA transcript. In some embodiments, the NSAE is incorporated into the target premRNA 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 inside the NSAE of the target premRNA transcript. In some embodiments, the NSAE includes a portion of the canonical exon or the entire canonical exon of the target premRNA transcript. In some embodiments, the ASO targets a sequence inside the exon of the target premRNA transcript. In some embodiments, the ASO targets the exon sequence upstream (or 5') of the 5' splice site of the target premRNA transcript. In some embodiments, the ASO targets the 3' splice site of the exon of the target premRNA transcript. The ASO targets the exon sequence downstream (or 3') from the 3' splice site of the target premRNA transcript. In some embodiments, the ASO targets the sequence inside the intron adjacent to the 3' splice site of the NSAE of the target premRNA transcript. In some embodiments, the ASO targets the sequence inside the intron of the target premRNA transcript. In some embodiments, the ASO targets the intron sequence upstream (or 5') from the 3' splice site of the intron of the target premRNA transcript. In some embodiments, the ASO targets the intron sequence downstream (or 3') from the 5' splice site of the intron of the target premRNA transcript. In some embodiments, the ASO targets the sequence inside the intron adjacent to the 5' splice site of the NSAE of the target premRNA transcript. In some embodiments, the ASO targets the sequence inside the intron of the target premRNA transcript. In some embodiments, the ASO targets the intron sequence upstream (or 5') from the 3' splice site of the intron of the target premRNA transcript. In some embodiments, the ASO targets an intron sequence downstream (or 3') of the 5' splice site of the intron of the target premRNA transcript. In some embodiments, the ASO targets a sequence containing an exon-intron boundary of the target premRNA transcript. In some embodiments, the exon is an NSAE. The exon-intron boundary can refer to the junction between the exon sequence and the intron sequence. In some embodiments, the intron sequence can be adjacent to the 5' end of the NSAE or the 3' end of the exon. In some embodiments, the ASO targets a sequence containing an exon-intron boundary of the target premRNA transcript. In some embodiments, the ASO targets a sequence containing an intron-exon boundary of the target NSAE premRNA transcript. In some embodiments, the ASO targets a sequence containing both a portion of the intron and a portion of the exon.

[0043]

[0081] In some embodiments, the ASO targets a sequence approximately 4 to 300 nucleotides upstream (or 5') of the 3' splice site of the SYNGAP1 premRNA transcript's NSAE. In some embodiments, the ASO targets a sequence approximately 1 to 20 nucleotides, 20 to 50 nucleotides, 50 to 100 nucleotides, 100 to 150 nucleotides, 150 to 200 nucleotides, 200 to 250 nucleotides, or 250 to 300 nucleotides upstream (or 5') of the 3' splice site of the SYNGAP1 premRNA transcript's NSAE. In some embodiments, the ASO may target a sequence more than 300 nucleotides upstream of the 3' splice site of the SYNGAP1 premRNA transcript's NSAE. In some embodiments, the ASO targets a sequence approximately 4 to 300 nucleotides downstream (or 3') of the 3' splice site of the SYNGAP1 premRNA transcript's NSAE. In some embodiments, the ASO targets sequences approximately 1 to 20 nucleotides downstream (or 3') of the 3' splice site of the SYNGAP1 premRNA transcript's NSAE, approximately 20 to 50 nucleotides, approximately 50 to 100 nucleotides, approximately 100 to 150 nucleotides, approximately 150 to 200 nucleotides, approximately 200 to 250 nucleotides, or approximately 250 to 300 nucleotides downstream (or 3'). In some embodiments, the ASO may target sequences more than 300 nucleotides downstream of the 3' splice site of the SYNGAP1 premRNA transcript's NSAE. In some embodiments, the ASO targets sequences approximately 4 to 300 nucleotides downstream (or 3') of the 5' splice site of the SYNGAP1 premRNA transcript's NSAE. In some embodiments, the ASO targets a sequence approximately 1 to 20 nucleotides downstream, approximately 20 to 50 nucleotides downstream, approximately 50 to 100 nucleotides downstream, approximately 100 to 150 nucleotides downstream, approximately 150 to 200 nucleotides downstream, approximately 200 to 250 nucleotides downstream, or approximately 250 to 300 nucleotides downstream from the 5' splice site of the NSAE of the SYNGAP1 premRNA transcript.In some embodiments, the ASO targets a sequence more than 300 nucleotides downstream from the 5' splice site of the NSAE of the SYNGAP1 premRNA transcript. In some embodiments, the ASO targets a sequence approximately 4 to approximately 300 nucleotides upstream (or 5') from the 5' splice site of the NSAE of the SYNGAP1 premRNA transcript. The sequence is targeted. In some embodiments, the ASO targets a sequence approximately 1 to 20 nucleotides, 20 to 50 nucleotides, 50 to 100 nucleotides, 100 to 150 nucleotides, 150 to 200 nucleotides, 200 to 250 nucleotides, or 250 to 300 nucleotides upstream from the 5' splice site of the NSAE exon of the SYNGAP1 premRNA transcript. In some embodiments, the ASO targets a sequence more than 300 nucleotides upstream from the 5' splice site of the NSAE exon of the SYNGAP1 premRNA transcript.

[0044]

[0082] In some embodiments, the ASO targets a sequence approximately 4 to 300 nucleotides upstream (or 5') from the 3' splice site of the target premRNA transcript, where the target is 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, B RD9, 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, F REM1, GAS8, GCK, GGA1, GGA3, GGT1, GLMN, GON4L, GRB14, HDAC3, HELQ, HP1BP3, HPS1, HPS4, IDUA, IFT122, IL17RC, IMPDH1, INVS, IRF3, KCTD3, KLKB1, KYA T1, LAMC3, LDAH, LIMS2, MALT1, MAP3K7, MAPK13, MCAT, MCEE, MPI, MSTO1, NBEAL2, NLE1, NLRC5, NOM1, NOP58, NPHP1, NPR1, NUP188, OSGEP, PABPC4, PCOLC E, PHKA2, PIDD1, PKD1, PLA2G6, PLD2, PLEKHG5, PNPO, POLE, PON2, PRMT7, PRODH, PRPF3, PRPF4, PYCR1, RAD52, REXO1, RFX5, RHBDF2, RMND1, ROBO3, RPGRI P1, RTTN, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIK3, SIRT3, SKIV2L, SLC2A13, SLC12A7, SLC22A3, SLC25A13, SLC25A37, SLC27A5, SLC30A9, SLC30A10, SMPD1,It is one of the following selected from the group consisting of 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 approximately 1 to 20 nucleotides, 20 to 50 nucleotides, 50 to 100 nucleotides, 100 to 150 nucleotides, 150 to 200 nucleotides, 200 to 250 nucleotides, or 250 to 300 nucleotides upstream (or 5') of the 3' splice site of the target premRNA transcript. In some embodiments, the ASO may target a sequence more than 300 nucleotides upstream of the 3' splice site of the NSAE of the target premRNA transcript. In some embodiments, the ASO targets a sequence approximately 4 to 300 nucleotides downstream (or 3') of the 3' splice site of the NSAE of the target premRNA transcript. In some embodiments, the ASO is derived from the 3' splice site of the target premRNA transcript, comprising approximately 1 to approximately 20 nucleotides, approximately 20 to approximately 50 nucleotides, approximately 50 to approximately 100 nucleotides, approximately 100 to approximately 150 nucleotides, approximately 150 to approximately 200 nucleotides, and approximately 200 to approximately... The ASO targets a sequence 250 nucleotides downstream, or approximately 250 to approximately 300 nucleotides downstream (or 3'). In some embodiments, the ASO may target a sequence more than 300 nucleotides downstream from the 3' splice site of the NSAE of the target premRNA transcript. In some embodiments, the ASO targets a sequence approximately 4 to approximately 300 nucleotides downstream (or 3') from the 5' splice site of the NSAE of the target premRNA transcript. In some embodiments, the ASO targets a sequence approximately 1 to approximately 20 nucleotides downstream, approximately 20 to approximately 50 nucleotides downstream, approximately 50 to approximately 100 nucleotides downstream, approximately 100 to approximately 150 nucleotides downstream, approximately 150 to approximately 200 nucleotides downstream, approximately 200 to approximately 250 nucleotides downstream, or approximately 250 to approximately 300 nucleotides downstream from the 5' splice site of the NSAE of the target premRNA transcript. In some embodiments, the ASO targets a sequence more than 300 nucleotides downstream from the 5' splice site of the NSAE of the target premRNA transcript. In some embodiments, the ASO targets a sequence approximately 4 to 300 nucleotides upstream (or 5') of the 5' splice site of the NSAE of the target premRNA transcript. In some embodiments, the ASO targets a sequence approximately 1 to 20 nucleotides, 20 to 50 nucleotides, 50 to 100 nucleotides, 100 to 150 nucleotides, 150 to 200 nucleotides, 200 to 250 nucleotides, or 250 to 300 nucleotides upstream of the 5' splice site of the NSAE exon of the target premRNA transcript. In some embodiments, the ASO targets a sequence more than 300 nucleotides upstream of the 5' splice site of the NSAE exon of the target premRNA transcript.

[0045]

[0083] In some embodiments, the ASOs disclosed herein are 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, C ES2, CHFR, CLCN2, CNOT3, CNTROB, COL5A3, CPSF1, CSPP1, CTF1, CTH, CYP3A5, DAB2IP, DBN1, DDX51, DEAF1, DGKE, DHDDS, DMKN, DNHD1, DOCK8, DOK5, EIF2B 5, 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, MS TO1, NBEAL2, NLE1, NLRC5, NOM1, NOP58, NPHP1, NPR1, NUP188, OSGEP, PABPC4, PCOLCE, PHKA2, PIDD1, PKD1, PLA2G6, PLD2, PLEKHG5, PNPO, POLE, PON2, PR MT7, PRODH, PRPF3, PRPF4, PYCR1, RAD52, REXO1, RFX5, RHBDF2, RMND1, ROBO3, RPGRIP1, RTTN, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIK3, SIRT3, SKIV2L, SLC 2A13, SLC12A7, SLC22A3, SLC25A13, SLC25A37, SLC27A5, SLC30A9, SLC30A10, SMPD1, SMTN, SNRPB, SP140, STAMBP, STXBP2, SULF2, SYNGAP1, SYNJ2, TAZ,The target is NSAE premRNA transcribed from genomic sequences selected from the group consisting of 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 the present embodiment, the ASO is 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,The target is NSAE premRNA transcripts from genomic sequences containing NSAE exons selected from the group consisting of 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, ASO is 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, C ASP9, CATSPER1, CCDC40, CCDC88B, CD4, CD58, CES2, CHFR, CLCN2, CNOT3, CNTROB, COL5A3, CPSF1, CSPP1, CTF1, CTH, CYP3A 5, 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、R、 TTN, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIK3, SIRT3, SKIV2L, SLC2A13, SLC12A7, SLC22A3, SLC25A13, SLC25A37, SLC27A5, SLC30A9, S LC30A10, SMPD1, SMTN, SNRPB, SP140, STAMBP, STXBP2, SULF2, SYNGAP1, SYNJ2, TAZ, TBL2, TDRD7, TECPR2, TFB1M, TM6SF1, TNK2, TOE The ASO targets NSAE premRNA transcripts from genome sequences selected from the group consisting of 1, TOR1B, TRAPPC6B, TRIP4, TRMT2A, TRMU, TRPV4, TTC19, TYMP, UMPS, UROD, WDR11, WDR62, WIPI1, WRAP53, XPO1, YY1AP1, and ZC3H14 genome sequences, which include introns adjacent to the 3' splice site of an NSAE exon and introns adjacent to the 5' splice site of an NSAE exon. In some embodiments, the ASO targets NSAE premRNA transcripts containing sequences selected from the group consisting of premRNA transcripts in Table 4. In some embodiments, ASO is 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, CLC N2, 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, MAP 3K7, MAPK13, MCAT, MCEE, MPI, MSTO1, NBEAL2, NLE1, NLRC5, NOM1, NOP58, NPHP1, NPR1, NUP188, OSGEP, P ABPC4, PCOLCE, PHKA2, PIDD1, PKD1, PLA2G6, PLD2, PLEKHG5, PNPO, POLE, PON2, PRMT7, PRODH, PRPF3, PR PF4, PYCR1, RAD52, REXO1, RFX5, RHBDF2, RMND1, ROBO3, RPGRIP1, RTTN, RUFY3, SEMA3B, SEMA3F, SH2D3A The target is a premRNA sequence containing an NSAE exon selected from the group consisting of 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 premRNA sequences. In some embodiments, ASO is 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,D、 EAF1, 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, IRF 3, KCTD3, KLKB1, KYAT1, LAMC3, LDAH, LIMS2, MALT1, MAP3K7, MAPK13, MCAT, MCEE, MPI, MSTO1, NBEAL2, NLE1, NLRC5, NOM1, NOP58, NPHP 1, 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, SL C12A7, SLC22A3, SLC25A13, SLC25A37, SLC27A5, SLC30A9, SLC30A10, SMPD1, SMTN, SNRPB, SP140, STAMBP, STXBP2, SULF2, SYNGAP1, SY The ASO targets premRNA sequences containing introns adjacent to the 3' splice site of an NSAE exon, selected from the group consisting of NJ2, 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 premRNA sequences. In some embodiments, the ASO targets premRNA sequences containing introns adjacent to the 3' splice site of an NSAE exon, selected from the group consisting of NJ2, 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 premRNA sequences.ANKRD29、ANKS3、ANO4、AP3B2、AP3M1、AP5Z1、ARNTL、ASAP3、ATRX、BBS2、BBS 4、BRD9、CALM3、CARS1、CASP9、CATSPER1、CCDC40、CCDC88B、CD4、CD58、CES2 、CHFR、CLCN2、CNOT3、CNTROB、COL5A3、CPSF1、CSPP1、CTF1、CTH、CYP3A5、DA B2IP、DBN1、DDX51、DEAF1、DGKE、DHDDS、DMKN、DNHD1、DOCK8、DOK5、EIF2B5、E LAC2、ELP1、ENTPD4、ESRRA、ESS2、ETAA1、ETHE1、FANCA、FASTK、FASTKD3、FP GS、FREM1、GAS8、GCK、GGA1、GGA3、GGT1、GLMN、GON4L、GRB14、HDAC3、HELQ、H P1BP3、HPS1、HPS4、IDUA、IFT122、IL17RC、IMPDH1、INVS、IRF3、KCTD3、KLKB 1、KYAT1、LAMC3、LDAH、LIMS2、MALT1、MAP3K7、MAPK13、MCAT、MCEE、MPI、MSTO 1、NBEAL2、NLE1、NLRC5、NOM1、NOP58、NPHP1、NPR1、NUP188、OSGEP、PABPC4、 PCOLCE、PHKA2、PIDD1、PKD1、PLA2G6、PLD2、PLEKHG5、PNPO、POLE、PON2、PRM T7、PRODH、PRPF3、PRPF4、PYCR1、RAD52、REXO1、RFX5、RHBDF2、RMND1、ROBO3 、RPGRIP1、RTTN、RUFY3、SEMA3B、SEMA3F、SH2D3A、SIK3、SIRT3、SKIV2L、SLC2 A13、SLC12A7、SLC22A3、SLC25A13、SLC25A37、SLC27A5、SLC30A9、SLC30A10 、SMPD1、SMTN、SNRPB、SP140、STAMBP、STXBP2、SULF2、SYNGAP1、SYNJ2、TAZ、T BL2、TDRD7、TECPR2、TFB1M、TM6SF1、TNK2、TOE1、TOR1B、TRAPPC6B、TRIP4、T RMT2A、TRMU、TRPV4、TTC19、TYMP、UMPS、UROD、WDR11、WDR62、WIPI1、WRAP53、XPS1, The target is a premRNA sequence containing an intron adjacent to the 5' splice site of an NSAE exon, selected from the group consisting of YY1AP1 and ZC3H14 premRNA sequences. In some embodiments, the transcript is selected from the group consisting of the transcripts in Table 4.

[0046]

[0084] In some embodiments, the premRNA transcript is one of the following listed herein: 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, C D58, 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, M PI, MSTO1, NBEAL2, NLE1, NLRC5, NOM1, NOP58, NPHP1, NPR1, NUP188, OSGEP, PABPC4, PCOLCE, PHKA2, PIDD1, PKD1, PLA2G6, PLD2, PLEKHG5, PNPO, POLE, PO N2, PRMT7, PRODH, PRPF3, PRPF4, PYCR1, RAD52, REXO1, RFX5, RHBDF2, RMND1, ROBO3, RPGRIP1, RTTN, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIK3, SIRT3, SKIV2 L, SLC2A13, SLC12A7, SLC22A3, SLC25A13, SLC25A37, SLC27A5, SLC30A9, SLC30A10, SMPD1, SMTN, SNRPB, SP140, STAMBP, STXBP2, SULF2, SYNGAP1, SYNJ2,The sequence contains a sequence having at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with a premRNA transcript selected from the group consisting of 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 premRNA transcripts or their complements.

[0047]

[0085] In some embodiments, 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, CNT ROB, COL5A3, CPSF1, CSPP1, CTF1, CTH, CYP3A5, DAB2IP, DBN1, DDX51, DEAF1, DGKE, DHDDS, DMKN, DNHD1, DOCK8, DOK5, EIF2B5, ELAC2, ELP1, ENTPD4, ESRRA, ES S2, ETAA1, ETHE1, FANCA, FASTK, FASTKD3, FPGS, FREM1, GAS8, GCK, GGA1, GGA3, GGT1, GLMN, GON4L, GRB14, HDAC3, HELQ, HP1BP3, HPS1, HPS4, IDUA, IFT122, IL 17RC, IMPDH1, INVS, IRF3, KCTD3, KLKB1, KYAT1, LAMC3, LDAH, LIMS2, MALT1, MAP3K7, MAPK13, MCAT, MCEE, MPI, MS TO1, 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, SL C25A37, SLC27A5, SLC30A9, SLC30A10, SMPD1, SMTN, SNRPB, SP140, STAMBP, STXBP2, SULF2, SYNGAP1, SYNJ2, TAZ, T BL2, TDRD7, TECPR2, TFB1M, TM6SF1, TNK2, TOE1, TOR1B, TRAPPC6B, TRIP4, TRMT2A, TRMU, TRPV4, TTC19, TYMP, UMPS The targeting portion of the premRNA selected from the group consisting of UROD, WDR11, WDR62, WIPI1, WRAP53, XPO1, YY1AP1, and ZC3H14 premRNAs contains a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to a region containing at least eight consecutive nucleic acids of the premRNA transcript sequence in Table 4 or the sequence or its complement in Table 3. In some embodiments, 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, EN TPD4, ESRRA, ESS2, ETAA1, ETHE1, FANCA, FASTK, FASTKD3, FPGS, FREM1, GAS8, GCK, GGA1, GGA3, GGT1, GLMN, GON4L, GRB14, HDAC3, HELQ, HP1BP3, HPS1, HP S4, 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, SL C22A3, SLC25A13, SLC25A37, SLC27A5, SLC30A9, SLC30A10, SMPD1, SMTN, SNRPB, SP140, STAMBP, STXBP2, SULF2, SYNGAP1, SYNJ2, TAZ, TBL2, TDRD7, TECP The targeting portion of the premRNA selected from the group consisting of R2, TFB1M, TM6SF1, TNK2, TOE1, TOR1B, TRAPPC6B, TRIP4, TRMT2A, TRMU, TRPV4, TTC19, TYMP, UMPS, UROD, WDR11, WDR62, WIPI1, WRAP53, XPO1, YY1AP1, and ZC3H14 premRNAs is at least 80%, 85%, 90%, 95%, and 97% of the region containing at least eight consecutive nucleic acids of a sequence or its complement selected from the group consisting of SEQ ID NOs. 170 to 1098., or include sequences having 100% sequence identity. In some embodiments, 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, ELAC 2, ELP1, ENTPD4, ESRRA, ESS2, ETAA1, ETHE1, FANCA, FASTK, FASTKD3, FPGS, FREM1, GAS8, GCK, GGA1, GGA3, GGT1, GLMN, GON4L, GRB14, HDAC3, HELQ, HP 1BP3, HPS1, HPS4, IDUA, IFT122, IL17RC, IMPDH1, INVS, IRF3, KCTD3, KLKB1, KYAT1, LAMC3, LDAH, LIMS2, MALT1, MAP3K7, MAPK13, MCAT, MCEE, MPI, M STO1, NBEAL2, NLE1, NLRC5, NOM1, NOP58, NPHP1, NPR1, NUP188, OSGEP, PABPC4, PCOLCE, PHKA2, PIDD1, PKD1, PLA2G6, PLD2, PLEKHG5, PNPO, POLE, PON 2, PRMT7, PRODH, PRPF3, PRPF4, PYCR1, RAD52, REXO1, RFX5, RHBDF2, RMND1, ROBO3, RPGRIP1, RTTN, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIK3, SIRT3, SKI V2L, SLC2A13, SLC12A7, SLC22A3, SLC25A13, SLC25A37, SLC27A5, SLC30A9, SLC30A10, SMPD1, SMTN, SNRPB, SP140, STAMBP, STXBP2, SULF2, SYNGAP1,The targeting portion of the premRNA selected from the group consisting of 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 premRNAs contains sequences complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive nucleic acids of the sequences or complements of Table 6A or Table 6B.

[0048]

[0086] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from the SYNGAP1 genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from the SYNGAP1 genome sequence containing an NSAE exon. In some embodiments, the NSAE exon is exon 11. In some embodiments, the ASO targets NSAE premRNA transcripts from the SYNGAP1 genome sequence containing exon 11. In some embodiments, the ASO targets NSAE premRNA transcripts from the SYNGAP1 genome sequence containing an intron adjacent to the 3' splice site of the NSAE exon and an intron adjacent to the 5' splice site of the NSAE exon. In some embodiments, the intron adjacent to the 3' splice site of the NSAE exon is intron 10, and the intron adjacent to the 5' splice site of the NSAE exon is intron 11. In some embodiments, the ASO targets NSAE premRNA transcripts from the SYNGAP1 genome sequence containing intron 10, exon 11, and intron 11. In some embodiments, ASO is premrna_ENST00000293748.9, premrna_ENST00000418600.7, premrna_ENST00000428982.4, premrna_ENST00000449372.7, premrna_ENST00000470232.1, p remrna_ENST00000479510.2, premrna_ENST00000628646.2, premrna_ENST00000629380.3, premrna_ ENST00000635885.1, premrna_ENST00000636075.1, premrna_ENST00000636116.1, premrna_ENST0000 0636146.1, premrna_ENST00000636193.1, premrna_ENST00000636436.1, premrna_ENST00000636443 .1, premrna_ENST00000636640.1, premrna_ENST00000636731.1, premrna_ENST00000636905.1, premr na_ENST00000637052.1, premrna_ENST00000637194.1, premrna_ENST00000637490.1, premrna_ENST 00000637587.1, premrna_ENST00000637671.1, premrna_ENST00000637721.1, premrna_ENST00000637 The ASO targets an NSAE premRNA transcript containing a sequence selected from the group consisting of 911.1, premrna_ENST00000638127.1, premrna_ENST00000638142.2, premrna_ENST00000644458.1, premrna_ENST00000645250.1, and premrna_ENST00000646630.1. In some embodiments, the ASO targets an NSAE premRNA transcript containing exons 10 and 11. In some embodiments, the ASO targets a SYNGAP1 premRNA sequence containing an NSAE exon. In some embodiments, the ASO targets a SYNGAP1 premRNA sequence containing exon 11. In some embodiments, the ASO targets a SYNGAP1 premRNA sequence containing an intron adjacent to the 3' splice site of the NSAE exon. In some embodiments, the ASO targets a SYNGAP1 premRNA sequence containing intron 10.In some embodiments, the ASO targets a SYNGAP1 premRNA sequence containing an intron adjacent to the 5' splice site of an NSAE exon. In some embodiments, the transcripts are transcript_ENST00000293748.9, transcript_ENST00000418600.7, transcript_ENST00000428982.4, transcript_ENST00000449372.7, transcript_ENST00000470232.1, transcript_ENST00000479510.2, transcript_ENST00000628646.2, transc ript_ENST00000629380.3, transcript_ENST00000635885.1, transcript_ENST00000636075.1, transcript_ENST00000636116.1, tr anscript_ENST00000636146.1, transcript_ENST00000636193.1, transcript_ENST00000636436.1, transcript_ENST00000636443.1 , transcript_ENST00000636640.1, transcript_ENST00000636731.1, transcript_ENST00000636905.1, transcript_ENST000006370 52.1, transcript_ENST00000637194.1, transcript_ENST00000637490.1, transcript_ENST00000637587.1, transcript_ENST000006 The group is selected from 37671.1, transcript_ENST00000637721.1, transcript_ENST00000637911.1, transcript_ENST00000638127.1, transcript_ENST00000638142.2, transcript_ENST00000644458.1, transcript_ENST00000645250.1, and transcript_ENST00000646630.1.

[0049]

[0087] In some embodiments, the SYNGAP1 premRNA transcript is referenced in Ensembl. The gene sequence is encoded by having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with reference number ENSG00000227460.8 or ENSG00000197283.17 or its complement. In some embodiments, the SYNGAP1 premRNA transcript comprises a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the SYNGAP1 premRNA transcript or its complement described herein.

[0050]

[0088] In some embodiments, the targeting portion of the SYNGAP1 premRNA is premrna_ENST00000293748.9, premrna_ENST00000418600.7, premrna_ENST00000428982.4, premrna_ENST00000449372.7, premrna_ENST00000470232.1, premrna_ENST00000479510.2, premrna_ENST00000628646.2, premrna_ENST 00000629380.3, premrna_ENST00000635885.1, premrna_ENST00000636075.1, premrna_ENST00000636116.1, premrna_ENST000006361 46.1, premrna_ENST00000636193.1, premrna_ENST00000636436.1, premrna_ENST00000636443.1, premrna_ENST00000636640.1, prem rna_ENST00000636731.1, premrna_ENST00000636905.1, premrna_ENST00000637052.1, premrna_ENST00000637194.1, premrna_ENST 00000637490.1, premrna_ENST00000637587.1, premrna_ENST00000637671.1, premrna_ENST00000637721.1, premrna_ENST000006379 The sequence includes sequences having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to regions containing at least eight consecutive nucleic acids of the sequences 11.1, premrna_ENST00000638127.1, premrna_ENST00000638142.2, premrna_ENST00000644458.1, premrna_ENST00000645250.1, premrna_ENST00000646630.1, or the sequences in Table 2 or their complements.In some embodiments, the targeting portion of the SYNGAP1 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of a sequence or its complement selected from the group consisting of SEQ ID NOs. 166 to 169. In some embodiments, the ASO includes a sequence that is at least about 80%, 85%, 90%, 95%, 97%, or 100% identical to any one of the sequences or its complements in Table 1.

[0051]

[0089] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from the ABCA5 genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from the ABCA5 genome sequence, including NSAE exons. In some embodiments, the ASO targets NSAE premRNA transcripts from the ABCA5 genome sequence, including introns adjacent to the 3' splice site of the NSAE exon and introns adjacent to the 5' splice site of the NSAE exon. In some embodiments, the ASOs are premrna_ENST00000392676.8, premrna_ENST00000586601.1, premrna_ENST00000586811.1, premrna_ENST00000586995.5, premrna_ENST00000587607.5, premrna_ENST00000588106.1, premrna_ENST00000588665.5, premrna_ENST00000588877.5, and premrna_ENST00000589609. The ASO targets an NSAE premRNA transcript containing a sequence selected from the group consisting of 1, premrna_ENST00000589975.5, premrna_ENST00000591234.5, premrna_ENST00000592568.1, premrna_ENST00000593153.5, and premrna_ENST00000593253.5. In some embodiments, the ASO targets an ABCA5 premRNA sequence containing an NSAE exon. In some embodiments, the ASO targets an ABCA5 premRNA sequence containing an intron adjacent to the 3' splice site of the NSAE exon. In some embodiments, the ASO targets an ABCA5 premRNA sequence containing an intron adjacent to the 5' splice site of the NSAE exon. In some embodiments, the transcripts are transcript_ENST00000392676.8, transcript_ENST00000586601.1, transcript_ENST00000586811.1, transcript_ENST00000586995.5, transcript_ENST00000587607.5, transcript_ENST00000588106.1, transcript_ENST00000588665.5, The following are selected from the group consisting of transcript_ENST00000588877.5, transcript_ENST00000589609.1, transcript_ENST00000589975.5, transcript_ENST00000591234.5, transcript_ENST00000592568.1, transcript_ENST00000593153.5, and transcript_ENST00000593253.5.

[0052]

[0090] In some embodiments, the ABCA5 premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000154265.16 or its complement. In some embodiments, the ABCA5 premRNA transcript includes a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the ABCA5 premRNA transcripts or their complements described herein.

[0053]

[0091] In some embodiments, the targeting portion of the ABCA5 premRNA is premrna_ENST00000392676.8, premrna_ENST00000586601.1, premrna_ENST00000586811.1, premrna_ENST00000586995.5, premrna_ENST00000587607.5, premrna_ENST00000588106.1, premrna_ENST00000588665.5, premrna_ENST00000588877.5, premr The sequences include those having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to regions containing at least eight consecutive nucleic acids of the sequences na_ENST00000589609.1, premrna_ENST00000589975.5, premrna_ENST00000591234.5, premrna_ENST00000592568.1, premrna_ENST00000593153.5, premrna_ENST00000593253.5 or the sequences in Table 3 or their complements. In some embodiments, the targeting portion of the ABCA5 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of a sequence or its complement selected from the group consisting of SEQ ID NOs: 170 to 173. In some embodiments, the targeting portion of the ABCA5 premRNA includes a sequence complementary to at least eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty consecutive nucleic acids of a sequence or its complement in Table 6A or Table 6B.

[0054]

[0092] In some embodiments, the ASO disclosed herein is the ABCA7 genome sequence or The ASO targets the transcribed NSAE premRNA. In some embodiments, the ASO targets NSAE premRNA transcripts from an ABCA7 genome sequence containing NSAE exons. In some embodiments, the ASO targets NSAE premRNA transcripts from an ABCA7 genome sequence containing introns adjacent to the 3' splice site of an NSAE exon and introns adjacent to the 5' splice site of an NSAE exon. In some embodiments, ASO is 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_ENS The target is an NSAE premRNA transcript containing a sequence selected from the group consisting of T00000529442.7, 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 an ABCA7 premRNA sequence containing an NSAE exon. In some embodiments, the ASO targets an ABCA7 premRNA sequence containing an intron adjacent to the 3' splice site of an NSAE exon. In some embodiments, the ASO targets an ABCA7 premRNA sequence containing an intron adjacent to the 5' splice site of an NSAE exon.In some embodiments, the transcripts are 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 Selected from the group consisting of 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.

[0055]

[0093] In some embodiments, the ABCA7 premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000064687.13 or its complement. In some embodiments, the ABCA7 premRNA transcript comprises a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the ABCA7 premRNA transcript or its complement described herein.

[0056]

[0094] In some embodiments, the targeting regions of the ABCA7 premRNA are premrna_ENST00000263094.11, premrna_ENST00000433129.6, premrna_ENST00000435683.7, premrna_ENST00000524383.1, and premrna_ENST0000052485 0.5, premrna_ENST00000525073.6, premrna_ENST00000525238.2, premrna_ENST00000526885.5, premrna_ENST00000527496.1, premrna_ENST00000529442.7, premrna_ENST00000530092.2, premrna_ENST00000530703.1, premrna_ENST00000531467.5, prem The targeting portion of the ABCA7 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of the sequences rna_ENST00000531478.5, premrna_ENST00000532194.3, premrna_ENST00000533574.1, premrna_ENST00000612569.1, premrna_ENST00000673773.1, or the sequences in Table 3 or their complements. In some embodiments, the targeting portion of the ABCA7 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of a sequence selected from the group consisting of SEQ ID NOs: 174 to 177 or its complement. In some embodiments, the targeting portion of the ABCA7 premRNA includes sequences complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive nucleic acids of the sequences or complements of Table 6A or Table 6B.

[0057]

[0095] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from the ABCC3 genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from the ABCC3 genome sequence, including NSAE exons. In some embodiments, the ASO targets NSAE premRNA transcripts from the ABCC3 genome sequence, including introns adjacent to the 3' splice site of the NSAE exon and introns adjacent to the 5' splice site of the NSAE exon. In some embodiments, ASO is 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_ENS The target is an NSAE premRNA transcript containing a sequence selected from the group consisting of T00000510633.5, 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 an ABCC3 premRNA sequence containing an NSAE exon. In some embodiments, the ASO targets an ABCC3 premRNA sequence containing an intron adjacent to the 3' splice site of an NSAE exon. In some embodiments, the ASO targets an ABCC3 premRNA sequence containing an intron adjacent to the 5' splice site of an NSAE exon.In some embodiments, the transcripts are 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,. The group selected consists of 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.

[0058]

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

[0059]

[0097] In some embodiments, the targeting portion of the ABCC3 premRNA is 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, prem The sequences include those having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to regions containing at least eight consecutive nucleic acids, such as rna_ENST00000510891.1, premrna_ENST00000513511.5, premrna_ENST00000513589.1, premrna_ENST00000513745.1, premrna_ENST00000515070.1, premrna_ENST00000515585.1, premrna_ENST00000515707.1, and premrna_ENST00000571855.1, or the sequences in Table 3 or their complements. In some embodiments, the targeting portion of the ABCC3 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of a sequence or its complement selected from the group consisting of SEQ ID NOs: 178 to 181. In some embodiments, the targeting portion of the ABCC3 premRNA includes a sequence complementary to at least eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty consecutive nucleic acids of a sequence or its complement in Table 6A or Table 6B.

[0060]

[0098] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from the ABCC5 genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from the ABCC5 genome sequence, including NSAE exons. In some embodiments, the ASO targets NSAE premRNA transcripts from the ABCC5 genome sequence, including introns adjacent to the 3' splice site of the NSAE exon and introns adjacent to the 5' splice site of the NSAE exon. In some embodiments, ASO is premrna_ENST00000265586.10, premrna_ENST00000334444.11, premrna_ENST00000382494.6, premrna_ENST00000392579.6, premrna_ENST00000427120.6, premrna_ENST00000437205.5, premrna_ENST00000437341.5, premrna_ The ASO targets NSAE premRNA transcripts containing sequences selected from the group consisting of ENST00000438979.6, premrna_ENST00000443376.5, premrna_ENST00000443497.1, premrna_ENST00000446941.2, premrna_ENST00000476402.1, and premrna_ENST00000492216.1. In some embodiments, the ASO targets ABCC5 premRNA sequences containing NSAE exons. In some embodiments, the ASO targets ABCC5 premRNA sequences containing introns adjacent to the 3' splice site of the NSAE exon. In some embodiments, the ASO targets ABCC5 premRNA sequences containing introns adjacent to the 5' splice site of the NSAE exon. In some embodiments, the transcripts are transcript_ENST00000265586.10, transcript_ENST00000334444.11, transcript_ENST00000382494.6, transcript_ENST00000392579.6, transcript_ENST00000427120.6, transcript_ENST00000437205.5, transcript_EN The group is selected from ST00000437341.5, transcript_ENST00000438979.6, transcript_ENST00000443376.5, transcript_ENST00000443497.1, transcript_ENST00000446941.2, transcript_ENST00000476402.1, and transcript_ENST00000492216.1.

[0061]

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

[0062]

[0100] In some embodiments, the targeting portion of the ABCC5 premRNA is premrna_ENST00000265586.10, premrna_ENST00000334444.11, premrna_ENST00000382494.6, premrna_ENST00000392579.6, premrna_ENST00000427120.6, premrna_ENST00000437205.5, premrna_ENST00000437341.5, premrna_ENST00000 The targeting portion of the ABCC5 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of the sequence 438979.6, premrna_ENST00000443376.5, premrna_ENST00000443497.1, premrna_ENST00000446941.2, premrna_ENST00000476402.1, premrna_ENST00000492216.1 or the sequence in Table 3 or its complement. In some embodiments, the targeting portion of the ABCC5 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of the sequence selected from the group consisting of SEQ ID NOs: 182 to 185 or its complement. In some embodiments, the targeting portion of the ABCC5 premRNA includes sequences that are complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive nucleic acids of the sequences or complements of Table 6A or Table 6B.

[0063]

[0101] In some embodiments, the ASO disclosed herein is the ABCC8 genome sequence or The ASO targets transcribed NSAE premRNA. In some embodiments, the ASO targets NSAE premRNA transcripts from an ABCC8 genome sequence containing NSAE exons. In some embodiments, the ASO targets NSAE premRNA transcripts from an ABCC8 genome sequence containing introns adjacent to the 3' splice site of an NSAE exon and introns adjacent to the 5' splice site of an NSAE exon. In some embodiments, ASO is premrna_ENST00000302539.9, premrna_ENST00000389817.7, premrna_ENST00000524561.1, premrna_ENST00000525022.1, premrna_ENST00000526002.1, premrna_ENST00000526037.5, premrna_ENST00000526168.5, p remrna_ENST00000526921.5, premrna_ENST00000527905.5, premrna_ENST00000528202.5, premrna_ENST0000052837 4.1, premrna_ENST00000529967.5, premrna_ENST00000530147.5, premrna_ENST00000531137.1, premrna_ENST00000 531642.5, premrna_ENST00000531891.1, premrna_ENST00000531911.1, premrna_ENST00000532220.1, premrna_ENST 00000532728.6, premrna_ENST00000612903.1, premrna_ENST00000635881.1, premrna_ENST00000642271.1, premrna _ENST00000642579.1, premrna_ENST00000642611.1, premrna_ENST00000642902.1, premrna_ENST00000643260.1, pr emrna_ENST00000643562.1, premrna_ENST00000643925.1, premrna_ENST00000644057.1, premrna_ENST00000644447.1, premrna_ENST00000644472.1, premrna_ENST00000644484.1, premrna_ENST00000644542.1, pre mrna_ENST00000644649.1, premrna_ENST00000644675.1, premrna_ENST00000644757.1, premrna_ ENST00000644772.1, premrna_ENST00000645004.1, premrna_ENST00000645076.1, premrna_ENST0 0000645417.1, premrna_ENST00000645744.1, premrna_ENST00000645760.1, premrna_ENST000006 45884.1, premrna_ENST00000646003.1, premrna_ENST00000646207.1, premrna_ENST00000646276 .1, premrna_ENST00000646592.1, premrna_ENST00000646737.1, premrna_ENST00000646902.1, pr The ASO targets an NSAE premRNA transcript containing a sequence selected from the group consisting of emrna_ENST00000646993.1, premrna_ENST00000647013.1, premrna_ENST00000647015.1, premrna_ENST00000647086.1, and premrna_ENST00000647158.1. In some embodiments, the ASO targets an ABCC8 premRNA sequence containing an NSAE exon. In some embodiments, the ASO targets an ABCC8 premRNA sequence containing an intron adjacent to the 3' splice site of the NSAE exon. In some embodiments, the ASO targets an ABCC8 premRNA sequence containing an intron adjacent to the 5' splice site of the NSAE exon. In some embodiments, the transcripts are transcript_ENST00000302539.9, transcript_ENST00000389817.7, transcript_ENST00000524561.1, transcript_ENST00000525022.1, and 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_ENST000006458 84.1, transcript_ENST00000646003.1, transcript_ENST00000646207.1, transcript_ENST00000646276.1, transcript_ENST000006 The data is selected from the group consisting of 46592.1, transcript_ENST00000646737.1, transcript_ENST00000646902.1, transcript_ENST00000646993.1, transcript_ENST00000647013.1, transcript_ENST00000647015.1, transcript_ENST00000647086.1, and transcript_ENST00000647158.1.

[0064]

[0102] In some embodiments, the ABCC8 premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000006071.15 or its complement. In some embodiments, the ABCC8 premRNA transcript includes a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the ABCC8 premRNA transcript or its complement described herein.

[0065]

[0103] In some embodiments, the targeting regions of the ABCC8 premRNA are premrna_ENST00000302539.9, premrna_ENST00000389817.7, premrna_ENST00000524561.1, premrna_ENST00000525022.1, premrna_ENST00000526002.1, premrna_ENST00000526037.5, and 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.The sequence includes 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 region containing at least eight consecutive nucleic acids of the sequence in Table 3 or its complement, and has at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity. In some embodiments, the targeting portion of the ABCC8 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of a sequence or its complement selected from the group consisting of SEQ ID NOs. In some embodiments, the targeting portion of the ABCC8 premRNA includes a sequence complementary to at least eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty consecutive nucleic acids of a sequence or its complement in Table 6A or Table 6B.

[0066]

[0104] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from the ABCD1 genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts containing NSAE exons from the ABCD1 genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from the ABCD1 genome sequence that include introns adjacent to the 3' splice site of the NSAE exon and introns adjacent to the 5' splice site of the NSAE exon. In some embodiments, the ASO targets NSAE premRNA transcripts containing sequences selected from the group consisting of premrna_ENST00000218104.6, premrna_ENST00000370129.4, and premrna_ENST00000443684.2. In some embodiments, the ASO targets an ABCD1 premRNA sequence containing an NSAE exon. In some embodiments, the ASO targets an ABCD1 premRNA sequence containing an intron adjacent to the 3' splice site of the NSAE exon. In some embodiments, the ASO targets an ABCD1 premRNA sequence containing an intron adjacent to the 5' splice site of the NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000218104.6, transcript_ENST00000370129.4, and transcript_ENST00000443684.2.

[0067]

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

[0068]

[0106] In some embodiments, the targeting portion of the ABCD1 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of the sequence of ofpremrna_ENST00000218104.6, premrna_ENST00000370129.4, premrna_ENST00000443684.2 or the sequence in Table 3 or its complement. In some embodiments, the targeting portion of the ABCD1 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of a sequence selected from the group consisting of SEQ ID NOs: 190 to 193 or its complement. In some embodiments, the targeting portion of the ABCD1 premRNA includes sequences complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive nucleic acids of the sequences or complements of Table 6A or Table 6B.

[0069]

[0107] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from an ABR genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from an ABR genome sequence containing an NSAE exon. In some embodiments, the ASO targets NSAE premRNA transcripts from an ABR genome sequence containing an intron adjacent to the 3' splice site of an NSAE exon and an intron adjacent to the 5' splice site of an NSAE exon. In some embodiments, ASO is 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_ENS T00000571306.1, premrna_ENST00000571383.5, premrna_ENST00000571543.1, prem rna_ENST00000571797.5, premrna_ENST00000571945.5, premrna_ENST00000572152. 5, premrna_ENST00000572441.5, premrna_ENST00000572585.5, premrna_ENST00000572650.1, premrna_ENST00000573325.1, premrna_ENST00000573559.3, premrna_ENST 00000573667.1, premrna_ENST00000573895.1, premrna_ENST00000574048.2, premrna_ENST00000574139.6, premrna_ENST 00000574257.5, premrna_ENST00000574266.1, premrna_ENST00000574437.5, premrna_ENST00000574544.1, premrna_ENST The ASO targets NSAE premRNA transcripts containing sequences selected from the group consisting of 00000574632.5, 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 ABR premRNA sequences containing NSAE exons. In some embodiments, the ASO targets ABR premRNA sequences containing introns adjacent to the 3' splice site of the NSAE exon. In some embodiments, the ASO targets ABR premRNA sequences containing introns adjacent to the 5' splice site of the NSAE exon. In some embodiments, the transcript is transcript_ENST00000291107.6, transcript_ENST00000302538.9, transcript_ENST00000536794.6, transcript_ENST00000543210.6, transcript_ENST00000544583.6, transcript_ENST00000570441.5, transc ript_ENST00000570525.5, transcript_ENST00000570688.1, transcript_ENST00000571022.5, transcript_ENST0 0000571120.5, transcript_ENST00000571306.1, transcript_ENST00000571383.5, transcript_ENST00000571543.1. It is selected from the group consisting of 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.

[0070]

[0108] In some embodiments, the ABR premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference numbers ENSG00000276016.4, ENSG00000278741.4, or ENSG00000159842.15 or its complement. In some embodiments, the ABR premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the ABR premRNA transcript or its complement described herein. It includes sequences that have sequence identity.

[0071]

[0109] In some embodiments, the targeting portion of the ABR premRNA is premrna_ENST00000291107.6, premrna_ENST00000302538.9, premrna_ENST00000536794.6, premrna_ENST00000543210.6, premrna_ENST00000544583.6, premrna_ENST00000570441.5, premrna_ENST00000570525.5, premrna_ENST00000570688.1, premr na_ENST00000571022.5, premrna_ENST00000571120.5, premrna_ENST00000571306.1, premrna_ENST00000571383.5, premrna_ENST000005715 43.1, premrna_ENST00000571797.5, premrna_ENST00000571945.5, premrna_ENST00000572152.5, premrna_ENST00000572441.5, premrna_ENS T00000572585.5, premrna_ENST00000572650.1, premrna_ENST00000573325.1, premrna_ENST00000573559.3, premrna_ENST00000573667.1, p remrna_ENST00000573895.1, premrna_ENST00000574048.2, premrna_ENST00000574139.6, premrna_ENST00000574257.5, premrna_ENST00000 574266.1, 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.The sequence includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of the sequence in Table 5 or the sequence in Table 3 or its complement. In some embodiments, the targeting portion of the ABR premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of the sequence selected from the group consisting of SEQ ID NOs: 194 to 201 or its complement. In some embodiments, the targeting portion of the ABR premRNA includes a sequence complementary to at least eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty consecutive nucleic acids of the sequence in Table 6A or Table 6B or its complement.

[0072]

[0110] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from the ACAD9 genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from the ACAD9 genome sequence containing NSAE exons. In some embodiments, the ASO targets NSAE premRNA transcripts from the ACAD9 genome sequence containing introns adjacent to the 3' splice site of the NSAE exon and introns adjacent to the 5' splice site of the NSAE exon. In some embodiments, the ASOs are 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, and premrna_ENS The ASO targets an NSAE premRNA transcript containing a sequence selected from the group consisting of T00000514643.5 and premrna_ENST00000515429.1. In some embodiments, the ASO targets an ACAD9 premRNA sequence containing an NSAE exon. In some embodiments, the ASO targets an ACAD9 premRNA sequence containing an intron adjacent to the 3' splice site of the NSAE exon. In some embodiments, the ASO targets an ACAD9 premRNA sequence containing an intron adjacent to 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.

[0073]

[0111] In some embodiments, the ACAD9 premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000177646.19 or its complement. In some embodiments, the ACAD9 premRNA transcript includes a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the ACAD9 premRNA transcript or its complement described herein.

[0074]

[0112] In some embodiments, the targeting portion of the ACAD9 premRNA is premrna_ENST00000308982.12, premrna_ENST00000505192.5, premrna_ENST00000505602.1, premrna_ENST00000505867.5, premrna_ENST00000508971.1, premrna_ENST00000511227.5, premrna_ENST00000511325.1, prem The sequence includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of the sequences rna_ENST00000511526.5, premrna_ENST00000512801.5, premrna_ENST00000514336.1, premrna_ENST00000514643.5, premrna_ENST00000515429.1 or the sequences in Table 3 or their complements. In some embodiments, the targeting portion of the ACAD9 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of a sequence selected from the group consisting of SEQ ID NOs. 202 to 207 or its complement. In some embodiments, the targeting portion of the ACAD9 premRNA includes sequences complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive nucleic acids of the sequences or complements of Table 6A or Table 6B.

[0075]

[0113] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from the ACAP1 genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from the ACAP1 genome sequence containing NSAE exons. In some embodiments, the ASO targets NSAE premRNA transcripts from the ACAP1 genome sequence containing introns adjacent to the 3' splice site of the NSAE exon and introns adjacent to the 5' splice site of the NSAE exon. Some embodiments So, the ASOs are premrna_ENST00000308982.12, premrna_ENST00000505192.5, premr-na_ENST00000505602.1, premrna_ENST00000505867.5, premrna_ENST00000508971.1, premr-na_ENST00000511227.5, premrna_ENST00 The ASO targets NSAE premRNA transcripts containing sequences selected from the group consisting of 000511325.1, premrna_ENST00000511526.5, premr-na_ENST00000512801.5, premrna_ENST00000514336.1, premrna_ENST00000514643.5, and premrna_ENST00000515429.1. In some embodiments, the ASO targets ACAP1 premRNA sequences containing NSAE exons. In some embodiments, the ASO targets ACAP1 premRNA sequences containing introns adjacent to the 3' splice site of the NSAE exon. In some embodiments, the ASO targets ACAP1 premRNA sequences containing introns adjacent to 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.

[0076]

[0114] In some embodiments, the ACAP1 premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000072818.12 or ENSG00000288169.1 or its complement. In some embodiments, the ACAP1 premRNA transcript includes a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the ACAP1 premRNA transcript or its complement described herein.

[0077]

[0115] In some embodiments, the targeting portion of the ACAP1 premRNA is premrna_ENST00000308982.12, premrna_ENST00000505192.5, premr-na_ENST00000505602.1, premrna_ENST00000505867.5, premrna_ENST00000508971.1, premrna_ENST00000511227.5, premrna_ENST00000511325.1, prem The sequence includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of the sequences rna_ENST00000511526.5, premrna_ENST00000512801.5, premrna_ENST00000514336.1, premrna_ENST00000514643.5, premrna_ENST00000515429.1 or the sequences in Table 3 or their complements. In some embodiments, the targeting portion of the ACAP1 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of a sequence selected from the group consisting of SEQ ID NOs. 208 to 211 or its complement. In some embodiments, the targeting region of the ACAP1 premRNA consists of at least 8, 9, or 10 sequences or their complements from Table 6A or Table 6B. It contains sequences that are complementary to 1, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive nucleic acids.

[0078]

[0116] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from the ACOX2 genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from the ACOX2 genome sequence, including NSAE exons. In some embodiments, the ASO targets NSAE premRNA transcripts from the ACOX2 genome sequence, including introns adjacent to the 3' splice site of the NSAE exon and introns adjacent to the 5' splice site of the NSAE exon. In some embodiments, the ASOs are premrna_ENST00000302819.10, premrna_ENST00000459701.6, premrna_ENST00000459888.1, premrna_ENST00000460921.1, premrna_ENST00000466689.1, premrna_ENST00000466810.5, and premrna_ENST00000467738. The ASO targets an NSAE premRNA transcript containing a sequence selected from the group consisting of 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 an ACOX2 premRNA sequence containing an NSAE exon. In some embodiments, the ASO targets an ACOX2 premRNA sequence containing an intron adjacent to the 3' splice site of the NSAE exon. In some embodiments, the ASO targets an ACOX2 premRNA sequence containing an intron adjacent to the 5' splice site of the NSAE exon.In some embodiments, the transcripts are transcript_ENST00000302819.10, transcript_ENST00000459701.6, transcript_ENST00000459888.1, transcript_ENST00000460921.1, transcript_ENST00000466689.1, transcript_ENST00000466810.5, transcript_ENS The group is selected from T00000467738.1, transcript_ENST00000474098.1, transcript_ENST00000475143.5, transcript_ENST00000480791.1, transcript_ENST00000481527.5, transcript_ENST00000489472.1, and transcript_ENST00000492530.1.

[0079]

[0117] In some embodiments, the ACOX2 premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000168306.13 or its complement. In some embodiments, the ACOX2 premRNA transcript includes a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the ACOX2 premRNA transcript or its complement described herein.

[0080]

[0118] In some embodiments, the targeting portion of ACOX2 premRNA is 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_ENST The sequence includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to a region containing at least eight consecutive nucleic acids of the sequence 00000480791.1, premrna_ENST00000481527.5, premrna_ENST00000489472.1, premrna_ENST00000492530.1 or the sequence in Table 3 or its complement. In some embodiments, the targeting portion of the ACOX2 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to a region containing at least eight consecutive nucleic acids of the sequence selected from the group consisting of SEQ ID NOs. 212 to 215 or its complement. In some embodiments, the targeting portion of the ACOX2 premRNA includes sequences complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive nucleic acids of the sequences or complements of Table 6A or Table 6B.

[0081]

[0119] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from an ACSF3 genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from an ACSF3 genome sequence containing an NSAE exon. In some embodiments, the ASO targets NSAE premRNA transcripts from an ACSF3 genome sequence containing an intron adjacent to the 3' splice site of an NSAE exon and an intron adjacent to the 5' splice site of an NSAE exon. In some embodiments, the ASOs are 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, and premrna_ENST00000538340.5 The target is an NSAE premRNA transcript containing a sequence selected from the group consisting of 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 an ACSF3 premRNA sequence containing an NSAE exon. In some embodiments, the ASO targets an ACSF3 premRNA sequence containing an intron adjacent to the 3' splice site of an NSAE exon. In some embodiments, the ASO targets an ACSF3 premRNA sequence containing an intron adjacent to the 5' splice site of an NSAE exon.In some embodiments, the transcripts are 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_ENS T00000537895.5, transcript_ENST00000538340.5, transcript_ENST00000540697.5, transcript_ENST00000541755.2, transcript_ENST00000542688.5 , transcript_ENST00000543676.1, transcript_ENST00000544543.5, transcript_ENST00000562204.1, transcript_ENST00000562750.1, and transcript. Selected from the group consisting of _ENST00000649953.1.

[0082]

[0120] In some embodiments, the ACSF3 premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000176715.17 or its complement. In some embodiments, the ACSF3 premRNA transcript includes a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the ACSF3 premRNA transcript or its complement described herein.

[0083]

[0121] In some embodiments, the targeting portion of the ACSF3 premRNA is 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_ENST000005 The sequences include those having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to regions containing at least eight consecutive nucleic acids of the sequences 40697.5, 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 the sequences in Table 3 or their complements. In some embodiments, the targeting portion of the ACSF3 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of a sequence or its complement selected from the group consisting of SEQ ID NOs. 216 to 221. In some embodiments, the targeting portion of the ACSF3 premRNA includes a sequence complementary to at least eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty consecutive nucleic acids of a sequence or its complement in Table 6A or Table 6B.

[0084]

[0122] In some embodiments, the ASOs disclosed herein target NSAE premRNA transcribed from the ACTN4 genome sequence. In some embodiments, the ASOs target NSAE premRNA transcripts from the ACTN4 genome sequence including NSAE exons. In some embodiments, the ASOs target NSAE premRNA transcripts from the ACTN4 genome sequence including introns adjacent to the 3' splice site of the NSAE exon and introns adjacent to the 5' splice site of the NSAE exon. In some embodiments, the ASOs target premrna_ENST00000252699.7, premrna_ENST00000390009.7, premrna_ENST00000424234.6, premrna_ENST00000440400.1, premrna_ENST00000477174.1, and premrna_ENST00000489451.1 The ASO targets an NSAE premRNA transcript containing a sequence selected from the group consisting of premrna_ENST00000495553.1, premrna_ENST00000497637.5, premrna_ENST00000586538.1, premrna_ENST00000588618.5, and premrna_ENST00000589528.1. In some embodiments, the ASO targets an ACTN4 premRNA sequence containing an NSAE exon. In some embodiments, the ASO targets an NSAE exon. The ASO targets an ACTN4 premRNA sequence containing an intron adjacent to the 3' splice site of Son. In some embodiments, the ASO targets an ACTN4 premRNA sequence containing an intron adjacent to 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.

[0085]

[0123] In some embodiments, the ACTN4 premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000130402.12 or ENSG00000282844.2 or its complement. In some embodiments, the ACTN4 premRNA transcript includes a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the ACTN4 premRNA transcript or its complement described herein.

[0086]

[0124] In some embodiments, the targeting portion of the ACTN4 premRNA is premrna_ENST00000252699.7, premrna_ENST00000390009.7, premrna_ENST00000424234.6, premrna_ENST00000440400.1, premrna_ENST00000477174.1, premrna_ENST00000489451.1, premrna_ENST000004 The sequence includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to a region containing at least eight consecutive nucleic acids of the sequence 95553.1, premrna_ENST00000497637.5, premrna_ENST00000586538.1, premrna_ENST00000588618.5, premrna_ENST00000589528.1 or the sequence in Table 3 or its complement. In some embodiments, the targeting portion of the ACTN4 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to a region containing at least eight consecutive nucleic acids of the sequence selected from the group consisting of SEQ ID NOs. 222 to 225 or its complement. In some embodiments, the targeting portion of the ACTN4 premRNA includes sequences complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive nucleic acids of the sequences or complements of Table 6A or Table 6B.

[0087]

[0125] In some embodiments, the ASOs disclosed herein target NSAE premRNAs transcribed from ADAM17 genome sequences. In some embodiments, the ASOs target NSAE premRNA transcripts from ADAM17 genome sequences that include NSAE exons. In some embodiments, the ASOs target NSAE premRNA transcripts from ADAM17 genome sequences that include introns adjacent to the 3' splice site of an NSAE exon and introns adjacent to the 5' splice site of an NSAE exon. In some embodiments, the ASOs target premrna_ENST00000310823.8, premrna_ENST00000478059.1, premrna_ENST00000618923.2, premrna_ENST00000647610.1, premrna_ENST00000647622.1, premrna_ENST0000064 The target is an NSAE premRNA transcript containing a sequence selected from the group consisting of 7979.1, 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 an ADAM17 premRNA sequence containing an NSAE exon. In some embodiments, the ASO targets an ADAM17 premRNA sequence containing an intron adjacent to the 3' splice site of the NSAE exon. In some embodiments, the ASO targets an ADAM17 premRNA sequence containing an intron adjacent to the 5' splice site of the NSAE exon. In some embodiments, the transcripts are transcript_ENST00000310823.8, transcript_ENST00000478059.1, transcript_ENST00000618923.2, transcript_ENST00000647610.1, transcript_ENST00000647622.1, transcript_ENST00000647979.1, transcript_ENST00000648002.1, transcript_ENST00000648548.1, The group selected consists of 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.

[0088]

[0126] In some embodiments, the ADAM17 premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000151694.14 or its complement. In some embodiments, the ADAM17 premRNA transcript comprises a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the ADAM17 premRNA transcript or its complement described herein.

[0089]

[0127] In some embodiments, the targeting portion of ADAM17 premRNA is 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, prem The sequence includes a region containing at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to the sequence rna_ENST00000649068.1, premrna_ENST00000649227.1, premrna_ENST00000649686.1, premrna_ENST00000649798.1, premrna_ENST00000649972.1, premrna_ENST00000650116.1, premrna_ENST00000650241.1 or a sequence in Table 3 or its complement, or a region containing at least 8 consecutive nucleic acids. In some embodiments, the targeting portion of ADAM17 premRNA has at least 80% sequence identity with respect to a region containing at least 8 consecutive nucleic acids with respect to a sequence selected from the group consisting of SEQ ID NOs. 226 to 229 or its complement. , including sequences having 85%, 90%, 95%, 97%, or 100% sequence identity. In some embodiments, the targeting portion of the ADAM17 premRNA includes sequences complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive nucleic acids of the sequences or complements of Table 6A or Table 6B.

[0090]

[0128] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from the ADAMTS13 genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from the ADAMTS13 genome sequence containing NSAE exons. In some embodiments, the ASO targets NSAE premRNA transcripts from the ADAMTS13 genome sequence containing introns adjacent to the 3' splice site of the NSAE exon and introns adjacent to the 5' splice site of the NSAE exon. In some embodiments, the ASO targets an NSAE premRNA transcript containing 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 an ADAMTS13 premRNA sequence containing an NSAE exon. In some embodiments, the ASO targets an ADAMTS13 premRNA sequence containing an intron adjacent to the 3' splice site of the NSAE exon. In some embodiments, the ASO targets an ADAMTS13 premRNA sequence containing an intron adjacent to 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.

[0091]

[0129] In some embodiments, the ADAMTS13 premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000160323.18 or ENSG00000281244.2 or its complement. In some embodiments, the ADAMTS13 premRNA transcript includes a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the ADAMTS13 premRNA transcript or its complement described herein.

[0092]

[0130] In some embodiments, the targeting portion of the ADAMTS13 premRNA is at least 80 consecutive nucleic acids in a region containing the sequences 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 sequences from Table 3 or their complements. The sequence includes sequences having %, 85%, 90%, 95%, 97%, or 100% sequence identity. In some embodiments, the targeting portion of ADAMTS13 premRNA includes sequences having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of a sequence or its complement selected from the group consisting of SEQ ID NOs. 230 to 238. In some embodiments, the targeting portion of ADAMTS13 premRNA includes sequences complementary to at least eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty consecutive nucleic acids of a sequence or its complement in Table 6A or Table 6B.

[0093]

[0131] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from the AKR1E2 genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from the AKR1E2 genome sequence including NSAE exons. In some embodiments, the ASO targets NSAE premRNA transcripts from the AKR1E2 genome sequence including introns adjacent to the 3' splice site of the NSAE exon and introns adjacent to the 5' splice site of the NSAE exon. In some embodiments, the ASOs are premrna_ENST00000298375.12, premrna_ENST00000334019.4, premrna_ENST00000345253.9, premrna_ENST00000441590.5, premrna_ENST00000462718.7, premrna_ENST00000463345.5, and premrna_ENST00000474119. The ASO targets an NSAE premRNA transcript containing a sequence selected from the group consisting of 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 an AKR1E2 premRNA sequence containing an NSAE exon. In some embodiments, the ASO targets an AKR1E2 premRNA sequence containing an intron adjacent to the 3' splice site of the NSAE exon. In some embodiments, the ASO targets an AKR1E2 premRNA sequence containing an intron adjacent to the 5' splice site of the NSAE exon.In some embodiments, the transcripts are transcript_ENST00000298375.12, transcript_ENST00000334019.4, transcript_ENST00000345253.9, transcript_ENST00000441590.5, transcript_ENST00000462718.7, transcript_ENST00000463345.5, transcript_ENS The data is selected from the group consisting of T00000474119.5, transcript_ENST00000487985.1, transcript_ENST00000525281.5, transcript_ENST00000525572.1, transcript_ENST00000525627.1, transcript_ENST00000532248.5, and transcript_ENST00000533295.5.

[0094]

[0132] In some embodiments, the AKR1E2 premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000165568.18 or its complement. In some embodiments, the AKR1E2 premRNA transcript includes a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the AKR1E2 premRNA transcript or its complement described herein.

[0095]

[0133] In some embodiments, the targeting portion of AKR1E2 premRNA is premrn a_ENST00000298375.12, premrna_ENST00000334019.4, premrna_ENST00000345253.9, premrna_ENST00000441590.5, premrna _ENST00000462718.7, premrna_ENST00000463345.5, premrna_ENST00000474119.5, premrna_ENST00000487985.1, premrna_E The targeting portion of the AKR1E2 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of the sequence NST00000525281.5, premrna_ENST00000525572.1, premrna_ENST00000525627.1, premrna_ENST00000532248.5, premrna_ENST00000533295.5 or the sequence in Table 3 or its complement. In some embodiments, the targeting portion of the AKR1E2 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of the sequence selected from the group consisting of SEQ ID NOs. 239 to 242 or its complement. In some embodiments, the targeting portion of the AKR1E2 premRNA includes sequences complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive nucleic acids of the sequences or complements of Table 6A or Table 6B.

[0096]

[0134] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from ALAD genome sequences. In some embodiments, the ASO targets NSAE premRNA transcripts from ALAD genome sequences containing NSAE exons. In some embodiments, the ASO targets NSAE premRNA transcripts from ALAD genome sequences containing introns adjacent to the 3' splice site of an NSAE exon and introns adjacent to the 5' splice site of an NSAE exon. In some embodiments, the ASO targets an NSAE premRNA transcript containing 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 an ALAD premRNA sequence containing an NSAE exon. In some embodiments, the ASO targets an ALAD premRNA sequence containing an intron adjacent to the 3' splice site of an NSAE exon. In some embodiments, the ASO targets an ALAD premRNA sequence containing an intron adjacent to the 5' splice site of an 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.

[0097]

[0135] In some embodiments, the ALAD premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000148218.16 or its complement. In some embodiments, the ALAD premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the ALAD premRNA transcript or its complement described herein. It contains sequences having at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.

[0098]

[0136] In some embodiments, the targeting regions of the ALAD premRNA are premrna_ENST00000409155.8, premrna_ENST00000445750.1, premrna_ENST00000448137.5, premrna_ENST00000452726.1, premrna_ENST00000464749.5, and premrna_ENST000004 The sequence includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to a region containing at least eight consecutive nucleic acids of the sequence 68504.5, premrna_ENST00000482001.1, premrna_ENST00000482847.5, premrna_ENST00000494848.1, or the sequences in Table 3 or their complements. In some embodiments, the targeting portion of the ALAD premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to a region containing at least eight consecutive nucleic acids of a sequence selected from the group consisting of SEQ ID NOs. 243 to 248 or its complement. In some embodiments, the targeting portion of the ALAD premRNA includes sequences that are complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive nucleic acids of the sequences or complements of Table 6A or Table 6B.

[0099]

[0137] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from an ALG3 genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from an ALG3 genome sequence containing an NSAE exon. In some embodiments, the ASO targets NSAE premRNA transcripts from an ALG3 genome sequence containing an intron adjacent to the 3' splice site of an NSAE exon and an intron adjacent to the 5' splice site of an NSAE exon. In some embodiments, ASO is premrna_ENST00000397676.8, premrna_ENST00000411922.5, premrna_ENST00000414845.5, premrna_ENST00000423996.5, premrna_ENST00000445626.6, premrna_ENST00000446569.1, premrna_ENST00000455059.5, premrna_EN The ASO targets NSAE premRNA transcripts containing sequences selected from the group consisting of ST00000461415.5, premrna_ENST00000462735.6, premrna_ENST00000463495.5, premrna_ENST00000477959.1, premrna_ENST00000482048.1, premrna_ENST00000485912.1, and premrna_ENST00000488976.5. In some embodiments, the ASO targets ALG3 premRNA sequences containing NSAE exons. In some embodiments, the ASO targets ALG3 premRNA sequences containing introns adjacent to the 3' splice site of the NSAE exon. In some embodiments, the ASO targets an ALG3 premRNA sequence that includes an intron adjacent to the 5' splice site of an NSAE exon.In some embodiments, the transcripts are 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_ENST00. Selected from the group consisting of 000485912.1 and transcript_ENST00000488976.5.

[0100]

[0138] In some embodiments, the ALG3 premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000214160.10 or its complement. In some embodiments, the ALG3 premRNA transcript includes a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the ALG3 premRNA transcript or its complement described herein.

[0101]

[0139] In some embodiments, the targeting portion of the ALG3 premRNA is 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, premr The sequences include those having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to regions containing at least eight consecutive nucleic acids of the sequences na_ENST00000462735.6, premrna_ENST00000463495.5, premrna_ENST00000477959.1, premrna_ENST00000482048.1, premrna_ENST00000485912.1, and premrna_ENST00000488976.5 or the sequences in Table 3 or their complements. In some embodiments, the targeting portion of the ALG3 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of a sequence or its complement selected from the group consisting of SEQ ID NOs. 249 to 255. In some embodiments, the targeting portion of the ALG3 premRNA includes a sequence complementary to at least eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty consecutive nucleic acids of a sequence or its complement in Table 6A or Table 6B.

[0102]

[0140] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from the ANKRD29 genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from the ANKRD29 genome sequence containing NSAE exons. In some embodiments, the ASO targets NSAE premRNA transcripts from the ANKRD29 genome sequence containing introns adjacent to the 3' splice site of the NSAE exon and introns adjacent to the 5' splice site of the NSAE exon. In some embodiments, the ASO targets an NSAE premRNA transcript containing 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 an ANKRD29 premRNA sequence containing an NSAE exon. In some embodiments, the ASO targets an ANKRD29 premRNA sequence containing an intron adjacent to the 3' splice site of the NSAE exon. In some embodiments, the ASO targets an ANKRD29 premRNA sequence containing an intron adjacent to the 5' splice site of the NSAE exon. In some embodiments, the transcripts are transcript_ENST00000322980.13, transcript_ENST00000585908.2, The following are selected from the group consisting of transcript_ENST00000586087.1, transcript_ENST00000586511.1, transcript_ENST00000587763.1, transcript_ENST00000591280.5, transcript_ENST00000591617.1, and transcript_ENST00000592179.6.

[0103]

[0141] In some embodiments, the ANKRD29 premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000154065.17 or its complement. In some embodiments, the ANKRD29 premRNA transcript includes a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the ANKRD29 premRNA transcript or its complement described herein.

[0104]

[0142] In some embodiments, the targeting portion of the ANKRD29 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to a region containing at least eight consecutive nucleic acids of the sequences 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 the sequences in Table 3 or their complements. In some embodiments, the targeting portion of the ANKRD29 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of a sequence or its complement selected from the group consisting of SEQ ID NOs. 256 to 259. In some embodiments, the targeting portion of the ANKRD29 premRNA includes a sequence complementary to at least eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty consecutive nucleic acids of a sequence or its complement in Table 6A or Table 6B.

[0105]

[0143] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from an ANKS3 genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from an ANKS3 genome sequence containing an NSAE exon. In some embodiments, the ASO targets NSAE premRNA transcripts from an ANKS3 genome sequence containing an intron adjacent to the 3' splice site of an NSAE exon and an intron adjacent to the 5' splice site of an NSAE exon. In some embodiments, the ASO is 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_ENST00 000588398.1, premrna_ENST00000588513.1, premrna_ENST00000589035.5, premrna_ENST00000589065.5, premrna_ENST00000590147.5, premrna_ENST0000 0590193.5, premrna_ENST00000590689.1, premrna_ENST00000590730.5, premrna_ENST00000590803.5, premrna_ENST00000591185.5, premrna_ENST000005 The target is an NSAE premRNA transcript containing a sequence selected from the group consisting of 91281.5, 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 an ANKS3 premRNA sequence containing an NSAE exon. In some embodiments, the ASO targets an ANKS3 premRNA sequence containing an intron adjacent to the 3' splice site of the NSAE exon. In some embodiments, the ASO targets an ANKS3 premRNA sequence containing an intron adjacent to the 5' splice site of the NSAE exon.In some embodiments, the transcripts are transcript_ENST00000304283.9, transcript_ENST00000446014.6, transcript_ENST00000585773.5, transcript_ENST00000586159.5, transcript_ENST00000586166.5, transcript_ENST00000586605.5, transcript_ENST00000586632.1 , transcript_ENST00000587005.5, transcript_ENST00000588398.1, transcript_ENST00000588513.1, transcript_ENST000005 89035.5, transcript_ENST00000589065.5, transcript_ENST00000590147.5, transcript_ENST00000590193.5, transcript_ENS T00000590689.1, transcript_ENST00000590730.5, transcript_ENST00000590803.5, transcript_ENST00000591185.5, transcr ipt_ENST00000591281.5, transcript_ENST00000591653.5, transcript_ENST00000592068.5, transcript_ENST00000592077.5, Selected from the group consisting of transcript_ENST00000592190.1, transcript_ENST00000592421.5, transcript_ENST00000592698.5, transcript_ENST00000592711.5, transcript_ENST00000592840.1, transcript_ENST00000593120.5, and transcript_ENST00000614075.4.

[0106]

[0144] In some embodiments, the ANKS3 premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000168096.15 or its complement. In some embodiments, the ANKS3 premRNA transcript includes a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the ANKS3 premRNA transcript or its complement described herein.

[0107]

[0145] In some embodiments, the targeting portion of the ANKS3 premRNA is 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_ENST0 0000588398.1, premrna_ENST00000588513.1, premrna_ENST00000589035.5, premrna_ENST0 0000589065.5, premrna_ENST00000590147.5, premrna_ENST00000590193.5, premrna_ENST0 0000590689.1, premrna_ENST00000590730.5, premrna_ENST00000590803.5, premrna_ENST0 0000591185.5, premrna_ENST00000591281.5, premrna_ENST00000591653.5, premrna_ENST0 The sequences include those having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to regions containing at least eight consecutive nucleic acids of the sequences 0000592068.5, 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 or the sequences in Table 3 or their complements. In some embodiments, the targeting portion of the ANKS3 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of a sequence or its complement selected from the group consisting of SEQ ID NOs. 260 to 263. In some embodiments, the targeting portion of the ANKS3 premRNA includes a sequence complementary to at least eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty consecutive nucleic acids of a sequence or its complement in Table 6A or Table 6B.

[0108]

[0146] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from the ANO4 genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from the ANO4 genome sequence containing NSAE exons. In some embodiments, the ASO targets NSAE premRNA transcripts from the ANO4 genome sequence containing introns adjacent to the 3' splice site of the NSAE exon and introns adjacent to the 5' splice site of the NSAE exon. In some embodiments, the ASO targets an NSAE premRNA transcript containing a sequence selected from the group consisting 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, and premrna_ENST00000644049.1. In some embodiments, the ASO targets an ANO4 premRNA sequence containing an NSAE exon. In some embodiments, the ASO targets an ANO4 premRNA sequence containing an intron adjacent to the 3' splice site of an NSAE exon. In some embodiments, the ASO targets an ANO4 premRNA sequence containing an intron adjacent to the 5' splice site of an 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.

[0109]

[0147] In some embodiments, the ANO4 premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000151572.18 or ENSG00000262139.9 or its complement. In some embodiments, the ANO4 premRNA transcript includes a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the ANO4 premRNA transcript or its complement described herein.

[0110]

[0148] In some embodiments, the targeting portion of the ANO4 premRNA is premrna_ENST00000392977.8, premrna_ENST00000392979.7, premrna_ENST00000546991.1, premrna_ENST00000548940.1, premrna_ENST00000549155.6, premrna_ENST000005 The sequence includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of the sequence 49234.1, premrna_ENST00000550015.1, premrna_ENST00000551148.1, premrna_ENST00000644049.1, or the sequence in Table 3 or its complement. In some embodiments, the targeting portion of the ANO4 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of a sequence selected from the group consisting of SEQ ID NOs. 264 to 267 or its complement. In some embodiments, the targeting portion of the ANO4 premRNA includes sequences complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive nucleic acids of the sequences or complements of Table 6A or Table 6B.

[0111]

[0149] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from the AP3B2 genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from the AP3B2 genome sequence including NSAE exons. In some embodiments, the ASO targets NSAE premRNA transcripts from the AP3B2 genome sequence including introns adjacent to the 3' splice site of the NSAE exon and introns adjacent to the 5' splice site of the NSAE exon. In some embodiments, ASO is premrna_ENST00000261722.8, premrna_ENST00000535348.5, premrna_ENST00000535359.6, premrna_ENST00000535385.6, premrna_ENST00000535513.2, premrna_ENST00000537735.2, premrna_EN ST00000541693.5, premrna_ENST00000542200.2, premrna_ENST00000543938.6, premrna_ENST00000559888 .1, premrna_ENST00000560529.1, premrna_ENST00000561455.5, premrna_ENST00000620652.4, premrna_EN ST00000642989.2, premrna_ENST00000652847.1, premrna_ENST00000657321.1, premrna_ENST00000659252 .1, premrna_ENST00000660624.1, premrna_ENST00000661532.1, premrna_ENST00000663651.1, premrna_EN ST00000664460.1, premrna_ENST00000665513.1, premrna_ENST00000666055.1, premrna_ENST00000666672 .1, premrna_ENST00000666894.1, premrna_ENST00000666973.1, premrna_ENST00000667758.1, premrna_EN The ASO targets an NSAE premRNA transcript containing a sequence selected from the group consisting of ST00000668385.1, premrna_ENST00000668458.1, premrna_ENST00000668990.2, premrna_ENST00000669880.1, and premrna_ENST00000669930.1. In some embodiments, the ASO targets an AP3B2 premRNA sequence containing an NSAE exon. In some embodiments, the ASO targets an AP3B2 premRNA sequence containing an intron adjacent to the 3' splice site of the NSAE exon. In some embodiments, the ASO targets an AP3B2 premRNA sequence containing an intron adjacent to the 5' splice site of the NSAE exon.In some embodiments, the transcripts are transcript_ENST00000261722.8, transcript_ENST00000535348.5, transcript_ENST00000535359.6, transcript_ENST00000535385.6, transcript_ENST00000535513.2, transcript_ENST00000537735.2, transcript_ENST00000541693.5, transcript_ENST000005 42200.2, transcript_ENST00000543938.6, transcript_ENST00000559888.1, transcript_ENST00000560529.1, transcript_ENST0000056145 5.5, transcript_ENST00000620652.4, transcript_ENST00000642989.2, transcript_ENST00000652847.1, transcript_ENST00000657321.1, transcript_ENST00000659252.1, transcript_ENST00000660624.1, transcript_ENST00000661532.1, transcript_ENST00000663651.1, tra nscript_ENST00000664460.1, transcript_ENST00000665513.1, transcript_ENST00000666055.1, transcript_ENST00000666672.1, transcr The data is selected from the group consisting of ipt_ENST00000666894.1, transcript_ENST00000666973.1, transcript_ENST00000667758.1, transcript_ENST00000668385.1, transcript_ENST00000668458.1, transcript_ENST00000668990.2, transcript_ENST00000669880.1, and transcript_ENST00000669930.1.

[0112]

[0150] In some embodiments, the AP3B2 premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000103723.15 or its complement. In some embodiments, the AP3B2 premRNA transcript includes a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the AP3B2 premRNA transcript or its complement described herein.

[0113]

[0151] In some embodiments, the targeting regions of AP3B2 premRNA are premrna_ENST00000261722.8, premrna_ENST00000535348.5, premrna_ENST00000535359.6, premrna_ENST00000535385.6, and premrna_ENST00000535513.2. , premrna_ENST00000537735.2, premrna_ENST00000541693.5, premrna_ENST00000542200.2, premrna_ENST00000543938.6, premrna_ENST00000559888.1, premrna_ENST00000560529.1, p remrna_ENST00000561455.5, premrna_ENST00000620652.4, premrna_ENST00000642989.2, pr emrna_ENST00000652847.1, premrna_ENST00000657321.1, premrna_ENST00000659252.1, prem rna_ENST00000660624.1, premrna_ENST00000661532.1, premrna_ENST00000663651.1, premr na_ENST00000664460.1, premrna_ENST00000665513.1, premrna_ENST00000666055.1, premrna The sequences include those having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to a region containing at least eight consecutive nucleic acids of the sequences _ENST00000666672.1, premrna_ENST00000666894.1, premrna_ENST00000666973.1, premrna_ENST00000667758.1, premrna_ENST00000668385.1, premrna_ENST00000668458.1, premrna_ENST00000668990.2, premrna_ENST00000669880.1, or premrna_ENST00000669930.1 or the sequences in Table 3 or their complements. In some embodiments, the targeting portion of the AP3B2 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of a sequence or its complement selected from the group consisting of SEQ ID NOs. 268 to 271. In some embodiments, the targeting portion of the AP3B2 premRNA includes a sequence complementary to at least eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty consecutive nucleic acids of a sequence or its complement in Table 6A or Table 6B.

[0114]

[0152] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from the AP3M1 genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from the AP3M1 genome sequence containing NSAE exons. In some embodiments, the ASO targets NSAE premRNA transcripts from the AP3M1 genome sequence containing introns adjacent to the 3' splice site of the NSAE exon and introns adjacent to the 5' splice site of the NSAE exon. In some embodiments, the ASO targets NSAE premRNA transcripts containing sequences 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 AP3M1 premRNA sequences containing NSAE exons. In some embodiments, the ASO targets an AP3M1 premRNA sequence containing an intron adjacent to the 3' splice site of an NSAE exon. In some embodiments, the ASO targets an AP3M1 premRNA sequence containing an intron adjacent to the 5' splice site of an 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.

[0115]

[0153] In some embodiments, the AP3M1 premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000185009.12 or its complement. In some embodiments, the AP3M1 premRNA transcript includes a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the AP3M1 premRNA transcript or its complement described herein.

[0116]

[0154] In some embodiments, the targeting portion of the AP3M1 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of the sequences premrna_ENST00000355264.8, premrna_ENST00000372745.1, premrna_ENST00000480373.1, premrna_ENST00000487653.1, or the sequences in Table 3 or their complements. In some embodiments, the targeting portion of the AP3M1 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of a sequence selected from the group consisting of SEQ ID NOs. 272 ​​to 275 or its complement. In some embodiments, the targeting portion of the AP3M1 premRNA includes sequences complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive nucleic acids of the sequences or complements of Table 6A or Table 6B.

[0117]

[0155] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from the AP5Z1 genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from the AP5Z1 genome sequence containing NSAE exons. In some embodiments, the ASO targets NSAE premRNA transcripts from the AP5Z1 genome sequence containing introns adjacent to the 3' splice site of the NSAE exon and introns adjacent to the 5' splice site of the NSAE exon. In some embodiments, the ASOs are 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, and premrna_ENST00000648360.1. The target is an NSAE premRNA transcript containing a sequence selected from the group consisting of 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 an AP5Z1 premRNA sequence containing an NSAE exon. In some embodiments, the ASO targets an AP5Z1 premRNA sequence containing an intron adjacent to the 3' splice site of an NSAE exon. In some embodiments, the ASO targets an AP5Z1 premRNA sequence containing an intron adjacent to the 5' splice site of an NSAE exon.In some embodiments, the transcript is transcript_ENST00000469614.1, transcript_ENST00000477454.1, transcript_ENST00000477680.6, transcript_ENST00000490487.1, transcript_ENST00000491375.1, transcript_ENST00000496303.6, transcript_ENST00000647628.1, tra nscript_ENST00000647984.1, transcript_ENST00000648237.1, transcript_ENST00000648360.1, transcript_ENST00000648765 .1, transcript_ENST00000648925.1, transcript_ENST00000649063.2, transcript_ENST00000649315.1, transcript_ENST00000. The group is selected from 649419.1, transcript_ENST00000649736.1, transcript_ENST00000650310.1, transcript_ENST00000650451.1, and transcript_ENST00000650581.1.

[0118]

[0156] In some embodiments, the AP5Z1 premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000242802.9 or its complement. In some embodiments, the AP5Z1 premRNA transcript includes a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the AP5Z1 premRNA transcript or its complement described herein.

[0119]

[0157] In some embodiments, the targeting portion of the AP5Z1 premRNA is 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_ENST000006 The sequences include those having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to a region containing at least eight consecutive nucleic acids of the sequences 48765.1, premrna_ENST00000648925.1, premrna_ENST00000649063.2, premrna_ENST00000649315.1, premrna_ENST00000649419.1, premrna_ENST00000649736.1, premrna_ENST00000650310.1, premrna_ENST00000650451.1, premrna_ENST00000650581.1, or the sequences in Table 3 or their complements. In some embodiments, the targeting portion of the AP5Z1 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of a sequence or its complement selected from the group consisting of SEQ ID NOs. 276 to 279. In some embodiments, the targeting portion of the AP5Z1 premRNA includes a sequence complementary to at least eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty consecutive nucleic acids of a sequence or its complement in Table 6A or Table 6B.

[0120]

[0158] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from an ARNTL genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from an ARNTL genome sequence containing an NSAE exon. In some embodiments, the ASO targets NSAE premRNA transcripts from an ARNTL genome sequence containing an intron adjacent to the 3' splice site of an NSAE exon and an intron adjacent to the 5' splice site of an NSAE exon. In some embodiments, the ASO is 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_ENST 00000524392.5, premrna_ENST00000527998.5, premrna_ENST00000529050.5, premrna_ENST00000529388.6, premrna_ENST00000529390.1, premrna_ENST 00000529825.6, premrna_ENST00000530357.6, premrna_ENST00000531665.5, premrna_ENST00000533520.5, premrna_ENST00000534102.1, premrna_ENST The target is an NSAE premRNA transcript containing a sequence selected from the group consisting of 00000534544.5, 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 an ARNTL premRNA sequence containing an NSAE exon. In some embodiments, the ASO targets an ARNTL premRNA sequence containing an intron adjacent to the 3' splice site of an NSAE exon. In some embodiments, the ASO targets an ARNTL premRNA sequence containing an intron adjacent to the 5' splice site of an NSAE exon.In some embodiments, the transcripts are 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_ENST000005 24392.5, transcript_ENST00000527998.5, transcript_ENST00000529050.5, transcript_ENST00000529388.6, transcript_ENS T00000529390.1, transcript_ENST00000529825.6, transcript_ENST00000530357.6, transcript_ENST00000531665.5, transcr ipt_ENST00000533520.5, transcript_ENST00000534102.1, transcript_ENST00000534544.5, transcript_ENST00000673626.1, The group selected consists of transcript_ENST00000673817.1, transcript_ENST00000673834.1, transcript_ENST00000673837.1, transcript_ENST00000673868.1, transcript_ENST00000673888.1, transcript_ENST00000673892.1, and transcript_ENST00000674108.1.

[0121]

[0159] In some embodiments, the ARNTL premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000133794.19 or its complement. In some embodiments, the ARNTL premRNA transcript includes a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the ARNTL premRNA transcript or its complement described herein.

[0122]

[0160] In some embodiments, the ARNTL premRNA targeting portion is 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_E NST00000529050.5, premrna_ENST00000529388.6, premrna_ENST00000529390.1, premrna_ENST00000529825.6, premrna_EN ST00000530357.6, premrna_ENST00000531665.5, premrna_ENST00000533520.5, premrna_ENST00000534102.1, premrna_EN ST00000534544.5, premrna_ENST00000673626.1, premrna_ENST00000673817.1, premrna_ENST00000673834.1, premrna_ENS The sequence includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to a region containing at least eight consecutive nucleic acids of the sequence T00000673837.1, premrna_ENST00000673868.1, premrna_ENST00000673888.1, premrna_ENST00000673892.1, premrna_ENST00000674108.1 or the sequence in Table 3 or its complement. In some embodiments, the targeting portion of the ARNTL premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to a region containing at least eight consecutive nucleic acids of the sequence selected from the group consisting of SEQ ID NOs. 280 to 283 or its complement.In some embodiments, the targeting portion of the ARNTL premRNA includes sequences complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive nucleic acids of the sequences or complements of Table 6A or Table 6B.

[0123]

[0161] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from the ASAP3 genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from the ASAP3 genome sequence containing NSAE exons. In some embodiments, the ASO targets NSAE premRNA transcripts from the ASAP3 genome sequence containing introns adjacent to the 3' splice site of the NSAE exon and introns adjacent to the 5' splice site of the NSAE exon. In some embodiments, the ASO is premrna_ENST00000336689.8, premrna_ENST00000437606.6, premrna_ENST00000449467.2, premrna_ENST00000465372.5, premrna_ENST00000475814.5, premrna_ENST00000478858.5, premrna_ENST The ASO targets NSAE premRNA transcripts containing sequences selected from the group consisting of 00000484418.1, premrna_ENST00000492982.6, premrna_ENST00000495646.5, premrna_ENST00000530874.1, premrna_ENST00000608765.1, and premrna_ENST00000618240.4. In some embodiments, the ASO targets ASAP3 premRNA sequences containing NSAE exons. In some embodiments, the ASO targets ASAP3 premRNA sequences containing introns adjacent to the 3' splice site of the NSAE exon. In some embodiments, the ASO targets ASAP3 premRNA sequences containing introns adjacent to the 5' splice site of the NSAE exon. In some embodiments, the transcript is transcript_ENST00000336689.8, transcript_ENST0000 Selected from the group consisting of 0437606.6, 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.

[0124]

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

[0125]

[0163] In some embodiments, the targeting portion of the ASAP3 premRNA is premrna_ENST00000336689.8, premrna_ENST00000437606.6, premrna_ENST00000449467.2, premrna_ENST00000465372.5, premrna_ENST00000475814.5, premrna_ENST00000478858.5, premrna_ENST00000484418.1, premr The sequence includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of the sequences na_ENST00000492982.6, premrna_ENST00000495646.5, premrna_ENST00000530874.1, premrna_ENST00000608765.1, premrna_ENST00000618240.4 or the sequences in Table 3 or their complements. In some embodiments, the targeting portion of the ASAP3 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of a sequence selected from the group consisting of SEQ ID NOs. 284 to 287 or its complement. In some embodiments, the targeting portion of the ASAP3 premRNA includes sequences complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive nucleic acids of the sequences or complements of Table 6A or Table 6B.

[0126]

[0164] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from ATRX genome sequences. In some embodiments, the ASO targets NSAE premRNA transcripts from ATRX genome sequences containing NSAE exons. In some embodiments, the ASO targets NSAE premRNA transcripts from ATRX genome sequences containing introns adjacent to the 3' splice site of an NSAE exon and introns adjacent to the 5' splice site of an NSAE exon. In some embodiments, the ASO is 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_ENST00 000623321.3, premrna_ENST00000623706.3, premrna_ENST00000624032.3, premrna_ENST00000624166.3, premrna _ENST00000624193.1, premrna_ENST00000624403.1, premrna_ENST00000624668.3, premrna_ENST00000624766.1, The ASO targets NSAE premRNA transcripts containing sequences selected from the group consisting of 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 ATRX premRNA sequences containing NSAE exons. In some embodiments, the ASO targets ATRX premRNA sequences containing introns adjacent to the 3' splice site of the NSAE exon. In some embodiments, the ASO targets ATRX premRNA sequences containing introns adjacent to the 5' splice site of the NSAE exon.In some embodiments, the transcripts are 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 Selected from the group consisting of 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.

[0127]

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

[0128]

[0166] In some embodiments, the targeting portion of the ATRX premRNA is 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, p remrna_ENST00000623706.3, premrna_ENST00000624032.3, premrna_ENST00000624166.3, premrna_ENST00000624193.1, prem rna_ENST00000624403.1, premrna_ENST00000624668.3, premrna_ENST00000624766.1, premrna_ENST00000625063.3, premrna The sequence includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of the sequences _ENST00000635865.1, premrna_ENST00000636152.1, premrna_ENST00000636868.1, premrna_ENST00000637175.1, premrna_ENST00000637959.1 or the sequences in Table 3 or their complements. In some embodiments, the targeting portion of the ATRX premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of a sequence selected from the group consisting of SEQ ID NOs. 288 to 297 or its complement. In some embodiments, the targeting portion of the ATRX premRNA includes sequences complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive nucleic acids of the sequences or complements of Table 6A or Table 6B.

[0129]

[0167] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from the BBS2 genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from the BBS2 genome sequence containing NSAE exons. In some embodiments, the ASO targets NSAE premRNA transcripts from the BBS2 genome sequence containing introns adjacent to the 3' splice site of the NSAE exon and introns adjacent to the 5' splice site of the NSAE exon. In some embodiments, the ASOs are 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, and premrna_ENST00000565781. The target is an NSAE premRNA transcript containing a sequence selected from the group consisting of 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 premRNA sequence containing an NSAE exon. In some embodiments, the ASO targets a BBS2 premRNA sequence containing an intron adjacent to the 3' splice site of the NSAE exon.In some embodiments, the ASO targets a BBS2 premRNA sequence containing an intron adjacent to the 5' splice site of an NSAE exon. In some embodiments, the transcripts are transcript_ENST00000245157.10, transcript_ENST00000561853.1, transcript_ENST00000561877.1, transcript_ENST00000561951.5, transcript_ENST00000562012.1, transcript_ENST00000562059.1, transcript_ENST00000562813.1, transcript_ENST. 00000564123.6, transcript_ENST00000564459.5, transcript_ENST00000565378.1, transcript_ENST00000565781.5, transcript_ENST00000565859.1, transcript_ENST00000566210.1, transcript_ENST00000566410.1, transcript_ENST The group is selected from 00000566452.1, transcript_ENST00000566495.1, transcript_ENST00000566689.5, transcript_ENST00000568104.5, transcript_ENST00000569192.5, transcript_ENST00000569342.5, and transcript_ENST00000569941.5.

[0130]

[0168] In some embodiments, the BBS2 premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000125124.12 or its complement. In some embodiments, the BBS2 premRNA transcript includes a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the BBS2 premRNA transcript or its complement described herein.

[0131]

[0169] In some embodiments, the targeting portion of the BBS2 premRNA is 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_ENST 00000564459.5, premrna_ENST00000565378.1, premrna_ENST00000565781.5, premrna_ENST000005 65859.1, premrna_ENST00000566210.1, premrna_ENST00000566410.1, premrna_ENST00000566452 .1, premrna_ENST00000566495.1, premrna_ENST00000566689.5, premrna_ENST00000568104.5, pr The targeting portion of the BBS2 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of the sequences emrna_ENST00000569192.5, premrna_ENST00000569342.5, premrna_ENST00000569941.5, or the sequences in Table 3 or their complements. In some embodiments, the targeting portion of the BBS2 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of a sequence selected from the group consisting of SEQ ID NOs. 298 to 301 or its complement. In some embodiments, the targeting portion of the BBS2 premRNA includes sequences complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive nucleic acids of the sequences or complements of Table 6A or Table 6B.

[0132]

[0170] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from a BBS4 genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from a BBS4 genome sequence containing an NSAE exon. In some embodiments, the ASO includes an intron adjacent to the 3' splice site of an NSAE exon and an intron adjacent to the 5' splice site of an NSAE exon, BB The target is an NSAE premRNA transcript from the S4 genome sequence. In some embodiments, the ASO is 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_ENST The target is an NSAE premRNA transcript containing a sequence selected from the group consisting of 00000566400.5, 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 premRNA sequence containing an NSAE exon. In some embodiments, the ASO targets a BBS4 premRNA sequence containing an intron adjacent to the 3' splice site of an NSAE exon. In some embodiments, the ASO targets a BBS4 premRNA sequence containing an intron adjacent to the 5' splice site of an NSAE exon.In some embodiments, the transcripts are 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, Selected from the group consisting of 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.

[0133]

[0171] In some embodiments, the BBS4 premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000140463.14 or its complement. In some embodiments, the BBS4 premRNA transcript includes a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the BBS4 premRNA transcript or its complement described herein.

[0134]

[0172] In some embodiments, the targeting portions of the BBS4 premRNA are premrna_ENST00000268057.9, premrna_ENST00000395205.6, premrna_ENST00000561914.5, premrna_ENST00000562084.5, premrna_ENST00000562219.1, and premrna_ENST00000563 600.5, premrna_ENST00000564239.1, premrna_ENST00000565160.5, premrna_ENST00000566197.1, premr na_ENST00000566400.5, premrna_ENST00000566829.1, premrna_ENST00000566938.5, premrna_ENST0000 The sequence includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of the sequence 0567279.5, premrna_ENST00000568535.1, premrna_ENST00000569001.1, premrna_ENST00000569151.1, premrna_ENST00000569338.5, premrna_ENST00000569440.5 or the sequence in Table 3 or its complement. In some embodiments, the targeting portion of the BBS4 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of the sequence selected from the group consisting of SEQ ID NOs. 302 to 309 or its complement. In some embodiments, the targeting portion of the BBS4 premRNA includes sequences complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive nucleic acids of the sequences or complements of Table 6A or Table 6B.

[0135]

[0173] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from a BRD9 genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from a BRD9 genome sequence containing an NSAE exon. In some embodiments, the ASO targets NSAE premRNA transcripts from a BRD9 genome sequence containing an intron adjacent to the 3' splice site of an NSAE exon and an intron adjacent to the 5' splice site of an NSAE exon. In some embodiments, the ASOs are 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, and premrna_ENST00000493082.5 The target is an NSAE premRNA transcript containing a sequence selected from the group consisting of 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 premRNA sequence containing an NSAE exon. In some embodiments, the ASO targets a BRD9 premRNA sequence containing an intron adjacent to the 3' splice site of an NSAE exon. In some embodiments, the ASO targets a BRD9 premRNA sequence containing an intron adjacent to the 5' splice site of an NSAE exon.In some embodiments, the transcripts are 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, tra nscript_ENST00000495794.5, transcript_ENST00000497410.5, transcript_ENST00000518250.5, transcript_ENST00000518251.1, transcri. The data is selected from the group consisting of pt_ENST00000519112.5, transcript_ENST00000519838.5, and transcript_ENST00000523139.5.

[0136]

[0174] In some embodiments, the BRD9 premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000028310.18 or its complement. In some embodiments, the BRD9 premRNA transcript includes a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the BRD9 premRNA transcript or its complement described herein.

[0137]

[0175] In some embodiments, the targeting portion of the BRD9 premRNA is 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_ENST000004 The sequences include those having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to regions containing at least eight consecutive nucleic acids of the sequences 94422.1, 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 or the sequences in Table 3 or their complements. In some embodiments, the targeting portion of the BRD9 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of a sequence or its complement selected from the group consisting of SEQ ID NOs: 310 to 313. In some embodiments, the targeting portion of the BRD9 premRNA includes a sequence complementary to at least eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty consecutive nucleic acids of a sequence or its complement in Table 6A or Table 6B.

[0138]

[0176] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from the CALM3 genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from the CALM3 genome sequence including NSAE exons. In some embodiments, the ASO targets NSAE premRNA transcripts from the CALM3 genome sequence including introns adjacent to the 3' splice site of the NSAE exon and introns adjacent to the 5' splice site of the NSAE exon. In some embodiments, the ASO targets premrna_ENST00000291295.14, premrna_ENST00000391918.6, premrna_ENST00000477244.5, premrna_ENST00000482455.5, premrna_ENST00000486500.1, premrna_ENST00000 594523.5, premrna_ENST00000595072.2, premrna_ENST00000596362.1, premrna_ENST000005977 43.5, premrna_ENST00000597868.5, premrna_ENST00000598871.5, premrna_ENST00000599839.5 The ASO targets an NSAE premRNA transcript containing a sequence selected from the group consisting of , and premrna_ENST00000602169.2. In some embodiments, the ASO targets a CALM3 premRNA sequence containing an NSAE exon. In some embodiments, the ASO targets a CALM3 premRNA sequence containing an intron adjacent to the 3' splice site of the NSAE exon. In some embodiments, the ASO targets a CALM3 premRNA sequence containing an intron adjacent to the 5' splice site of the NSAE exon. In some embodiments, the transcripts are transcript_ENST00000291295.14, transcript_ENST00000391918.6, transcript_ENST00000477244.5, transcript_ENST00000482455.5, transcript_ENST00000486500.1, transcript_ENST00000594523.5, transcript_ENS The selection is made from the group consisting of T00000595072.2, transcript_ENST00000596362.1, transcript_ENST00000597743.5, transcript_ENST00000597868.5, transcript_ENST00000598871.5, transcript_ENST00000599839.5, and transcript_ENST00000602169.2.

[0139]

[0177] In some embodiments, the CALM3 premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000160014.17 or its complement. In some embodiments, the CALM3 premRNA transcript includes a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the CALM3 premRNA transcript or its complement described herein.

[0140]

[0178] In some embodiments, the targeting portion of the CALM3 premRNA is premrna_ENST00000291295.14, premrna_ENST00000391918.6, premrna_ENST00000477244.5, premrna_ENST00000482455.5, premrna_ENST00000486500.1, premrna_ENST00000594523.5, premrna_ENST00000595072.2, premrna_ENST00000 The sequence includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to a region containing at least eight consecutive nucleic acids of the sequence 596362.1, premrna_ENST00000597743.5, premrna_ENST00000597868.5, premrna_ENST00000598871.5, premrna_ENST00000599839.5, premrna_ENST00000602169.2 or the sequence in Table 3 or its complement. In some embodiments, the targeting portion of the CALM3 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to a region containing at least eight consecutive nucleic acids of the sequence selected from the group consisting of SEQ ID NOs: 314 to 317 or its complement. In some embodiments, the targeting portion of the CALM3 premRNA includes sequences complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive nucleic acids of the sequences or complements of Table 6A or Table 6B.

[0141]

[0179] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from the CARS1 genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from the CARS1 genome sequence containing NSAE exons. In some embodiments, the ASO targets the NSAE premRNA transcript adjacent to the 3' splice site of the NSAE exon. The target is an NSAE premRNA transcript from the CARS1 genome sequence, including introns and introns adjacent to the 5' splice sites of NSAE exons. In some embodiments, the ASO is 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_ENS The ASO targets NSAE premRNA transcripts containing sequences selected from the group consisting of T00000470221.6, 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 CARS1 premRNA sequences containing NSAE exons. In some embodiments, the ASO targets CARS1 premRNA sequences containing introns adjacent to the 3' splice site of the NSAE exon. In some embodiments, the ASO targets a CARS1 premRNA sequence that includes an intron adjacent to the 5' splice site of an NSAE exon.In some embodiments, the transcripts are transcript_ENST00000278224.13, transcript_ENST00000380525.8, transcript_ENST00000397111.9, transcript_ENST00000439280.6, transcript_ENST00000465207.5, transcript_ENST00000465240.1, transcript_ENST00000465331.1, transcript_ENST00000466442.6 Selected from the group consisting of 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.

[0142]

[0180] In some embodiments, the CARS1 premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000110619.17 or ENSG00000278191.4 or its complement. In some embodiments, the CARS1 premRNA transcript includes a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the CARS1 premRNA transcript or its complement described herein.

[0143]

[0181] In some embodiments, the targeting regions of CARS1 premRNA are premrna_ENST00000278224.13, premrna_ENST00000380525.8, premrna_ENST00000397111.9, premrna_ENST00000439280.6, premrna_ENST00000465207.5, and premrna_ENST000004 65240.1, premrna_ENST00000465331.1, premrna_ENST00000466442.6, premrna_ENST00000470221.6, pre mrna_ENST00000484484.5, premrna_ENST00000524825.5, premrna_ENST00000526890.5, premrna_ENST00 The targeting portion of the CARS1 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of the sequence 000527330.2, premrna_ENST00000529772.5, premrna_ENST00000531387.5, premrna_ENST00000639317.1 or the sequence in Table 3 or its complement. In some embodiments, the targeting portion of the CARS1 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of a sequence selected from the group consisting of SEQ ID NOs. 318 to 321 or its complement. In some embodiments, the targeting portion of the CARS1 premRNA includes sequences that are complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive nucleic acids of the sequences or complements of Table 6A or Table 6B.

[0144]

[0182] In some embodiments, the ASOs disclosed herein target NSAE premRNA transcribed from the CASP9 genome sequence. In some embodiments, the ASOs target NSAE premRNA transcripts from the CASP9 genome sequence, including NSAE exons. In some embodiments, the ASOs target NSAE premRNA transcripts from the CASP9 genome sequence, including introns adjacent to the 3' splice site of the NSAE exon and introns adjacent to the 5' splice site of the NSAE exon. In some embodiments, the ASOs target premrna_ENST00000333868.10, premrna_ENST00000348549.9, premrna_ENST00000375890.8, premrna_ENST00000400777.7, premrna_ENST00000424908.5, and premrna_ENST00000440484. The ASO targets an NSAE premRNA transcript containing a sequence selected from the group consisting of 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 premRNA sequence containing an NSAE exon. In some embodiments, the ASO targets a CASP9 premRNA sequence containing an intron adjacent to the 3' splice site of the NSAE exon. In some embodiments, the ASO targets a CASP9 premRNA sequence containing an intron adjacent to the 5' splice site of the NSAE exon.In some embodiments, the transcript is selected from the group consisting of 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.

[0145]

[0183] In some embodiments, the CASP9 premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000132906.18 or its complement. In some embodiments, the CASP9 premRNA transcript includes a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the CASP9 premRNA transcript or its complement described herein.

[0146]

[0184] In some embodiments, the targeting portion of the CASP9 premRNA is premrna_ENST00000333868.10, premrna_ENST00000348549.9, premrna_ENST00000375890.8, premrna_ENST00000400777.7, premrna_ENST00000424908.5, premrna_ENST00000440484.1, premrna_ENST00000 The sequence includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of the sequence 447522.5, premrna_ENST00000469637.1, premrna_ENST00000474305.2, premrna_ENST00000546424.5, premrna_ENST00000546969.1 or the sequence in Table 3 or its complement. In some embodiments, the targeting portion of the CASP9 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of the sequence selected from the group consisting of SEQ ID NOs. 322 to 325 or its complement. In some embodiments, the targeting portion of the CASP9 premRNA includes sequences complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive nucleic acids of the sequences or complements of Table 6A or Table 6B.

[0147]

[0185] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from a CATSPER1 genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from a CATSPER1 genome sequence containing an NSAE exon. In some embodiments, the ASO targets NSAE premRNA transcripts from a CATSPER1 genome sequence containing an intron adjacent to the 3' splice site of an NSAE exon and an intron adjacent to the 5' splice site of an NSAE exon. In some embodiments, the ASO targets NSAE premRNA transcripts containing a sequence selected from the group consisting of premrna_ENST00000312106.6 and premrna_ENST00000529244.1. In some embodiments, the ASO targets a CATSPER1 premRNA sequence containing an NSAE exon. In some embodiments, the ASO targets a CATSPER1 premRNA sequence containing an intron adjacent to the 3' splice site of an NSAE exon. In some embodiments, the ASO targets a CATSPER1 premRNA sequence containing an intron adjacent to the 5' splice site of an NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000312106.6 and transcript_ENST00000529244.1.

[0148]

[0186] In some embodiments, the CATSPER1 premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000175294.6 or its complement. In some embodiments, the CATSPER1 premRNA transcript includes a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the CATSPER1 premRNA transcript or its complement described herein.

[0149]

[0187] In some embodiments, the targeting portion of CATSPER1 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to a region containing at least eight consecutive nucleic acids of the sequence premrna_ENST00000312106.6, premrna_ENST00000529244.1, or the sequence in Table 3 or its complement. In some embodiments, the targeting portion of CATSPER1 premRNA includes a sequence having at least 80% sequence identity with respect to a region containing at least eight consecutive nucleic acids of a sequence selected from the group consisting of SEQ ID NOs. 326 to 329. , including sequences having 85%, 90%, 95%, 97%, or 100% sequence identity. In some embodiments, the targeting portion of the CATSPER1 premRNA includes sequences complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive nucleic acids of the sequences or complements of Table 6A or Table 6B.

[0150]

[0188] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from a CCDC40 genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from a CCDC40 genome sequence containing NSAE exons. In some embodiments, the ASO targets NSAE premRNA transcripts from a CCDC40 genome sequence containing introns adjacent to the 3' splice site of an NSAE exon and introns adjacent to the 5' splice site of an NSAE exon. In some embodiments, ASO is 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_ENST The ASO targets NSAE premRNA transcripts containing sequences selected from the group consisting of 00000573474.5, 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 CCDC40 premRNA sequences containing NSAE exons. In some embodiments, the ASO targets CCDC40 premRNA sequences containing introns adjacent to the 3' splice site of the NSAE exon. In some embodiments, the ASO targets a CCDC40 premRNA sequence that includes an intron adjacent to the 5' splice site of an NSAE exon.In some embodiments, the transcripts are transcript_ENST00000269318.9, transcript_ENST00000374876.4, transcript_ENST00000374877.7, transcript_ENST00000397545.9, transcript_ENST00000571028.1, transcript_ENST00000572083.5, transcript_ENST00000572253.5, transcript_ENST00000572270.1, Selected from the group consisting of 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.

[0151]

[0189] In some embodiments, the CCDC40 premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000141519.15 or its complement. In some embodiments, the CCDC40 premRNA transcript comprises a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the CCDC40 premRNA transcript or its complement described herein.

[0152]

[0190] In some embodiments, the targeting portion of the CCDC40 premRNA is 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, prem The sequences include those having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to regions containing at least eight consecutive nucleic acids of the sequences rna_ENST00000573903.1, premrna_ENST00000574099.1, premrna_ENST00000574799.5, premrna_ENST00000574933.1, premrna_ENST00000575431.1, premrna_ENST00000576033.5, premrna_ENST00000576241.1 or the sequences in Table 3 or their complements. In some embodiments, the targeting portion of the CCDC40 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of a sequence or its complement selected from the group consisting of SEQ ID NOs. 330 to 333. In some embodiments, the targeting portion of the CCDC40 premRNA includes a sequence complementary to at least eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty consecutive nucleic acids of a sequence or its complement in Table 6A or Table 6B.

[0153]

[0191] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from the CCDC88B genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from the CCDC88B genome sequence containing NSAE exons. In some embodiments, the ASO targets NSAE premRNA transcripts from the CCDC88B genome sequence containing introns adjacent to the 3' splice site of the NSAE exon and introns adjacent to the 5' splice site of the NSAE exon. In some embodiments, the ASO targets an NSAE premRNA transcript containing 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 premRNA sequence containing an NSAE exon. In some embodiments, the ASO targets a CCDC88B premRNA sequence containing an intron adjacent to the 3' splice site of the NSAE exon. In some embodiments, the ASO targets a CCDC88B premRNA sequence containing an intron adjacent to 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.

[0154]

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

[0155]

[0193] In some embodiments, the targeting portion of the CCDC88B premRNA is premrna_ENST00000301897.5, premrna_ENST00000356786.10, premrna_ENST00000359902.2, premrna_ENST00000463837.5, premrna_ENST00000472524.1, premrna_ENST00000473405.1, pre The targeting portion of the CCDC88B premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of the sequence mrna_ENST00000479965.5, premrna_ENST00000492980.1, premrna_ENST00000494080.5, premrna_ENST00000494566.5 or the sequences in Table 3 or their complements. In some embodiments, the targeting portion of the CCDC88B premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of a sequence selected from the group consisting of SEQ ID NOs. 334 to 337 or its complement. In some embodiments, the targeting portion of the CCDC88B premRNA includes sequences complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive nucleic acids of the sequences or complements of Table 6A or Table 6B.

[0156]

[0194] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from a CD4 genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from a CD4 genome sequence containing an NSAE exon. In some embodiments, the ASO targets NSAE premRNA transcripts from a CD4 genome sequence containing an intron adjacent to the 3' splice site of an NSAE exon and an intron adjacent to the 5' splice site of an NSAE exon. In some embodiments, ASO is premrna_ENST00000011653.9, premrna_ENST00000437800.6, premrna_ENST00000535466.5, premrna_ENST00000535707.5, premrna_ENST00000536563.1, premrna_ENST00000536590.1, premrna_ENST The ASO targets NSAE premRNA transcripts containing sequences selected from the group consisting of 00000536610.5, premrna_ENST00000538827.5, premrna_ENST00000539492.1, premrna_ENST00000541982.5, premrna_ENST00000543755.1, and premrna_ENST00000544344.5. In some embodiments, the ASO targets CD4 premRNA sequences containing NSAE exons. In some embodiments, the ASO targets CD4 premRNA sequences containing introns adjacent to the 3' splice site of the NSAE exon. In some embodiments, the ASO targets CD4 premRNA sequences containing introns adjacent to the 5' splice site of the NSAE exon. In some embodiments, the transcripts are transcript_ENST00000011653.9, transcript_ENST00000437800.6, transcript_ENST00000535466.5, transcript_ENST00000535707.5, transcript_ENST00000536563.1, transcript_ENST00000536590.1, transc The data is selected from the group consisting of ript_ENST00000536610.5, transcript_ENST00000538827.5, transcript_ENST00000539492.1, transcript_ENST00000541982.5, transcript_ENST00000543755.1, and transcript_ENST00000544344.5.

[0157]

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

[0158]

[0196] In some embodiments, the targeting portion of the CD4 premRNA is premrna_ENST00000011653.9, premrna_ENST00000437800.6, premrna_ENST00000535466.5, premrna_ENST00000535707.5, premrna_ENST00000536563.1, premrna_ENST00000536590.1, premrna_ENST00000536610.5, premrn The targeting portion of the CD4 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of a sequence selected from the group consisting of SEQ ID NOs. 338 to 341, or a region containing at least eight consecutive nucleic acids of a sequence or a complement of a sequence in Table 3. In some embodiments, the targeting portion of the CD4 premRNA includes sequences complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive nucleic acids of the sequences or complements of Table 6A or Table 6B.

[0159]

[0197] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from CD58 genomic sequences. In some embodiments, the ASO targets NSAE premRNA transcripts from CD58 genomic sequences that include NSAE exons. In some embodiments, the ASO targets NSAE premRNA transcripts from CD58 genomic sequences that include introns adjacent to the 3' splice site of an NSAE exon and introns adjacent to the 5' splice site of an NSAE exon. In some embodiments, the ASO targets NSAE premRNA transcripts containing sequences 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 premRNA sequence containing an NSAE exon. In some embodiments, the ASO targets a CD58 premRNA sequence containing an intron adjacent to the 3' splice site of the NSAE exon. In some embodiments, the ASO targets a CD58 premRNA sequence containing an intron adjacent to the 5' splice site of the NSAE exon. In some embodiments, the transcripts are transcript_ENST00000369487.3, transcript_ENST00000369489.10, transcript_ENST0 The group is selected from 0000457047.6, transcript_ENST00000464088.5, and transcript_ENST00000526981.1.

[0160]

[0198] In some embodiments, the CD58 premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000116815.16 or its complement. In some embodiments, the CD58 premRNA transcript includes a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the CD58 premRNA transcripts or their complements described herein.

[0161]

[0199] In some embodiments, the targeting portion of the CD58 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to a region containing at least eight consecutive nucleic acids of the sequences premrna_ENST00000369487.3, premrna_ENST00000369489.10, premrna_ENST00000457047.6, premrna_ENST00000464088.5, premrna_ENST00000526981.1 or the sequences in Table 3 or their complements. In some embodiments, the targeting portion of the CD58 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of a sequence or its complement selected from the group consisting of SEQ ID NOs: 342 to 347. In some embodiments, the targeting portion of the CD58 premRNA includes a sequence complementary to at least eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty consecutive nucleic acids of a sequence or its complement in Table 6A or Table 6B.

[0162]

[0200] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from a CES2 genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from a CES2 genome sequence containing an NSAE exon. In some embodiments, the ASO targets NSAE premRNA transcripts from a CES2 genome sequence containing an intron adjacent to the 3' splice site of an NSAE exon and an intron adjacent to the 5' splice site of an NSAE exon. In some embodiments, the ASOs are premrna_ENST00000317091.10, premrna_ENST00000417689.6, premrna_ENST00000561697.5, premrna_ENST00000561843.1, premrna_ENST00000563988.1, premrna_ENST00000564420.1, premrna_ENST00000566182.1, and premrna_ENS The target is an NSAE premRNA transcript containing a sequence selected from the group consisting of T00000566359.1, premrna_ENST00000567128.1, premrna_ENST00000568347.1, premrna_ENST00000568470.6, premrna_ENST00000570032.2, premrna_ENST00000652196.1, and premrna_ENST00000652667.1.

[0163]

[0201] In some embodiments, the ASO targets a CES2 premRNA sequence containing an NSAE exon. In some embodiments, the ASO targets a CES2 premRNA sequence containing an intron adjacent to the 3' splice site of the NSAE exon. In some embodiments, the ASO targets a CES2 premRNA sequence containing an intron adjacent to the 5' splice site of the NSAE exon. In some embodiments, the transcripts are transcript_ENST00000317091.10, transcript_ENST0 0000417689.6, transcript_ENST00000561697.5, transcript_ENST00000561843.1, transcript_ENST00000563 988.1, transcript_ENST00000564420.1, transcript_ENST00000566182.1, transcript_ENST00000566359.1, t The following are selected from the group consisting of ranscript_ENST00000567128.1, transcript_ENST00000568347.1, transcript_ENST00000568470.6, transcript_ENST00000570032.2, transcript_ENST00000652196.1, and transcript_ENST00000652667.1.

[0164]

[0202] In some embodiments, the CES2 premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000172831.14 or its complement. In some embodiments, the CES2 premRNA transcript includes a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the CES2 premRNA transcript or its complement described herein.

[0165]

[0203] In some embodiments, the targeting portion of the CES2 premRNA is premrna_ENST00000317091.10, premrna_ENST00000417689.6, premrna_ENST00000561697.5, premrna_ENST00000561843.1, premrna_ENST00000563988.1, premrna_ENST00000564420.1, premrna_ENST00000566182.1, premrna_ENST00000566359.1, premr The sequences include those having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to regions containing at least eight consecutive nucleic acids of the sequences na_ENST00000567128.1, premrna_ENST00000568347.1, premrna_ENST00000568470.6, premrna_ENST00000570032.2, premrna_ENST00000652196.1, premrna_ENST00000652667.1 or the sequences in Table 3 or their complements. In some embodiments, the targeting portion of the CES2 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of a sequence or its complement selected from the group consisting of SEQ ID NOs. 348 to 359. In some embodiments, the targeting portion of the CES2 premRNA includes a sequence complementary to at least eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty consecutive nucleic acids of a sequence or its complement in Table 6A or Table 6B.

[0166]

[0204] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from CHFR genome sequences. In some embodiments, the ASO targets NSAE premRNA transcripts from CHFR genome sequences containing NSAE exons. In some embodiments, the ASO targets NSAE premRNA transcripts from CHFR genome sequences containing introns adjacent to the 3' splice site of an NSAE exon and introns adjacent to the 5' splice site of an NSAE exon. In some embodiments, ASO is premrna_ENST00000266880.11, premrna_ENST00000315585.11, premrna_ENST00000432561.6, premrna_ENST00000443047.6, premrna_ENST00000450056.6, premrna_ENST00000499045.2, premrna_ENST00000502279.2, premrna_ENS T00000511001.2, 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_ENST The ASO targets NSAE premRNA transcripts containing sequences selected from the group consisting of 00000540537.5, 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 CHFR premRNA sequences containing NSAE exons. In some embodiments, the ASO targets CHFR premRNA sequences containing introns adjacent to the 3' splice site of the NSAE exon. In some embodiments, the ASO targets a CHFR premRNA sequence that includes an intron adjacent to the 5' splice site of an NSAE exon.In some embodiments, the transcripts are 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 Selected from the group consisting of transcript_ENST00000536843.5, transcript_ENST00000536932.5, transcript_ENST00000537551.5, transcript_ENST00000538235.2, transcript_ENST00000540537.5, transcript_ENST00000540963.1, transcript_ENST00000541341.5, transcript_ENST00000541817.5, transcript_ENST00000542714.5, transcript_ENST00000544093.5, transcript_ENST00000544268.5, and transcript_ENST00000545046.5.

[0167]

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

[0168]

[0206] In some embodiments, the targeting regions of the CHFR premRNA are premrna_ENST00000266880.11, premrna_ENST00000315585.11, premrna_ENST00000432561.6, premrna_ENST00000443047.6, premrna_ENST00000450056.6, premrna_ENST00000499045.2, premrna_ENST00000502279.2, and premrna_ENST00000511001. 2, premrna_ENST00000535181.5, premrna_ENST00000535527.5, premrna_ENST00000535897.1, premrna_ENST00000536196.1, premrna_ENST000005368 43.5, premrna_ENST00000536932.5, premrna_ENST00000537551.5, premrna_ENST00000538235.2, premrna_ENST00000540537.5, premrna_ENST000005 The sequences include those having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to regions containing at least eight consecutive nucleic acids of the sequences 40963.1, premrna_ENST00000541341.5, premrna_ENST00000541817.5, premrna_ENST00000542714.5, premrna_ENST00000544093.5, premrna_ENST00000544268.5, premrna_ENST00000545046.5, or the sequences in Table 3 or their complements. In some embodiments, the targeting portion of the CHFR premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of a sequence or its complement selected from the group consisting of SEQ ID NOs. 360 to 363. In some embodiments, the targeting portion of the CHFR premRNA includes a sequence complementary to at least eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty consecutive nucleic acids of a sequence or its complement in Table 6A or Table 6B.

[0169]

[0207] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from the CLCN2 genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from the CLCN2 genome sequence, including NSAE exons. In some embodiments, the ASO targets NSAE premRNA transcripts from the CLCN2 genome sequence, including introns adjacent to the 3' splice site of the NSAE exon and introns adjacent to the 5' splice site of the NSAE exon. In some embodiments, ASO is 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_ENS The target is an NSAE premRNA transcript containing a sequence selected from the group consisting of T00000636419.1, 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 premRNA sequence containing an NSAE exon. In some embodiments, the ASO targets a CLCN2 premRNA sequence containing an intron adjacent to the 3' splice site of the NSAE exon.In some embodiments, the ASO targets a CLCN2 premRNA sequence containing an intron adjacent to the 5' splice site of an NSAE exon. In some embodiments, the transcripts are transcript_ENST00000265593.9, transcript_ENST00000344937.11, transcript_ENST00000430397.5, and transcript_ENST0000. 0434054.6, 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, tr The group is selected from anscript_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.

[0170]

[0208] In some embodiments, the CLCN2 premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000114859.16 or its complement. In some embodiments, the CLCN2 premRNA transcript includes a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the CLCN2 premRNA transcript or its complement described herein.

[0171]

[0209] In some embodiments, the targeting portion of the CLCN2 premRNA is premrna_ENST00000265593.9, premrna_ENST00000344937.11, premrna_ENST00000430397.5, premrna_ENST00000434054.6, premrna_ENST00000457512.1, premrna_ENST0 0000465231.1, premrna_ENST00000475279.2, premrna_ENST00000485667.1, premrna_ENST000004911 62.1, premrna_ENST00000636180.1, premrna_ENST00000636241.1, premrna_ENST00000636419.1, prem rna_ENST00000636492.1, premrna_ENST00000636658.1, premrna_ENST00000636661.1, premrna_ENST 00000636830.1, premrna_ENST00000636860.1, premrna_ENST00000637258.1, premrna_ENST000006373 The targeting portion of the CLCN2 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of the sequence 92.1, premrna_ENST00000637538.1, premrna_ENST00000637909.1, premrna_ENST00000638134.1, or the sequences in Table 3 or their complements. In some embodiments, the targeting portion of the CLCN2 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of a sequence selected from the group consisting of SEQ ID NOs. 364 to 369 or its complement. In some embodiments, the targeting portion of the CLCN2 premRNA includes sequences complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive nucleic acids of the sequences or complements of Table 6A or Table 6B.

[0172]

[0210] In some embodiments, the ASO disclosed herein is the CNOT3 genome sequence or The ASO targets transcribed NSAE premRNA. In some embodiments, the ASO targets NSAE premRNA transcripts from a CNOT3 genome sequence containing NSAE exons. In some embodiments, the ASO targets NSAE premRNA transcripts from a CNOT3 genome sequence containing introns adjacent to the 3' splice site of an NSAE exon and introns adjacent to the 5' splice site of an NSAE exon. In some embodiments, the ASOs are premrna_ENST00000221232.11, premrna_ENST00000358389.7, transcript_ENST00000440571.6, transcript_ENST00000447684.5, transcript_ENST00000457463.1, transcript_ENST00000471126.1, transcript_ENST00000496327.2, transcript_ENST00000613073. The ASO targets NSAE premRNA transcripts containing sequences selected from the group consisting of 4, transcript_ENST00000617930.2, transcript_ENST00000618939.5, transcript_ENST00000642159.1, transcript_ENST00000644245.1, transcript_ENST00000644707.1, transcript_ENST00000646002.1, and premrna_ENST00000647082.1. In some embodiments, the ASO targets CNOT3 premRNA sequences containing NSAE exons. In some embodiments, the ASO targets CNOT3 premRNA sequences containing introns adjacent to the 3' splice site of the NSAE exon. In some embodiments, the ASO targets CNOT3 premRNA sequences containing introns adjacent to the 5' splice site of the NSAE exon.In some embodiments, the transcripts are transcript_ENST00000221232.11, transcript_ENST00000358389.7, transcript_ENST00000440571.6, transcript_ENST00000447684.5, transcript_ENST00000457463.1, transcript_ENST00000471126.1, transcript_ENST00000496327.2, transcript_ENS The following are selected from the group consisting of T00000613073.4, transcript_ENST00000617930.2, transcript_ENST00000618939.5, transcript_ENST00000642159.1, transcript_ENST00000644245.1, transcript_ENST00000644707.1, transcript_ENST00000646002.1, and transcript_ENST00000647082.1.

[0173]

[0211] In some embodiments, the CNOT3 premRNA transcript is encoded by a gene sequence having at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference numbers ENSG00000088038.19, ENSG00000273943.4, ENSG00000274176.4, ENSG00000274616.4, ENSG00000274941.4, ENSG00000275979.4, ENSG00000276082.4, ENSG00000277600.4, ENSG00000277114.4, or ENSG00000277615.4, or their complements. In some embodiments, the CNOT3 premRNA transcript comprises a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the CNOT3 premRNA transcript or its complement described herein.

[0174]

[0212] In some embodiments, the targeting regions of the CNOT3 premRNA are premrna_ENST00000221232.11, premrna_ENST00000358389.7, premrna_ENST00000440571.6, premrna_ENST00000447684.5, and premrna_ENST0000045746 3.1, premrna_ENST00000471126.1, premrna_ENST00000496327.2, premrna_ENST00000613073.4, premrn a_ENST00000617930.2, premrna_ENST00000618939.5, premrna_ENST00000642159.1, premrna_ENST00000 The sequence includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to a region containing at least eight consecutive nucleic acids of the sequence 644245.1, premrna_ENST00000644707.1, premrna_ENST00000646002.1, premrna_ENST00000647082.1, or the sequences in Table 3 or their complements. In some embodiments, the targeting portion of the CNOT3 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to a region containing at least eight consecutive nucleic acids of a sequence selected from the group consisting of SEQ ID NOs. 370 to 377, or its complement. In some embodiments, the targeting portion of the CNOT3 premRNA includes sequences complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive nucleic acids of the sequences or complements of Table 6A or Table 6B.

[0175]

[0213] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from a CNTROB genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from a CNTROB genome sequence containing NSAE exons. In some embodiments, the ASO targets NSAE premRNA transcripts from a CNTROB genome sequence containing introns adjacent to the 3' splice site of an NSAE exon and introns adjacent to the 5' splice site of an NSAE exon. In some embodiments, the ASOs are premrna_ENST00000380262.7, premrna_ENST00000563694.6, premrna_ENST00000565740.5, premrna_ENST00000570782.1, premrna_ENST00000570784.1, premrna_ENST00000571540.5, premrna_ENST00000571632.5, and premrna_ENST00000573862.1 The ASO targets NSAE premRNA transcripts containing sequences selected from the group consisting of 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 CNTROB premRNA sequences containing NSAE exons. In some embodiments, the ASO targets CNTROB premRNA sequences containing introns adjacent to the 3' splice site of the NSAE exon. In some embodiments, the ASO targets a CNTROB premRNA sequence that includes an intron adjacent to the 5' splice site of an NSAE exon.In some embodiments, the transcripts are transcript_ENST00000380262.7, transcript_ENST00000563694.6, transcript_ENST00000565740.5, transcript_ENST00000570782.1, transcript_ENST00000570784.1, transcript_ENST00000571540.5, transcript_ENST00000571632.5, transcript_E From the group consisting of NST00000573862.1, transcript_ENST00000574430.5, transcript_ENST00000575408.5, transcript_ENST00000576536.1, transcript_ENST00000576538.5, transcript_ENST00000576587.1, transcript_ENST00000576723.5, and transcript_ENST00000576922.5. Selected.

[0176]

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

[0177]

[0215] In some embodiments, the targeting portion of the CNTROB premRNA is 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_ENST00000 The sequences include those having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to regions containing at least eight consecutive nucleic acids of the sequences 574430.5, premrna_ENST00000575408.5, premrna_ENST00000576536.1, premrna_ENST00000576538.5, premrna_ENST00000576587.1, premrna_ENST00000576723.5, premrna_ENST00000576922.5 or the sequences in Table 3 or their complements. In some embodiments, the targeting portion of the CNTROB premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of a sequence or its complement selected from the group consisting of SEQ ID NOs. 378 to 381. In some embodiments, the targeting portion of the CNTROB premRNA includes a sequence complementary to at least eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty consecutive nucleic acids of a sequence or its complement in Table 6A or Table 6B.

[0178]

[0216] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from a COL5A3 genomic sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from a COL5A3 genomic sequence containing an NSAE exon. In some embodiments, the ASO targets NSAE premRNA transcripts from a COL5A3 genomic sequence containing an intron adjacent to the 3' splice site of an NSAE exon and an intron adjacent to the 5' splice site of an NSAE exon. In some embodiments, the ASO targets NSAE premRNA transcripts containing a sequence selected from the group consisting of premrna_ENST00000264828.4 and premrna_ENST00000461214.1. In some embodiments, the ASO targets a COL5A3 premRNA sequence containing an NSAE exon. In some embodiments, the ASO targets a COL5A3 premRNA sequence containing an intron adjacent to the 3' splice site of an NSAE exon. In some embodiments, the ASO targets a COL5A3 premRNA sequence containing an intron adjacent to the 5' splice site of an NSAE exon. In some embodiments, the transcript is selected from the group consisting of transcript_ENST00000264828.4 and transcript_ENST00000461214.1.

[0179]

[0217] In some embodiments, the COL5A3 premRNA transcript is at least about 80% of Ensembl reference number ENSG00000080573.7 or its complement. The gene sequences are encoded by having 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity. In some embodiments, the COL5A3 premRNA transcript comprises a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the COL5A3 premRNA transcript or its complement described herein.

[0180]

[0218] In some embodiments, the targeting portion of the COL5A3 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to a region containing at least eight consecutive nucleic acids of the sequences premrna_ENST00000264828.4, premrna_ENST00000461214.1, or the sequences in Table 3 or their complements. In some embodiments, the targeting portion of the COL5A3 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to a region containing at least eight consecutive nucleic acids of a sequence selected from the group consisting of SEQ ID NOs. 382 to 385 or its complements. In some embodiments, the targeting portion of the COL5A3 premRNA includes sequences complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive nucleic acids of the sequences or complements of Table 6A or Table 6B.

[0181]

[0219] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from the CPSF1 genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from the CPSF1 genome sequence, including NSAE exons. In some embodiments, the ASO targets NSAE premRNA transcripts from the CPSF1 genome sequence, including introns adjacent to the 3' splice site of the NSAE exon and introns adjacent to the 5' splice site of the NSAE exon. In some embodiments, ASO is premrna_ENST00000526271.2, premrna_ENST00000527827.1, premrna_ENST00000527916.1, premrna_ENST00000529288.1, premrna_ENST00000531042.5, premrna_ENST00000531480.2, premrna_ENST00000531727.5, premrna_ENST The ASO targets NSAE premRNA transcripts containing sequences selected from the group consisting of 00000532560.5, 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 CPSF1 premRNA sequences containing NSAE exons. In some embodiments, the ASO targets CPSF1 premRNA sequences containing introns adjacent to the 3' splice site of the NSAE exon. In some embodiments, the ASO targets a CPSF1 premRNA sequence that includes an intron adjacent to the 5' splice site of an NSAE exon.In some embodiments, the transcripts are transcript_ENST00000526271.2, transcript_ENST00000527827.1, transcript_ENST00000527916.1, transcript_ENST00000529288.1, transcript_ENST00000531042.5, transcript_ENST00000531480.2, transcript_ENST00 000531727.5, transcript_ENST00000532560.5, transcript_ENST00000532725.1, transcript_ENST00000532935.5, tran script_ENST00000533492.1, transcript_ENST00000616140.2, transcript_ENST00000620219.4, and transcript_ENST0. Selected from the group consisting of 0000622776.1.

[0182]

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

[0183]

[0221] In some embodiments, the targeting portion of the CPSF1 premRNA is premrna_ENST00000526271.2, premrna_ENST00000527827.1, premrna_ENST00000527916.1, premrna_ENST00000529288.1, premrna_ENST00000531042.5, premrna_ENST00000531480.2, premrna_ENST00000531727.5, premrna_ENST00000532560.5, premr The sequences include those having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to regions containing at least eight consecutive nucleic acids of the sequences na_ENST00000532725.1, premrna_ENST00000532935.5, premrna_ENST00000533492.1, premrna_ENST00000616140.2, premrna_ENST00000620219.4, premrna_ENST00000622776.1 or the sequences in Table 3 or their complements. In some embodiments, the targeting portion of the CPSF1 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of a sequence or its complement selected from the group consisting of SEQ ID NOs. 386 to 389. In some embodiments, the targeting portion of the CPSF1 premRNA includes a sequence complementary to at least eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty consecutive nucleic acids of a sequence or its complement in Table 6A or Table 6B.

[0184]

[0222] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from a CSPP1 genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from a CSPP1 genome sequence containing NSAE exons. In some embodiments, the ASO targets NSAE premRNA transcripts from a CSPP1 genome sequence containing introns adjacent to the 3' splice site of an NSAE exon and introns adjacent to the 5' splice site of an NSAE exon. In some embodiments, the ASO targets an NSAE premRNA transcript containing 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 premRNA sequence containing an NSAE exon. In some embodiments, the ASO targets a CSPP1 premRNA sequence containing an intron adjacent to the 3' splice site of an NSAE exon. In some embodiments, the ASO targets a CSPP1 premRNA sequence containing an intron adjacent to the 5' splice site of an NSAE exon. In some embodiments, the transcripts are transcript_ENST00000262210.9, transcript_ENST00000519163.6, transcript_ENST00000519668.1, transcript_ The data is selected from the group consisting of ENST00000519701.5, transcript_ENST00000521168.5, transcript_ENST00000521324.1, and transcript_ENST00000521919.5.

[0185]

[0223] In some embodiments, the CSPP1 premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000104218.14 or its complement. In some embodiments, the CSPP1 premRNA transcript includes a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the CSPP1 premRNA transcript or its complement described herein.

[0186]

[0224] In some embodiments, the targeting portion of the CSPP1 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to a region containing at least eight consecutive nucleic acids of the sequences premrna_ENST00000262210.9, premrna_ENST00000519163.6, premrna_ENST00000519668.1, premrna_ENST00000519701.5, premrna_ENST00000521168.5, premrna_ENST00000521324.1, and premrna_ENST00000521919.5 or the sequences in Table 3 or their complements. In some embodiments, the targeting portion of the CSPP1 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of a sequence or its complement selected from the group consisting of SEQ ID NOs: 390 to 393. In some embodiments, the targeting portion of the CSPP1 premRNA includes a sequence complementary to at least eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty consecutive nucleic acids of a sequence or its complement in Table 6A or Table 6B.

[0187]

[0225] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from a CTF1 genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from a CTF1 genome sequence containing an NSAE exon. In some embodiments, the ASO targets NSAE premRNA transcripts from a CTF1 genome sequence containing an intron adjacent to the 3' splice site of an NSAE exon and an intron adjacent to the 5' splice site of an NSAE exon. In some embodiments, the ASO targets NSAE premRNA transcripts containing a sequence selected from the group consisting of premrna_ENST00000279804.2 and premrna_ENST00000395019.3. In some embodiments, the ASO targets a CTF1 premRNA sequence containing an NSAE exon. In some embodiments, the ASO targets a CTF1 premRNA sequence containing an intron adjacent to the 3' splice site of an NSAE exon. In some embodiments, the ASO targets a CTF1 premRNA sequence containing an intron adjacent to the 5' splice site of an NSAE exon. In some embodiments, the transcripts are transcript_ENST00000279804.2 and transcript_ENST00000395019.3.

[0188]

[0226] In some embodiments, the CTF1 premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000150281.6 or its complement. In some embodiments, the CTF1 premRNA transcript has at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the CTF1 premRNA transcript or its complement described herein. Contains sequences with 00% sequence identity.

[0189]

[0227] In some embodiments, the targeting portion of the CTF1 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to a region containing at least eight consecutive nucleic acids of the sequences premrna_ENST00000279804.2, premrna_ENST00000395019.3, or the sequences in Table 3 or their complements. In some embodiments, the targeting portion of the CTF1 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to a region containing at least eight consecutive nucleic acids of a sequence selected from the group consisting of SEQ ID NOs. 394 to 399 or its complements. In some embodiments, the targeting portion of the CTF1 premRNA includes sequences complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive nucleic acids of the sequences or complements of Table 6A or Table 6B.

[0190]

[0228] In some embodiments, the ASOs disclosed herein target NSAE premRNAs transcribed from CTH genome sequences. In some embodiments, the ASOs target NSAE premRNA transcripts from CTH genome sequences containing NSAE exons. In some embodiments, the ASOs target NSAE premRNA transcripts from CTH genome sequences containing introns adjacent to the 3' splice site of an NSAE exon and introns adjacent to the 5' splice site of an NSAE exon. In some embodiments, the ASOs target NSAE premRNA transcripts containing sequences 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 premRNA sequence containing an NSAE exon. In some embodiments, the ASO targets a CTH premRNA sequence containing an intron adjacent to the 3' splice site of the NSAE exon. In some embodiments, the ASO targets a CTH premRNA sequence containing an intron adjacent to 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.

[0191]

[0229] In some embodiments, the CTH premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000116761.12 or its complement. In some embodiments, the CTH premRNA transcript includes a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the CTH premRNA transcript or its complement described herein.

[0192]

[0230] In some embodiments, the targeting portion of the CTH premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to a region containing at least eight consecutive nucleic acids of the sequences premrna_ENST00000346806.2, premrna_ENST00000370938.8, premrna_ENST00000411986.6, premrna_ENST00000464926.1, premrna_ENST00000482383.1 or the sequences in Table 3 or their complements. In some embodiments, the targeting portion of the CTH premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to a region containing at least eight consecutive nucleic acids. The sequence includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of a sequence or its complement selected from the group consisting of sequence numbers 400 to sequence number 407. In some embodiments, the targeting portion of the CTH premRNA includes a sequence that is complementary to at least eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty consecutive nucleic acids of a sequence or its complement in Table 6A or Table 6B.

[0193]

[0231] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from a CYP3A5 genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from a CYP3A5 genome sequence containing an NSAE exon. In some embodiments, the ASO targets NSAE premRNA transcripts from a CYP3A5 genome sequence containing an intron adjacent to the 3' splice site of the NSAE exon and an intron adjacent to the 5' splice site of the NSAE exon. In some embodiments, the ASO is 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_ENST The ASO targets NSAE premRNA transcripts containing sequences selected from the group consisting of 00000469622.5, 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 CYP3A5 premRNA sequences containing NSAE exons. In some embodiments, the ASO targets CYP3A5 premRNA sequences containing introns adjacent to the 3' splice site of the NSAE exon. In some embodiments, the ASO targets a CYP3A5 premRNA sequence that includes an intron adjacent to the 5' splice site of an NSAE exon.In some embodiments, the transcripts are transcript_ENST00000222982.8, transcript_ENST00000339843.6, transcript_ENST00000439761.3, transcript_ENST00000456417.5, transcript_ENST00000461920.5, transcript_ENST00000463364.5, transcript_ENST00000463907.5, transcript_ENST00000466061.5, The group selected consists of 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.

[0194]

[0232] In some embodiments, the CYP3A5 premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000106258.15 or its complement. In some embodiments, the CYP3A5 premRNA transcript includes a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the CYP3A5 premRNA transcript or its complement described herein.

[0195]

[0233] In some embodiments, the targeting portion of the CYP3A5 premRNA is 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, prem The sequences include those having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to a region containing at least eight consecutive nucleic acids, such as rna_ENST00000469887.5, premrna_ENST00000473347.1, premrna_ENST00000480723.5, premrna_ENST00000481825.5, premrna_ENST00000488187.1, premrna_ENST00000489231.1, or premrna_ENST00000646887.1, or the sequences in Table 3 or their complements. In some embodiments, the targeting portion of the CYP3A5 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of a sequence or its complement selected from the group consisting of SEQ ID NOs. 408 to 411. In some embodiments, the targeting portion of the CYP3A5 premRNA includes a sequence complementary to at least eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty consecutive nucleic acids of a sequence or its complement in Table 6A or Table 6B.

[0196]

[0234] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from a DAB2IP genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from a DAB2IP genome sequence containing an NSAE exon. In some embodiments, the ASO targets NSAE premRNA transcripts from a DAB2IP genome sequence containing an intron adjacent to the 3' splice site of an NSAE exon and an intron adjacent to the 5' splice site of an NSAE exon. In some embodiments, ASO is premrna_ENST00000259371.6, premrna_ENST00000309989.1, premrna_ENST00000373782.7, premrna_ENST00000394340.7, premrna_ENST00000408936.7, premrna_ENST00000436835.5, premrna_ENST The ASO targets NSAE premRNA transcripts containing sequences selected from the group consisting of 00000459906.1, premrna_ENST00000465078.1, premrna_ENST00000487716.1, premrna_ENST00000489314.1, premrna_ENST00000648444.1, and premrna_ENST00000648693.1. In some embodiments, the ASO targets DAB2IP premRNA sequences containing NSAE exons. In some embodiments, the ASO targets DAB2IP premRNA sequences containing introns adjacent to the 3' splice site of the NSAE exon. In some embodiments, the ASO targets DAB2IP premRNA sequences containing introns adjacent to the 5' splice site of the NSAE exon.In some embodiments, the transcripts are 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_ENST000004. The group is selected from 89314.1, transcript_ENST00000648444.1, and transcript_ENST00000648693.1.

[0197]

[0235] In some embodiments, the DAB2IP premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000136848.17 or its complement. In some embodiments, the DAB2IP premRNA transcript includes a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the DAB2IP premRNA transcript or its complement described herein.

[0198]

[0236] In some embodiments, the targeting portion of the DAB2IP premRNA is premrna_ENST00000259371.6, premrna_ENST00000309989.1, premrna_ENST00000373782.7, premrna_ENST00000394340.7, premrna_ENST00000408936.7, premrna_ENST00000436835.5, premrna_ENST00000459906.1, prem The targeting portion of the DAB2IP premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of the sequences rna_ENST00000465078.1, premrna_ENST00000487716.1, premrna_ENST00000489314.1, premrna_ENST00000648444.1, premrna_ENST00000648693.1 or the sequences in Table 3 or their complements. In some embodiments, the targeting portion of the DAB2IP premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of a sequence selected from the group consisting of SEQ ID NOs. 412 to 415 or its complement. In some embodiments, the targeting portion of the DAB2IP premRNA includes sequences complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive nucleic acids of the sequences or complements of Table 6A or Table 6B.

[0199]

[0237] In some embodiments, the ASOs disclosed herein target NSAE premRNA transcribed from DBN1 genome sequences. In some embodiments, the ASOs target NSAE premRNA transcripts from DBN1 genome sequences that include NSAE exons. In some embodiments, the ASOs target NSAE premRNA transcripts from DBN1 genome sequences that include introns adjacent to the 3' splice site of an NSAE exon and introns adjacent to the 5' splice site of an NSAE exon. In some embodiments, the ASOs target premrna_ENST00000292385.9, premrna_ENST00000309007.9, premrna_ENST00000393565.5, premrna_ENST00000467054.2, premrna_ENST00000471767.1, and premrna_ENST00000472831.5 The ASO targets an NSAE premRNA transcript containing a sequence selected from the group consisting of premrna_ENST00000477391.6, premrna_ENST00000505550.1, premrna_ENST00000506117.5, premrna_ENST00000512501.1, and premrna_ENST00000514833.1. In some embodiments, the ASO targets a DBN1 premRNA sequence containing an NSAE exon. In some embodiments, the ASO targets a DBN1 premRNA sequence containing an intron adjacent to the 3' splice site of the NSAE exon. In some embodiments, the ASO targets a DBN1 premRNA sequence containing an intron adjacent to 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.

[0200]

[0238] In some embodiments, the DBN1 premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000113758.13 or its complement. In some embodiments, the DBN1 premRNA transcript includes a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the DBN1 premRNA transcript or its complement described herein.

[0201]

[0239] In some embodiments, the targeting regions of DBN1 premRNA are premrna_ENST00000292385.9, premrna_ENST00000309007.9, premrna_ENST00000393565.5, premrna_ENST00000467054.2, premrna_ENST00000471767.1, premrna_ENST00000472831.5, premrna_ENST000004 The targeting portion of the DBN1 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of the sequence 77391.6, premrna_ENST00000505550.1, premrna_ENST00000506117.5, premrna_ENST00000512501.1, premrna_ENST00000514833.1 or the sequence in Table 3 or its complement. In some embodiments, the targeting portion of the DBN1 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of the sequence selected from the group consisting of SEQ ID NOs. 416 to 424 or its complement. In some embodiments, the targeting portion of the DBN1 premRNA includes sequences complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive nucleic acids of the sequences or complements of Table 6A or Table 6B.

[0202]

[0240] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from a DDX51 genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from a DDX51 genome sequence containing NSAE exons. In some embodiments, the ASO targets NSAE premRNA transcripts from a DDX51 genome sequence containing introns adjacent to the 3' splice site of an NSAE exon and introns adjacent to the 5' splice site of an NSAE exon. In some embodiments, the ASO targets an NSAE premRNA transcript containing 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 premRNA sequence containing an NSAE exon. In some embodiments, the ASO targets a DDX51 premRNA sequence containing an intron adjacent to the 3' splice site of the NSAE exon. In some embodiments, Morphologically, the ASO targets a DDX51 premRNA sequence containing an intron adjacent to the 5' splice site of an 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.

[0203]

[0241] In some embodiments, the DDX51 premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000185163.10 or ENSG00000288503.1 or its complement. In some embodiments, the DDX51 premRNA transcript includes a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the DDX51 premRNA transcript or its complement described herein.

[0204]

[0242] In some embodiments, the targeting portion of the DDX51 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to a region containing at least eight consecutive nucleic acids of the sequences premrna_ENST00000329073.8, premrna_ENST00000397333.4, premrna_ENST00000462829.2, premrna_ENST00000541489.5, premrna_ENST00000545991.1, premrna_ENST00000546058.1 or the sequences in Table 3 or their complements. In some embodiments, the targeting portion of the DDX51 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with a region containing at least eight consecutive nucleic acids of a sequence or its complement selected from the group consisting of SEQ ID NOs. 425 to 428. In some embodiments, the targeting portion of the DDX51 premRNA includes a sequence complementary to at least eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty consecutive nucleic acids of a sequence or its complement in Table 6A or Table 6B.

[0205]

[0243] In some embodiments, the ASO disclosed herein targets NSAE premRNA transcribed from a DEAF1 genome sequence. In some embodiments, the ASO targets NSAE premRNA transcripts from a DEAF1 genome sequence that includes an NSAE exon. In some embodiments, the ASO targets NSAE premRNA transcripts from a DEAF1 genome sequence that includes an intron adjacent to the 3' splice site of an NSAE exon and an intron adjacent to the 5' splice site of an NSAE exon. In some embodiments, ASO is premrna_ENST00000382409.3, premrna_ENST00000524786.1, premrna_ENST00000525626.5, premrna_ENST00000525904.5, premrna_ENST00000526790.1, premrna_ENST00000526857.2, premrna_ENST The ASO targets NSAE premRNA transcripts containing sequences selected from the group consisting of 00000527170.5, premrna_ENST00000527658.1, premrna_ENST00000528864.5, premrna_ENST00000529717.5, premrna_ENST00000529727.1, and premrna_ENST00000530813.1. In some embodiments, the ASO targets DEAF1 premRNA sequences containing NSAE exons. In some embodiments, the ASO targets DEAF1 premRNA sequences containing introns adjacent to the 3' splice site of the NSAE exon. In some embodiments, ASO targets the DEAF1 premRNA sequence, which includes an intron adjacent to the 5' splice region 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.

[0206]

[0244] In some embodiments, the DEAF1 premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000177030.17 or ENSG00000282712.1 or its complement. In some embodiments, the DEAF1 premRNA transcript includes a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the DEAF1 premRNA transcript or its complement described herein.

[0207]

[0245] In some embodiments, the targeting portion of DEAF1 premRNA is premrna_ENST00000382409.3, premrna_ENST00000524786.1, premrna_ENST00000525626.5, premrna_ENST00000525904.5, premrna_ENST00000526790.1, premrna_ENST00000526857.2, premrna_ENST00000527170.5, premr The sequence includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to a region containing at least eight consecutive nucleic acids of the sequences na_ENST00000527658.1, premrna_ENST00000528864.5, premrna_ENST00000529717.5, premrna_ENST00000529727.1, premrna_ENST00000530813.1 or the sequences in Table 3 or their complements. In some embodiments, the targeting portion of the DEAF1 premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to a region containing at least eight consecutive nucleic acids of a sequence selected from the group consisting of SEQ ID NOs. 429 to 432 or its complement. In some embodiments, the targeting portion of the DEAF1 premRNA includes sequences complementary to at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive nucleic acids of the sequences or complements of Table 6A or Table 6B.

[0208]

[0246] In some embodiments, the ASOs disclosed herein target NSAE premRNAs transcribed from DGKE genome sequences. In some embodiments, the ASOs target NSAE premRNA transcripts from DGKE genome sequences containing NSAE exons. In some embodiments, the ASOs target NSAE premRNA transcripts from DGKE genome sequences containing introns adjacent to the 3' splice site of an NSAE exon and introns adjacent to the 5' splice site of an NSAE exon. In some embodiments, the ASOs target premrna_ENST00000284061.8, premrna_ENST00000570738.1, premrna_ENST00000571084.1, premrna_ENST00000572810.1, premrna_ENST00000572944.1, and premrna_ENST0000057686 The ASO targets an NSAE premRNA transcript containing a sequence selected from the group consisting of 9.5. In some embodiments, the ASO targets a DGKE premRNA sequence containing an NSAE exon. In some embodiments, the ASO targets a DGKE premRNA sequence containing an intron adjacent to the 3' splice site of the NSAE exon. In some embodiments, the ASO targets a DGKE premRNA sequence containing an intron adjacent to 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.

[0209]

[0247] In some embodiments, the DGKE premRNA transcript is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with Ensembl reference number ENSG00000153933.10 or its complement. In some embodiments, the DGKE premRNA transcript includes a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the DGKE premRNA transcript or its complement described herein.

[0210]

[0248] In some embodiments, the targeting portion of the DGKE premRNA includes a sequence having at least 80%, 85%, 90%, 95%, 97%, or 100% sequence identity with respect to a region containing at least eight consecutive nucleic acids of the sequences premrna_ENST00000284061.8, premrna_ENST00000570738.1, premrna_ENST00000571084.1, premrna_ENST00000572810.1, premrna_ENST00000572944.1, premrna_ENST00000576869.5 or the sequences in Table 3 or their...

Claims

1. A composition comprising an NSAE regulator that interacts with a target motif in a preprocessed mRNA transcript to regulate the exclusion of nonsense mutation-dependent RNA degradation mechanism selective exons (NSAEs) from the processed mRNA transcript and to regulate the inclusion of canonical exons in the processed mRNA transcript, wherein the target motif is (i) Within the intron region between two canonical exons, (ii) In one of the two canonical exons, (iii) Within a region that spans both introns and canonical exons Located, NSAE, (a) only a portion of the canonical exon, or (b) At least a portion of the canonical exon and the intron adjacent to the canonical exon Includes, A composition comprising an NSAE regulator that modulates the exclusion of NSAEs from processed mRNA transcripts and modulates the inclusion of canonical exons in processed mRNA transcripts.

2. The composition according to claim 1, wherein the NSAE regulator promotes the exclusion of NSAEs from the processed mRNA transcript and promotes the inclusion of canonical exons in the processed mRNA transcript.

3. The composition according to claim 1, wherein the processed mRNA transcript encodes a target protein, and the NSAE regulator increases the expression of the target protein in cells containing the preprocessed mRNA transcript.

4. The target proteins are 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, CATSPEPER1, CCDC40, CCDC88B, CD4, CD58, CES2, CHFR, CLCN2, CNOT3, CNTROB, COL5A3, CPSF1, CSPP1, CTF1, CTH, CYP3A5, DAB2IP, DBN1, DDX51, DEAF1, DGKE, DHDD, DMKN, DNHD1, DOCK8, DOK5, EIF2B5, ELAC2, ELP1, ENTPD4, ESRRA, ESS2, ETAAL, 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, NLRRC5, 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, RTNN, RUY3, SEM3B, SEM3F, SH2D3A, SIK3, SIRT3, SKIV2L, SLC2A13, SLC12A7, SLC22A3, SLC25A13, SLC25A37, SLC27A5, SLC30A9, SLC30A The composition according to claim 3, selected from the group consisting of 10, 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.

5. A composition comprising a nonsense mutation-dependent RNA degradation mechanism selective 5' or 3' splice site (NSASS) modulator that interacts with a target motif in a preprocessed mRNA transcript to modulate splicing at a selective 5' or 3' splice site of the preprocessed mRNA transcript and modulates the inclusion of canonical exons in a processed mRNA transcript processed from the preprocessed mRNA transcript, wherein the target motif is (i) Within the intron region between two canonical exons, (ii) In one of the two canonical exons, (iii) Within a region that spans both introns and canonical exons Located, The regulation of splicing at the alternative 5' or 3' splice site of the preprocessed mRNA transcript modulates the exclusion of alternative exons from the processed mRNA transcript, and alternative exons, (a) only a portion of the canonical exon, or (b) At least a portion of the canonical exon and the intron adjacent to the canonical exon Includes, A composition in which an NSASS regulator modulates the selective exclusion of exons from processed mRNA transcripts and the inclusion of canonical exons in processed mRNA transcripts.

6. The composition according to claim 5, wherein the NSASS regulator promotes the selective exclusion of exons from the processed mRNA transcript and promotes the inclusion of canonical exons in the processed mRNA transcript.

7. The composition according to claim 5, wherein the processed mRNA transcript encodes a target protein, and the NSASS regulator increases the expression of the target protein in cells containing the preprocessed mRNA transcript.

8. The target proteins are ABCA5, ABCA7, ABCC3, ABCC5, ABCC8, ABCD1, ABR, ACAD9, ACAP1, ACOX2, ACSF3, ACTN4, ADAM17, ADAMTS13, AKR1E2, ALAD, ALG3, ANKRD29, ANKS3, ANO4, AP3B2, AP 3M1, AP5Z1, ARNTL, ASAP3, ATRX, BBS2, BBS4, BRD9, CALM3, CARS1, CASP9, CATSPER1, C CDC40, CCDC88B, CD4, CD58, CES2, CHFR, CLCN2, CNOT3, CNTROB, COL5A3, CPSF1, CSPP1 , CTF1, CTH, CYP3A5, DAB2IP, DBN1, DDX51, DEAF1, DGKE, DHDDS, DMKN, DNHD1, DOCK8, D OK5, EIF2B5, ELAC2, ELP1, ENTPD4, ESRRA, ESS2, ETAA1, ETHE1, FANCA, FASTK, FASTKD 3, FPGS, FREM1, GAS8, GCK, GGA1, GGA3, GGT1, GLMN, GON4L, GRB14, HDAC3, HELQ, HP1BP 3, HPS1, HPS4, IDUA, IFT122, IL17RC, IMPDH1, INVS, IRF3, KCTD3, KLKB1, KYAT1, LAMC 3, LDAH, LIMS2, MALT1, MAP3K7, MAPK13, MCAT, MCEE, MPI, MSTO1, NBEAL2, NLE1, NLRC5, NOM 1, NOP58, NPHP1, NPR1, NUP188, OSGEP, PABPC4, PCOLCE, PHKA2, PIDD1, PKD1, PLA2G6, PLD2, PLEKHG5, PNPO, POLE, PON2, PRMT7, PRODH, PRPF3, PRPF4, PYCR1, RAD52, REXO1, RFX5, RHBD F2, RMND1, ROBO3, RPGRIP1, RTTN, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIK3, SIRT3, SKIV2L, SL C2A13, SLC12A7, SLC22A3, SLC25A13, SLC25A37, SLC27A5, SLC30A9, SLC30A10, SMPD1, SMT N, SNRPB, SP140, STAMBP, STXBP2, SULF2, SYNGAP1, SYNJ2, TAZ, TBL2, TDRD7, TECPR2, TFB1M The composition according to claim 7, selected from the group consisting of TM6SF1, TNK2, TOE1, TOR1B, TRAPPC6B, TRIP4, TRMT2A, TRMU, TRPV4, TTC19, TYMP, UMPS, UROD, WDR11, WDR62, WIPI1, WRAP53, XPO1, YY1AP1, and ZC3H14.

9. A composition comprising a nonsense mutation-dependent RNA degradation mechanism selective exon (NSAE) modulator that modulates the expression of a target protein in cells containing a preprocessed mRNA transcript (premRNA) encoding the target protein, wherein the premRNA is The exon contains an alternative nonsense mutation-dependent RNA degradation mechanism (NMD) exon, which includes an alternative 5' splice site downstream of the 5' splice site of the canonical exon and within the canonical exon, or upstream of the 5' splice site of the canonical exon and within the intron. A composition in which an NSAE regulator modulates the processing of mRNA transcripts from preprocessed mRNA transcripts by regulating the splicing of premRNA at the 5' alternative splice site, and the splicing of premRNA at the 5' alternative splice site regulates the expression of a target protein in cells.

10. The target proteins are ABCC3, ABCC5, ABCC8, ACOX2, ACSF3, ADAM17, ADAMTS13, ALAD, ANKS3, ANO4, AP3B2, AP5Z1, ARNTL, BBS2, BRD9, CALM3, CARS1, CASP9, CD58, CHFR, CLCN2, CNOT3, and CNTR. OB, CTF1, CYP3A5, DHDDS, DNHD1, ENTPD4, ESRRA, ESS2, ETAA1, FASTKD3, FREM1, GAS8, G GA3, GGT1, GLMN, GRB14, HDAC3, HP1BP3, HPS4, IDUA, IFT122, IMPDH1, KCTD3, KYAT1, MAP 3K7, NBEAL2, NOP58, NPHP1, NUP188, PHKA2, PIDD1, PKD1, PLA2G6, PLD2, PLEKHG5, PRMT 7, PRODH, PRPF3, PRPF4, RAD52, REXO1, RFX5, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIRT3, SK The composition according to claim 9, selected from the group consisting of IV2L, SLC25A13, SLC2A13, SLC30A10, SLC30A9, SMTN, STXBP2, SYNGAP1, TBL2, TECPR2, TNK2, TOE1, TRMT2A, TRPV4, UROD, WDR62, WRAP53, and XPO1.

11. The composition according to claim 9 or 10, wherein splicing of premRNA at the 5' alternative splice site increases the expression of the target protein in the cell.

12. The composition according to claim 10, wherein the selective nonsense mutation-dependent RNA degradation mechanism-inducing (NMD) exon includes an alternative 5' splice site downstream of the 5' splice site of the canonical exon and within the canonical exon.

13. The composition according to claim 10, wherein the selective nonsense mutation-dependent RNA degradation mechanism-inducing (NMD) exon includes an alternative 5' splice site upstream of the 5' splice site of the canonical exon and within the intron.

14. A composition comprising a nonsense mutation-dependent RNA degradation mechanism selective 5' or 3' splice site (NSASS) modulator that modulates the expression of a target protein in cells containing a preprocessed mRNA transcript (premRNA) encoding the target protein, wherein the premRNA is A selective exon containing a selective 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 a canonical exon and within the intron. Includes, A composition in which an NSASS regulator modulates the processing of mRNA transcripts from preprocessed mRNA transcripts by regulating the splicing of premRNA at the 5' alternative splice site, and the splicing of premRNA at the 5' alternative splice site regulates the expression of a target protein in cells.

15. The target proteins are ABCC3, ABCC5, ABCC8, ACOX2, ACSF3, ADAM17, ADAMTS13, ALAD, ANKS3, ANO4, AP3B2, AP5Z1, ARNTL, BBS2, BRD9, CALM3, CARS1, CASP9, CD58, CHFR, CLCN2, CNOT3, and CNTR. OB, CTF1, CYP3A5, DHDDS, DNHD1, ENTPD4, ESRRA, ESS2, ETAA1, FASTKD3, FREM1, GAS8, G GA3, GGT1, GLMN, GRB14, HDAC3, HP1BP3, HPS4, IDUA, IFT122, IMPDH1, KCTD3, KYAT1, MAP 3K7, NBEAL2, NOP58, NPHP1, NUP188, PHKA2, PIDD1, PKD1, PLA2G6, PLD2, PLEKHG5, PRMT 7, PRODH, PRPF3, PRPF4, RAD52, REXO1, RFX5, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIRT3, SK The composition according to claim 14, selected from the group consisting of IV2L, SLC25A13, SLC2A13, SLC30A10, SLC30A9, SMTN, STXBP2, SYNGAP1, TBL2, TECPR2, TNK2, TOE1, TRMT2A, TRPV4, UROD, WDR62, WRAP53, and XPO1.

16. The composition according to claim 14 or 15, wherein splicing of premRNA at the 5' alternative splice site increases the expression of the target protein in the cell.

17. The composition according to claim 15, wherein the premRNA comprises an alternative exon containing an alternative 5' splice site downstream of the 5' splice site of the canonical exon and within the canonical exon.

18. The composition according to claim 15, wherein the premRNA comprises an alternative exon containing an alternative 5' splice site upstream of the 5' splice site of the canonical exon and within an intron.

19. A composition comprising a nonsense mutation-dependent RNA degradation mechanism selective exon (NSAE) modulator that modulates the expression of a target protein in cells containing a preprocessed mRNA transcript (premRNA) encoding the target protein, wherein the premRNA is Selective 3' splice is located upstream of the 3' splice site of the canonical exon and within the canonical exon, or downstream of the 3' splice site of the canonical exon and within the intron. It contains a selective nonsense mutation-dependent RNA degradation mechanism-inducing (NMD) exon, including the Price site. A composition in which an NSAE regulator modulates the processing of mRNA transcripts from preprocessed mRNA transcripts by regulating the splicing of premRNA at the 3' alternative splice site, and the splicing of premRNA at the 3' alternative splice site regulates the expression of a target protein in cells.

20. The target proteins are ABCA5, ABCA7, ABCD1, ABR, ACAD9, ACAP1, ACTN4, ADAMTS13, AKR1E2, ALG3, ANKRD29, AP3M1, ASAP3, ATRX, BBS4, CATSPER1, CCDC40, CCDC88B, CD4, CES2, COL5A3, CPSF1, CSPP1, CTH, and DAB2. IP, DBN1, DDX51, DEAF1, DGKE, DMKN, DOCK8, DOK5, EIF2B5, ELAC2, ELP1, ETHE1, FANCA, FASTK, FPG S, GAS8, GCK, GGA1, GON4L, HELQ, HPS1, IL17RC, INVS, IRF3, KLKB1, LAMC3, LDAH, LIMS2, MALT1, MAP K13, MCAT, MCEE, MPI, MSTO1, NLE1, NLRC5, NOM1, NPR1, OSGEP, PABPC4, PCOLCE, PLD2, PNPO, POLE, PON2, PYCR1, RAD52, RHBDF2, RMND1, ROBO3, RPGRIP1, RTTN, SIK3, SLC12A7, SLC22A3, SLC25A37, SL The composition according to claim 19, selected from the group consisting of C27A5, SMPD1, SNRPB, SP140, STAMBP, SULF2, SYNJ2, TAZ, TDRD7, TFB1M, TM6SF1, TOR1B, TRAPPC6B, TRIP4, TRMU, TTC19, TYMP, UMPS, WDR11, WIPI1, YY1AP1, and ZC3H14.

21. The composition according to claim 19 or 20, wherein splicing of premRNA at the 3' alternative splice site increases the expression of the target protein in the cell.

22. The composition according to claim 20, wherein the selective nonsense mutation-dependent RNA degradation mechanism-inducing (NMD) exon includes an alternative 3' splice site upstream of the 3' splice site of the canonical exon and within the canonical exon.

23. The composition according to claim 20, wherein the selective nonsense mutation-dependent RNA degradation mechanism-inducing (NMD) exon includes a selective 3' splice site downstream of the 3' splice site of the canonical exon and within the intron.

24. A composition comprising a nonsense mutation-dependent RNA degradation mechanism selective 5' or 3' splice site (NSASS) modulator that modulates the expression of a target protein in cells containing a preprocessed mRNA transcript (premRNA) encoding the target protein, wherein the premRNA is A selective exon containing 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 a canonical exon and within an intron. Includes, A composition in which an NSASS regulator modulates the processing of mRNA transcripts from preprocessed mRNA transcripts by regulating the splicing of premRNA at the 3' alternative splice site, and the splicing of premRNA at the 3' alternative splice site regulates the expression of a target protein in cells.

25. The target proteins are ABCA5, ABCA7, ABCD1, ABR, ACAD9, AC AP1, ACTN4, ADAMTS13, AKR1E2, ALG3, ANKRD29, AP3M1, ASAP3, ATRX, BBS4, CATSPER1, CCDC4 0, CCDC88B, CD4, CES2, COL5A3, CPSF1, CSPP1, CTH, DAB2IP, DBN1, DDX51, DEAF1, DGKE, DMKN, DOCK8, DOK5, EIF2B5, ELAC2, ELP1, ETHE1, FANCA, FASTK, FPGS, GAS8, GCK, GGA1, GON4L, HEL Q, HPS1, IL17RC, INVS, IRF3, KLKB1, LAMC3, LDAH, LIMS2, MALT1, MAPK13, MCAT, MCEE, MPI, MS TO1, NLE1, NLRC5, NOM1, NPR1, OSGEP, PABPC4, PCOLCE, PLD2, PNPO, POLE, PON2, PYCR1, RAD5 2, RHBDF2, RMND1, ROBO3, RPGRIP1, RTTN, SIK3, SLC12A7, SLC22A3, SLC25A37, SLC27A5, SMPD 1. The composition according to claim 24, selected from the group consisting of SNRPB, SP140, STAMBP, SULF2, SYNJ2, TAZ, TDRD7, TFB1M, TM6SF1, TOR1B, TRAPPC6B, TRIP4, TRMU, TTC19, TYMP, UMPS, WDR11, WIPI1, YY1AP1, and ZC3H14.

26. The composition according to claim 24 or 25, wherein splicing of premRNA at the 3' alternative splice site increases the expression of the target protein in the cell.

27. The composition according to claim 25, wherein the premRNA comprises an alternative exon that includes an alternative 3' splice site upstream of the 3' splice site of the canonical exon and within the canonical exon.

28. The composition according to claim 25, wherein the premRNA comprises an alternative exon containing an alternative 3' splice site downstream of the 3' splice site of the canonical exon and within an intron.

29. The composition according to any one of claims 1 to 28, wherein the agent is a small molecule.

30. The composition according to any one of claims 1 to 28, wherein the agent is a polypeptide.

31. The composition according to claim 30, wherein the polypeptide is a nucleic acid-binding protein.

32. The composition according to claim 31, wherein the nucleic acid-binding protein contains a TAL-effector or zinc finger-binding domain.

33. The composition according to claim 31, wherein the nucleic acid-binding protein is a Cas family protein.

34. The composition according to claim 31, wherein the polypeptide is accompanied or complexed with one or more nucleic acid molecules.

35. The composition according to any one of claims 1 to 28, wherein the agent is an antisense oligomer (ASO) complementary to the targeting region of premRNA.

36. The composition according to claim 35, wherein 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 targeting region of the premRNA encoding the target protein.

37. The composition according to claim 35 or 36, wherein the agent comprises a skeletal modification including a phosphorothioate bond or a phosphorodiamidate bond.

38. The composition according to any one of claims 35 to 37, wherein the agent comprises phosphorodiamidate morpholino.

39. The composition according to any one of claims 35 to 38, wherein the agent comprises locked nucleic acid.

40. The composition according to any one of claims 35 to 39, wherein the agent comprises a peptide nucleic acid.

41. The composition according to any one of claims 35 to 40, wherein the agent comprises 2'-O-methyl.

42. The composition according to any one of claims 35 to 41, wherein the agent comprises a 2'-fluoro or 2'-O-methoxyethyl moiety.

43. The composition according to any one of claims 35 to 42, wherein the agent comprises at least one modified sugar moiety.

44. The composition according to claim 43, wherein each sugar portion is a modified sugar portion.

45. The agent is an antisense oligomer, and the agent is composed of 8-50 nucleic acid bases, 8-40 nucleic acid bases, 8-35 nucleic acid bases, 8-30 nucleic acid bases, 8-25 nucleic acid bases, 8-20 nucleic acid bases, 8-15 nucleic acid bases, 9-50 nucleic acid bases, 9-40 nucleic acid bases, 9-35 nucleic acid bases, 9-30 nucleic acid bases, 9-25 nucleic acid bases, 9-20 nucleic acid bases, 9-15 nucleic acid bases, 10-50 nucleic acid bases, 10-40 nucleic acid bases, 10-35 nucleic acid bases, 10-30 nucleic acid bases, and 10-25 nucleic acid salts. A composition according to any one of claims 1 to 28 or 35 to 44, comprising a group, 10 to 20 nucleic acid bases, 10 to 15 nucleic acid bases, 11 to 50 nucleic acid bases, 11 to 40 nucleic acid bases, 11 to 35 nucleic acid bases, 11 to 30 nucleic acid bases, 11 to 25 nucleic acid bases, 11 to 20 nucleic acid bases, 11 to 15 nucleic acid bases, 12 to 50 nucleic acid bases, 12 to 40 nucleic acid bases, 12 to 35 nucleic acid bases, 12 to 30 nucleic acid bases, 12 to 25 nucleic acid bases, 12 to 20 nucleic acid bases, or 12 to 15 nucleic acid bases.

46. The composition according to any one of claims 1 to 28 or 35 to 44.

47. A composition comprising a nucleic acid molecule encoding an agent according to any one of claims 1 to 28 or 30 to 46.

48. The composition according to claim 47, wherein a nucleic acid molecule is incorporated into the virus delivery system.

49. The composition according to claim 48, wherein the virus delivery system is an adenovirus-associated vector.

50. A method for regulating protein expression, (a) A step of contacting a target motif in a preprocessed mRNA transcript with a nonsense mutation-dependent RNA degradation mechanism selective exon (NSAE) modulator, NSAE, (i) only a portion of the canonical exon, or (ii) At least a portion of the canonical exon and the intron adjacent to the canonical exon Steps including (b) A step of processing an mRNA transcript from a preprocessed mRNA transcript to form a processed mRNA transcript, wherein an NSAE modifier modulates the exclusion of NSAEs from the processed mRNA transcript and modulates the inclusion of canonical exons in the processed mRNA transcript, and (c) A step of translating a processed mRNA transcript, wherein the exclusion of NSAEs and the inclusion of canonical exons modulate the expression of the target protein compared to the expression of an equivalent mRNA transcript containing NSAEs instead of canonical exons. Methods that include...

51. The method according to claim 50, wherein the target motif is located within an intron region between two canonical exons.

52. The method according to claim 50, wherein the target motif is located within one of two canonical exons.

53. The method according to claim 50, wherein the target motif is located within a region that spans both introns and canonical exons.

54. The target proteins are 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, CATSPE1, 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,The method according to claim 50, selected from the group consisting of TFB1M, TM6SF1, TNK2, TOE1, TOR1B, TRAPPC6B, TRIP4, TRMT2A, TRMU, TRPV4, TTC19, TYMP, UMPS, UROD, WDR11, WDR62, WIPI1, WRAP53, XPO1, YY1AP1, and ZC3H14.

55. A method for regulating the expression of a target protein by cells having a preprocessed mRNA transcript (premRNA) encoding the target protein, wherein the premRNA is The exon contains an alternative nonsense mutation-dependent RNA degradation mechanism (NMD) exon, which includes an alternative 3' splice site upstream of the 3' splice site of the canonical exon and within the canonical exon, or downstream of the 3' splice site of the canonical exon and within an intron. A step of contacting a cell with a nonsense mutation-dependent RNA degradation mechanism selective exon (NSAE) modulator, wherein the nonsense mutation-dependent RNA degradation mechanism selective exon (NSAE) modulator modulates the processing of mRNA transcripts from preprocessed mRNA transcripts by modulating the splicing of premRNA at the 3' alternative splice site, and the splicing of premRNA at the 3' alternative splice site modulates the expression of a target protein. Methods that include...

56. The target proteins are ABCA5, ABCA7, ABCD1, ABR, ACAD9, ACAP1, ACTN4, ADAMTS13, AKR1E2, ALG3, ANKRD29, AP3M1, ASAP3, ATRX, BBS4, CATSPER1, CCDC40, CCDC88B, CD4, CES2, COL5A3, CPSF1, CSPP1, CTH, and DAB2. IP, DBN1, DDX51, DEAF1, DGKE, DMKN, DOCK8, DOK5, EIF2B5, ELAC2, ELP1, ETHE1, FANCA, FASTK, FPG S, GAS8, GCK, GGA1, GON4L, HELQ, HPS1, IL17RC, INVS, IRF3, KLKB1, LAMC3, LDAH, LIMS2, MALT1, MAP K13, MCAT, MCEE, MPI, MSTO1, NLE1, NLRC5, NOM1, NPR1, OSGEP, PABPC4, PCOLCE, PLD2, PNPO, POLE, PON2, PYCR1, RAD52, RHBDF2, RMND1, ROBO3, RPGRIP1, RTTN, SIK3, SLC12A7, SLC22A3, SLC25A37, S The method according to claim 55, selected from the group consisting of LC27A5, SMPD1, SNRPB, SP140, STAMBP, SULF2, SYNJ2, TAZ, TDRD7, TFB1M, TM6SF1, TOR1B, TRAPPC6B, TRIP4, TRMU, TTC19, TYMP, UMPS, WDR11, WIPI1, YY1AP1, and ZC3H14.

57. A method for regulating the expression of a target protein by cells having a preprocessed mRNA transcript (premRNA) encoding the target protein, wherein the premRNA is The exon contains an alternative nonsense mutation-dependent RNA degradation mechanism (NMD) exon, which includes an alternative 5' splice site downstream of the 5' splice site of the canonical exon and within the canonical exon, or upstream of the 5' splice site of the canonical exon and within the intron. A step of contacting a cell with a nonsense mutation-dependent RNA degradation mechanism selective exon (NSAE) modulator, wherein the nonsense mutation-dependent RNA degradation mechanism selective exon (NSAE) modulator modulates the processing of mRNA transcripts from preprocessed mRNA transcripts by modulating the splicing of premRNA at the 5' alternative splice site, and the splicing of premRNA at the 5' alternative splice site modulates the expression of a target protein. Methods that include...

58. The target proteins are ABCC3, ABCC5, ABCC8, ACOX2, ACSF3, ADAM17, ADAMTS13, ALAD, ANKS3, ANO4, AP3B2, AP5Z1, ARNTL, BBS2, BRD9, CALM3, CARS1, CASP9, and CD. 58, CHFR, CLCN2, CNOT3, CNTROB, CTF1, CYP3A5, DHDDS, DNHD1, ENTPD4, ESRRA, ESS2, ETAA1, FASTKD3, FREM1, GAS8, GGA3, GGT1, GLMN, GRB1 4, HDAC3, HP1BP3, HPS4, IDUA, IFT122, IMPDH1, KCTD3, KYAT1, MAP3K7, NBEAL2, NOP58, NPHP1, NUP188, PHKA2, PIDD1, PKD1, PLA2G6, PLD2, The method according to claim 57, selected from the group consisting of PLEKHG5, PRMT7, PRODH, PRPF3, PRPF4, RAD52, REXO1, RFX5, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIRT3, SKIV2L, SLC25A13, SLC2A13, SLC30A10, SLC30A9, SMTN, STXBP2, SYNGAP1, TBL2, TECPR2, TNK2, TOE1, TRMT2A, TRPV4, UROD, WDR62, WRAP53, and XPO1.

59. The method according to any one of claims 55 to 58, wherein a nonsense mutation-dependent RNA degradation mechanism selective exon (NSAE) modulator binds to a targeted portion of a preprocessed mRNA transcript.

60. The method according to any one of claims 55 to 59, wherein a nonsense mutation-dependent RNA degradation mechanism selective exon (NSAE) regulator binds to a factor involved in the splicing of NSAE or NMD exons.

61. The method according to any one of claims 55 to 60, wherein a nonsense mutation-dependent RNA degradation mechanism selective exon (NSAE) regulator inhibits the activity of a factor involved in NMD exon splicing.

62. The method according to any one of claims 55 to 61, wherein a nonsense mutation-dependent RNA degradation mechanism selective exon (NSAE) modulator interferes with the binding of factors involved in splicing NMD exons to a region of a preprocessed mRNA transcript targeting site.

63. The method according to any one of claims 50 to 62, wherein regulation of premRNA splicing increases the expression of a target protein.

64. The levels of target protein in cells were approximately 1.1 to 10 times, 1.5 to 10 times, 2 to 10 times, 3 to 10 times, 4 to 10 times, 1.1 to 5 times, 1.1 to 6 times, 1.1 to 7 times, 1.1 to 8 times, 1.1 to 9 times, 2 to 5 times, 2 to 6 times, and 2 to 7 times compared to the levels of processed mRNA encoding the target protein in control cells. The method according to claim 63, which increases by a factor of 2, approximately 2 to approximately 8, approximately 2 to approximately 9, approximately 3 to approximately 6, approximately 3 to approximately 7, approximately 3 to approximately 8, approximately 3 to approximately 9, approximately 4 to approximately 7, approximately 4 to approximately 8, approximately 4 to approximately 9, at least approximately 1.1, at least approximately 1.5, at least approximately 2, at least approximately 2.5, at least approximately 3, at least approximately 3.5, at least approximately 4, at least approximately 5, or at least approximately 10.

65. The method according to any one of claims 50 to 62, wherein the regulation of premRNA splicing increases the production of processed mRNA encoding a target protein.

66. The levels of processed mRNA encoding the target protein in cells exposed to the therapeutic agent were approximately 1.1 to 10 times, 1.5 to 10 times, 2 to 10 times, 3 to 10 times, 4 to 10 times, 1.1 to 5 times, and 1.1 to 6 times higher compared to the levels of processed mRNA encoding the target protein in control cells. The method according to claim 65, which increases to approximately 1.1 to approximately 7 times, approximately 1.1 to approximately 8 times, approximately 1.1 to approximately 9 times, approximately 2 to approximately 5 times, approximately 2 to approximately 6 times, approximately 2 to approximately 7 times, approximately 2 to approximately 8 times, approximately 2 to approximately 9 times, approximately 3 to approximately 6 times, approximately 3 to approximately 7 times, approximately 3 to approximately 8 times, approximately 3 to approximately 9 times, approximately 4 to approximately 7 times, approximately 4 to approximately 8 times, approximately 4 to approximately 9 times, at least approximately 1.1 times, at least approximately 1.5 times, at least approximately 2 times, at least approximately 2.5 times, at least approximately 3 times, at least approximately 3.5 times, at least approximately 4 times, at least approximately 5 times, or at least approximately 10 times.

67. The method according to any one of claims 50 to 66, wherein the target protein is a canonical isoform of a protein.

68. The method according to any one of claims 50 to 67, wherein the target protein is SynGAP1.

69. The target proteins are ABCA5, ABCA7, ABCC3, ABCC5, ABCC8, ABCD1, ABR, ACAD9, ACAP1, AC0X2, ACSF3, ACTN4, ADAM17, ADAMTS13, AKR1E2, ALAD, ALG3, ANKRD29,ANKS3, ANO4, AP3B2, AP3M1, AP5Z1, ARNTL, ASAP3, ATRX, BBS2, BBS4, BRD9, CALM3, CARS1, CASP9, CATSPE1, CCD40, CCD88B, CD4, CD58, CES2, CHFR, CLCN2, CNOT3, CNTROB, COL5A3, CPSF1, CSPP1, CTF1, CTH, CYP3A5, DAB2IP, DBN1, DDX51, DEAF1, DGKE, DHDD5, DMKN, DNHDI, DOCK8, DOK5, EIF2B5, ELAC2, ELPI, ENTPD4, ESRRA, ESS2, ETAAl, 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, NLRCS, 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, RTIN, RUFY3, SEMAB, SEMAF, SH2D3A, SIK3, SIRT3, SKIV2L, SLC2A13, SLC12A7, SLC22A3, SLC25A13, SLC25A37, SLC27A5, SLC30A9, SLC30A10, SMPD1, SMTN, SNRPE, SP140, STAMB, STXB2, SULF2, SYNGAP1, SYNJ2, TAZ, TBL2, TDRD7, TECPR2The method according to any one of claims 50 to 67, wherein the selected element is one of the group consisting of TFB1M, TM6SF1, TNK2, TOE1, TOR1B, TRAPPC6B, TRIP4, TRMT2A, TRMU, TRPV4, TTC19, TYMP, UMPS, UROD, WDR11, WDR62, WIPI1, WRAP53, XPO1, YY1AP1, and ZC3H14.

70. The method according to any one of claims 50 to 68, wherein the nonsense mutation-dependent RNA degradation mechanism selective exon (NSAE) regulator is the composition according to any one of claims 1 to 49.

71. A therapeutic agent comprising the composition according to any one of claims 1 to 49, and a pharmaceutical composition comprising pharmaceutically acceptable excipients and / or a delivery medium.

72. A method for treating or preventing a disease or condition in a subject requiring treatment or prevention of a disease or condition, comprising the step of administering the pharmaceutical composition according to claim 71 to the subject.

73. A method for treating or preventing a disease or condition in a subject requiring treatment or prevention of the disease or condition, (a) Nonsense mutation-dependent RNA degradation mechanism selective exon (NSAE) modulators that interact with target motifs in preprocessed mRNA transcripts to regulate the exclusion of NSAEs from processed mRNA transcripts and to regulate the inclusion of canonical exons in processed mRNA transcripts. And, NSAE, (i) only a portion of the canonical exon, or (ii) At least a portion of the canonical exon and the intron adjacent to the canonical exon NSAE modifiers, including, (b) pharmaceutically acceptable excipients and / or delivery media A step of administering a pharmaceutical composition containing the above to a subject. Includes, A method by which a disease or condition is treated or prevented in a subject by the administration of an NSAE modulator, thereby regulating the expression of a target protein translated from a processed mRNA transcript.

74. The target proteins are ABCA5, ABCA7, ABCC3, ABCC5, ABCC8, ABCD1, ABR, ACAD9, ACAP1, AC0X2, ACSF3, ACTN4, ADAM17, ADAMTS13, AKR1E2, ALAD, ALG3, ANKRD29, ANKS3, ANO4, AP3B2, AP3M1, AP5Z1, ARNTL, ASAP3, ATRX, BBS2, BBS4, BRD9, CALM3, CARS1, CASP9, CATSPE1, CCD40, CCD88B, CD4, CD58, CES2, CHFR, CLCN2, CNOT3, CNTROB, COL5A3, CPSF1, CSPP1, CTF1, CTH, CYP3A5, DAB2IP, DBN1, DDX51, DEAF1, DGKE, DHDDs, DMKN, DNHDI, DOCK8, DOK5, EIF2B5, ELAC2, ELPI, ENTPD4, ESRRA, ESS2, ETAAl, 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, NLRCS, NOM1, NOP58, NPHP1, NPR1, NUP188, OSGEP, PABPC4, PCOLCE, PHKA2, PIDDI, PKD1, PLA2G6, PLD2, PLEKHG5, PNPO, POLE, PON2, PRMT7, PRODH, PRPF3, PRPF4, PYCR1, RAD52, REXO1, RFX5, RHBDF2, RMND1, ROBO3, RPGRIP1, RTIN, RUFY3, SEM3B, SEM3F, 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、 The method according to claim 73, selected from the group consisting of TRIP4, TRMT2A, TRMU, TRPV4, TTC19, TYMP, UMPS, UROD, WDR11, WDR62, WIPI1, WRAP53, XPO1, YY1AP1, and ZC3H14.

75. A method for treating a disease or condition in a subject requiring treatment of a disease or condition by regulating the expression of a target protein in the cells of the subject, wherein the cells of the subject have a preprocessed mRNA transcript (premRNA) encoding the target protein, and the premRNA is (a) Canonical exons that are followed by a canonical intron adjacent to the 3' splice site of a canonical exon, and (b) Alternative nonsense mutation-dependent RNA degradation mechanism-inducing (NMD) exons containing an alternative 3' splice site upstream of the 3' splice site of the canonical exon and within the canonical exon, or downstream of the 3' splice site of the canonical exon and within the canonical intron. Includes, A step of bringing a therapeutic agent into contact with cells, wherein the therapeutic agent modulates the processing of mRNA transcripts from preprocessed mRNA transcripts by regulating the splicing of premRNA at the 3' alternative splice site, and the splicing of premRNA at the 3' alternative splice site modulates the expression of a target protein in the target cells. Methods that include...

76. The target proteins are ABCA5, ABCA7, ABCD1, ABR, ACAD9, ACAP1, ACTN4, ADAMTS13, AKR1E2, ALG3, ANKRD29, AP3M1, ASAP3, ATRX, BBS4, CATSPER1, CCDC40, CCDC88B, CD4, CES2, COL5A3, CPSF1, CSPP1, CTH, and DAB2. IP, DBN1, DDX51, DEAF1, DGKE, DMKN, DOCK8, DOK5, EIF2B5, ELAC2, ELP1, ETHE1, FANCA, FASTK, FPG S, GAS8, GCK, GGA1, GON4L, HELQ, HPS1, IL17RC, INVS, IRF3, KLKB1, LAMC3, LDAH, LIMS2, MALT1, MAP K13, MCAT, MCEE, MPI, MSTO1, NLE1, NLRC5, NOM1, NPR1, OSGEP, PABPC4, PCOLCE, PLD2, PNPO, POLE, PON2, PYCR1, RAD52, RHBDF2, RMND1, ROBO3, RPGRIP1, RTTN, SIK3, SLC12A7, SLC22A3, SLC25A37, S The method according to claim 75, selected from the group consisting of LC27A5, SMPD1, SNRPB, SP140, STAMBP, SULF2, SYNJ2, TAZ, TDRD7, TFB1M, TM6SF1, TOR1B, TRAPPC6B, TRIP4, TRMU, TTC19, TYMP, UMPS, WDR11, WIPI1, YY1AP1, and ZC3H14.

77. A method for treating a disease or condition in a subject requiring treatment of a disease or condition by regulating the expression of a target protein in the cells of the subject, wherein the cells of the subject have a preprocessed mRNA transcript (premRNA) encoding the target protein, and the premRNA is (a) a canonical exon preceded by a canonical intron adjacent to the 5' splice site of the canonical exon, and (b) Alternative nonsense mutation-dependent RNA degradation mechanism-inducing (NMD) exons containing an alternative 5' splice site downstream of the 5' splice site of the canonical exon and inside the canonical exon, or upstream of the 5' splice site of the canonical exon and inside the canonical intron. Includes, A step of bringing a therapeutic agent into contact with cells, wherein the therapeutic agent modulates the processing of mRNA transcripts from preprocessed mRNA transcripts by regulating the splicing of premRNA at the 5' alternative splice site, and the splicing of premRNA at the 5' alternative splice site modulates the expression of a target protein in the target cells. Methods that include...

78. The target proteins are ABCC3, ABCC5, ABCC8, ACOX2, ACSF3, ADAM17, ADAMTS13, ALAD, ANKS3, ANO4, AP3B2, AP5Z1, ARNTL, BBS2, BRD9, CALM3, CARS1, CASP9, CD58, CHFR, CLCN2, CNOT3, and CNTR. OB, CTF1, CYP3A5, DHDDS, DNHD1, ENTPD4, ESRRA, ESS2, ETAA1, FASTKD3, FREM1, GAS8, G GA3, GGT1, GLMN, GRB14, HDAC3, HP1BP3, HPS4, IDUA, IFT122, IMPDH1, KCTD3, KYAT1, MAP 3K7, NBEAL2, NOP58, NPHP1, NUP188, PHKA2, PIDD1, PKD1, PLA2G6, PLD2, PLEKHG5, PRMT 7, PRODH, PRPF3, PRPF4, RAD52, REXO1, RFX5, RUFY3, SEMA3B, SEMA3F, SH2D3A, SIRT3, SK The method according to claim 77, selected from the group consisting of IV2L, SLC25A13, SLC2A13, SLC30A10, SLC30A9, SMTN, STXBP2, SYNGAP1, TBL2, TECPR2, TNK2, TOE1, TRMT2A, TRPV4, UROD, WDR62, WRAP53, and XPO1.

79. The method according to any one of claims 72 to 78, wherein the disorder is autosomal dominant intellectual disability, epileptic encephalopathy, or autism.

80. The method according to any one of claims 72 to 79, wherein the disease or condition is caused by a deficiency in the amount or activity of a target protein.

81. The method according to any one of claims 72 to 80, wherein the therapeutic agent increases the level of processed mRNA encoding a target protein in cells.

82. The method according to any one of claims 72 to 81, wherein the therapeutic agent increases the expression of a target protein in cells.

83. The levels of processed mRNA encoding the target protein in cells exposed to the therapeutic agent were approximately 1.1 to 10 times, 1.5 to 10 times, 2 to 10 times, 3 to 10 times, 4 to 10 times, 1.1 to 5 times, 1.1 to 6 times, 1.1 to 7 times, 1.1 to 8 times, 1.1 to 9 times, 2 to 5 times, and 2 to 7 times, compared to the levels of processed mRNA encoding the target protein in control cells. The method according to any one of claims 72 to 82, which increases to 6 times, about 2 to about 7 times, about 2 to about 8 times, about 2 to about 9 times, about 3 to about 6 times, about 3 to about 7 times, about 3 to about 8 times, about 3 to about 9 times, about 4 to about 7 times, about 4 to about 8 times, about 4 to about 9 times, at least about 1.1 times, at least about 1.5 times, at least about 2 times, at least about 2.5 times, at least about 3 times, at least about 3.5 times, at least about 4 times, at least about 5 times, or at least about 10 times.

84. The level of the target protein in cells was approximately 1.1 to 10 times higher, or about 1.5 times higher, compared to the level of processed mRNA encoding the target protein in control cells. The method according to any one of claims 72 to 83, which increases by approximately 10 times, approximately 2 to approximately 10 times, approximately 3 to approximately 10 times, approximately 4 to approximately 10 times, approximately 1.1 to approximately 5 times, approximately 1.1 to approximately 6 times, approximately 1.1 to approximately 7 times, approximately 1.1 to approximately 8 times, approximately 1.1 to approximately 9 times, approximately 2 to approximately 5 times, approximately 2 to approximately 6 times, approximately 2 to approximately 7 times, approximately 2 to approximately 8 times, approximately 2 to approximately 9 times, approximately 3 to approximately 6 times, approximately 3 to approximately 7 times, approximately 3 to approximately 8 times, approximately 3 to approximately 9 times, approximately 4 to approximately 7 times, approximately 4 to approximately 8 times, approximately 4 to approximately 9 times, at least approximately 1.1 times, at least approximately 1.5 times, at least approximately 2 times, at least approximately 2.5 times, at least approximately 3 times, at least approximately 3.5 times, at least approximately 4 times, at least approximately 5 times, or at least approximately 10 times.

85. The method according to any one of claims 72 to 84, further comprising the step of evaluating the mRNA level or expression level of a target protein.

86. The method according to any one of claims 72 to 85, further comprising the step of evaluating the target genome with respect to at least one gene mutation associated with the disease.

87. The method according to claim 86, wherein at least one gene mutation is located within a locus of a disease-related gene.

88. The method according to claim 86, wherein at least one gene mutation is located within a locus associated with the expression of a disease-related gene.

89. The method according to claim 86, wherein at least one gene mutation is located within the SYNGAP1 gene locus.

90. The method according to claim 86, wherein at least one gene mutation is located within a locus associated with SYNGAP1 gene expression.

91. At least one gene mutation is located within the target gene locus, and the target gene locus is one of the following: 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, FR EM1, 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, The method according to claim 86, wherein the locus is selected from the group consisting of 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.

92. At least one gene mutation is located within a locus associated with target gene expression, and the target gene is 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, CS PP1, CTF1, CTH, CYP3A5, DAB2IP, DBN1, DDX51, DEAF1, DGKE, DHDDS, DMKN, DNH D1, DOCK8, DOK5, EIF2B5, ELAC2, ELP1, ENTPD4, ESRRA, ESS2, ETAA1, ETHE1, FANCA, FASTK, FASTKD3, FPGS, FREM1, GAS8, GCK, GGA1, GGA3, GGT1, GLMN, GON 4L, GRB14, HDAC3, HELQ, HP1BP3, HPS1, HPS4, IDUA, IFT122, IL17RC, IMPDH1 , INVS, IRF3, KCTD3, KLKB1, KYAT1, LAMC3, LDAH, LIMS2, MALT1, MAP3K7, MAPK 13, MCAT, MCEE, MPI, MSTO1, NBEAL2, NLE1, NLRC5, NOM1, NOP58, NPHP1, NPR1 , NUP188, OSGEP, PABPC4, PCOLCE, PHKA2, PIDD1, PKD1, PLA2G6, PLD2, PLEKHG 5, PNPO, POLE, PON2, PRMT7, PRODH, PRPF3, PRPF4, PYCR1, RAD52, REXO1, RFX 5, RHBDF2, RMND1, ROBO3, RPGRIP1, RTTN, RUFY3, SEMA3B, SEMA3F, SH2D3A, SI K3, SIRT3, SKIV2L, SLC2A13, SLC12A7, SLC22A3, SLC25A13, SLC25A37, SLC27 A5, SLC30A9, SLC30A10, SMPD1, SMTN, SNRPB, SP140, STAMBP, STXBP2, SULF2,The method according to claim 86, wherein the gene is one selected from the group consisting of 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.

93. The method according to any one of claims 72 to 92, wherein the subject is a human.

94. The method according to any one of claims 72 to 92, wherein the subject is a non-human animal.

95. The method according to any one of claims 72 to 93, wherein the subject is a fetus, embryo, or child.

96. The method according to any one of claims 72 to 95, wherein one or more cells are present ex vivo, in tissue, or in an ex vivo organ.

97. The method according to any one of claims 72 to 96, wherein the therapeutic agent is administered to the subject by intraventricular injection, intraperitoneal injection, intramuscular injection, intrathecal injection, subcutaneous injection, oral administration, bursal injection, intravitreous administration, subretinal injection, topical application, implantation, or intravenous injection.

98. A therapeutic agent for use in the method according to any one of claims 72 to 97.

99. A pharmaceutical composition comprising the therapeutic agent and pharmaceutically acceptable excipients described in claim 98.

100. A method for treating a subject requiring treatment, comprising the step of administering the pharmaceutical composition according to claim 99 to the subject by intraventricular injection, intraperitoneal injection, intramuscular injection, intrathecal injection, subcutaneous injection, oral administration, bursal injection, intravitreous administration, subretinal injection, topical application, implantation, or intravenous injection.

Images