Methods and compositions for modulating splicing and translation

Abstract

To provide a method for modulating the expression of a target peptide sequence, thereby providing a method for treating a disease or condition and a therapeutic agent.SOLUTION: A method of modulating expression of a target peptide sequence by a cell having a pre-mRNA that encodes the target peptide sequence and comprises an inefficient translation region, the method comprising contacting the cell with a therapeutic agent that binds to a targeted region of the pre-mRNA encoding the target peptide sequence. The therapeutic agent is preferably an antisense oligonucleotide of a specific sequence consisting of 18 nucleobases, incorporating a backbone modification including 2'-O-methoxyethyl (2'MOE)-modified sugar moieties and phosphorothioate linkages.SELECTED DRAWING: None

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Application No. 62 / 838,010, filed April 24, 2019, which is incorporated herein by reference in its entirety.

[0002] Reference to sequence listing This application contains a Sequence Listing that has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy was created on April 22, 2020, is named 47991-725_601_SL.txt, and is 4,882,023 bytes in size. [Background technology]

[0003] Alternative splicing events in genes can result in non-productive or less productive mRNA transcripts. Therapeutic agents that can target alternative splicing events in genes can regulate the expression level 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

[0004] In some aspects, disclosed herein are methods of modulating expression of a target peptide sequence by a cell having a pre-mRNA encoding the target peptide sequence and comprising an inefficiently translated region, the method comprising contacting the cell with a therapeutic agent that binds to a targeted region of the pre-mRNA encoding the target peptide sequence, thereby modulating splicing of the inefficiently translated region from the pre-mRNA encoding the target peptide sequence, thereby modulating the level of a first processed mRNA that does not comprise the inefficiently translated region and encodes a first protein comprising the target peptide sequence, thereby modulating expression of the target peptide sequence in the cell, wherein the first processed mRNA has a higher translation efficiency for producing the first protein comprising the target peptide sequence in the cell compared to the translation efficiency of the second processed mRNA for producing a second protein comprising the target peptide sequence, and the second processed mRNA comprises the inefficiently translated region.

[0005] In some aspects, disclosed herein are methods of treating a disease or condition in a subject in need thereof by modulating expression of a target peptide sequence in the subject's cells, the cells having a pre-mRNA that encodes the target peptide sequence and that includes an inefficiently translated region, the method comprising contacting the subject's cells with a therapeutic agent that modulates splicing of the inefficiently translated region from the pre-mRNA encoding the target peptide sequence, the therapeutic agent binding to the targeted region of the pre-mRNA, thereby modulating splicing of the inefficiently translated region from the pre-mRNA, thereby modulating the level of a first processed mRNA that does not include the inefficiently translated region and encodes a first protein that includes the target peptide sequence, thereby modulating expression of the target peptide sequence in the subject's cells, wherein the first processed mRNA has a higher translation efficiency for producing the first protein that includes the target peptide sequence in the cell compared to the translation efficiency of the second processed mRNA for producing a second protein that includes the target peptide sequence, the second processed mRNA including the inefficiently translated region.

[0006] In some cases, the second processed mRNA contains an inefficiently translated region or The pre-mRNA encoding the target peptide sequence includes a first start codon, a second start codon, and a premature termination codon (PTC) located downstream of the first start codon and upstream of the second start codon, and the inefficiently translated region includes the premature termination codon (PTC) and the second start codon. In some cases, the inefficiently translated region includes a region encoding a proline-rich peptide sequence.

[0007] In some aspects, disclosed herein are methods of regulating expression of a target peptide sequence by a cell having a pre-mRNA that encodes the target peptide sequence and that includes a first start codon, a second start codon, and a premature termination codon (PTC) located downstream of the first start codon and upstream of the second start codon, the method comprising contacting the cell with a therapeutic agent that binds to a targeted portion of the pre-mRNA that encodes the target peptide sequence, thereby modulating splicing of the PTC and second start codon from the pre-mRNA, thereby modulating the level of a first processed mRNA that encodes a first protein that does not include the PTC and second start codon and that includes the target peptide sequence, thereby modulating expression of the target peptide sequence in the cell.

[0008] In some aspects, disclosed herein are methods of treating a disease or condition in a subject in need thereof by modulating expression of a target peptide sequence in the subject's cells, the cells having a pre-mRNA that encodes the target peptide sequence and that includes a first start codon, a second start codon, and a premature termination codon (PTC) located downstream of the first start codon and upstream of the second start codon, the method comprising contacting the subject's cells with a therapeutic agent that modulates splicing of the PTC and the second start codon from the pre-mRNA encoding the target peptide sequence, the therapeutic agent binding to the targeted region of the pre-mRNA, thereby modulating splicing of the PTC and the second start codon from the pre-mRNA, thereby modulating the level of a first processed mRNA that encodes a first protein that does not include the PTC and second start codon and that includes the target peptide sequence, thereby modulating expression of the target peptide sequence in the subject's cells.

[0009] In some cases, the target peptide sequence has at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 750, or 1000 amino acids. In some cases, the therapeutic agent is a small molecule. In some cases, the therapeutic agent is an antisense oligomer (ASO) that is complementary to a targeted region of a pre-mRNA. In some cases, the therapeutic agent is an ASO that 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 a targeted region of a pre-mRNA encoding the target peptide sequence. In some cases, at least a portion of the targeted region of the pre-mRNA is upstream of an exon containing an inefficiently translated region or a PTC and a second start codon. In some cases, at least a portion of the targeted region of the pre-mRNA is downstream of an exon containing an inefficiently translated region or a PTC and a second start codon. In some cases, at least a portion of the targeted region of the pre-mRNA is within an inefficiently translated region or an exon containing a PTC and a second start codon. In some cases, the cell has a second processed mRNA that contains the sequence of the first processed mRNA, the PTC, and the second start codon and encodes a second protein containing the target peptide sequence. In some cases, both the first processed mRNA and the second processed mRNA are splicing products of the pre-mRNA in the cell. In some cases, the second processed mRNA contains the sequence of the first processed mRNA, the PTC, and the second start codon. In some cases, the PTC and the second start codon are at least 2 nt apart on the pre-mRNA. In some cases, the PTC and the second start codon are at most 75 nt apart on the pre-mRNA. In some cases, the PTC and the second start codon are spaced apart by 2 nt to 75 nt, 5 nt to 70 nt, 10 nt to 65 nt, 15 nt to 60 nt, 20 nt to 55 nt, 25 nt to 50 nt, 30 nt to 45 nt, 40 nt to 50 nt, 45 nt to 55 nt, 50 nt to 60 nt, 55 nt to 70 nt, or 60 nt to 75 nt on the pre-mRNA. In some cases, the PTC and the second start codon are spaced apart by 2 nt to 75 nt on the pre-mRNA.

[0010] In some cases, a first protein comprising a target peptide sequence is translated starting from a first start codon on the first processed mRNA, and a second protein is translated starting from a second start codon on the second processed mRNA. In some cases, the first processed mRNA has a higher translation efficiency for producing the first protein compared to the translation efficiency of the second processed mRNA for producing the second protein.

[0011] In some cases, the exclusion of inefficiently translated regions or the exclusion of PTCs and second start codons from the pre-mRNA encoding the target peptide sequence is increased. In some cases, the therapeutic agent increases the level of the first processed mRNA encoding the target peptide sequence in the cell. In some cases, the therapeutic agent increases the level of the target peptide sequence in the cell.

[0012] In some cases, the target peptide sequence is a portion of a full-length protein. In some cases, the target peptide sequence produced is a fully functional protein. In some cases, the target peptide sequence is the N-terminal portion of a full-length protein. In some cases, the target peptide sequence is encoded by a portion of the pre-mRNA upstream of the inefficiently translated region. In some cases, the inefficiently translated region is in the 3' untranslated region (3'UTR) of the second processed mRNA.

[0013] In some cases, the target peptide sequence is the C-terminal portion of a full-length protein. In some cases, the target peptide sequence is encoded by an inefficiently translated region or a portion of the pre-mRNA downstream of the PTC.

[0014] In some cases, the target peptide sequence is a portion of an MeCP2 protein isoform. In some cases, the target peptide sequence is translated from a sequence selected from the group consisting of SEQ ID NOs: 32-34. In some cases, the therapeutic agent decreases the level of the e2 isoform of MeCP2 mRNA and increases the level of the e1 isoform of MeCP2 mRNA in a cell. In some cases, the therapeutic agent decreases the level of the e2 isoform of MeCP2 protein and increases the level of the e1 isoform of MeCP2 protein in a cell. In some cases, the pre-mRNA comprises a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to any one selected from the group consisting of SEQ ID NOs: 2-27. In some cases, the therapeutic agent binds to a targeted region of the MeCP2 pre-mRNA, the targeted region being within a sequence selected from the group consisting of SEQ ID NOs: 28-31. In some cases, the therapeutic agent binds to a targeted region of MeCP2 pre-mRNA, the targeted region being within the sequence of SEQ ID NO: 28. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 28-31. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 28-31. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having 100% sequence identity to SEQ ID NO: 28. In some cases, the therapeutic agent is an antisense oligomer having a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 35-129. In some cases, the therapeutic agent is an antisense oligomer having a sequence having 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 35-129. In some cases, the disease or condition is Rett syndrome.

[0015] In some cases, the target peptide sequence is selected from the group consisting of ACIN1, ACTN1, ACTN2, ADH4, AKR1C3, ALDH1A2, ALG8, AMPD2, AMT, ANKRD11, ANKS3, APOL4, APPL1, ARCN1, ARMC8, ARNTL, BOC, BRCA1, C8B, CALM1, CALM3, CASP5, CAST, CEP19, CEP57, CHEK1, CIB2, COX4I1, DCLRE1C, DECR1, DHFR, DKK2, DLG2, DOK2, DPF3, DTNA, DYRK1A, FOLH1, FUZ, GANAB, GEMIN4, GGA3, GOSR2, GPM6A, G RB10, GSN, HDAC8, HIVEP1, HK1, IFNGR1, IKBKB, ISCU, KARS, KIAA0319, KIAA0586, KIZ, KLK6, LMNA, LMNTD1, LRRC 7, LRTOMT, LZTFL1, MAGI2, MECP2, MERTK, MFSD2A, MLF1, MOB1B, MSRB3, NR1I3, NT5C3A, NUTM1, OTOF, PDCD4, PDPK 1, PHKB, PIGA, PLOD2, POLR2F, PPP6C, PRKN, PRUNE1, PSMA6, PSMC3IP, PTPN1, RAB11B, RBPJ, RNPS1, RPL5, RPS20, The therapeutic agent is a portion of a protein selected from the group consisting of SECISBP2, SELENBP1, SEPT11, SIRT2, SLC25A26, SMARCE1, SMC1A, SMG1, SPACA7, SPRED1, SRP54, SRPK2, STK36, STRADA, SUMO1, TBL1XR1, TLR8, TXNRD2, UBE3A, UFM1, WAC, WDR81, YME1L1, and ZMYND10. In some cases, the therapeutic agent increases the level of a first processed mRNA encoding a first protein having a sequence selected from the group consisting of SEQ ID NOs: 8096-8297 and decreases the level of a second processed mRNA encoding a second protein having a sequence selected from the group consisting of SEQ ID NOs: 332-533.

[0016] In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of a sequence selected from the group consisting of SEQ ID NOs: 130-331. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of a sequence selected from the group consisting of SEQ ID NOs: 130-331.

[0017] In some cases, the targeted regions of the pre-mRNA were GRCh38 / hg38:chr14 23071186, GRCh38 / hg38:chr14 68925672, GRCh38 / hg38:chr1 236735635, GRCh38 / hg38:chr4 99143305, GRCh38 / hg38:chr4 99143305, GRCh38 / hg38:chr6 32182698, GRCh38 / hg38:chr10 5077900, GRCh38 / hg38:chr15 58058108, GRCh38 / hg38:chr11 78138767, GRCh38 / hg38:c hr1 109620914、GRCh38 / hg38:chr3 49422257、GRCh38 / hg38:chr3 49422257、GRCh38 / hg38:chr3 49422257、GRCh38 / hg38:chr16 89317078、GRCh38 / hg38:chr16 89317078、GRCh38 / hg38:chr16 89317078、GRCh38 / hg38:chr16 89317075、GRCh38 / hg38:chr16 89317078、GRCh38 / hg38:chr16 89317078、GRCh38 / hg38:chr16 89317075、GRCh38 / hg38:chr16 89317078、GRCh38 / hg38:chr16 89317078、GRCh38 / hg38:chr16 89317075、GRCh38 / hg38:chr16 89317078、GRCh38 / hg38:chr16 89317075、GRCh38 / hg38:chr16 89317078、GRCh38 / hg38:chr16 89317078、GRCh38 / hg38:chr16 4726780、GRCh38 / hg38:chr22 36201796、GRCh38 / hg38:chr3 57230714、GRCh38 / hg38:chr11 118573620、GRCh38 / hg38:chr3 138188455、GRCh38 / hg38:chr3 138188455、GRCh38 / hg38:chr11 13355226、GRCh38 / hg38:chr11 13355226、GRCh38 / hg38:chr3 113249722、GRCh38 / hg38:chr3 113249722、GRCh38 / hg38:chr3 113249722、GRCh38 / hg38:chr3 113249722、GRCh38 / hg38:chr17 43106533、GRCh38 / hg38:chr17 43106533、GRCh38 / hg38:chr1 56959657、GRCh38 / hg38:chr1 56959657、GRCh38 / hg38:chr14 90398991、GRCh38 / hg38:chr19 46608205、GRCh38 / hg38:chr11 105009053、GRCh38 / hg38:chr596726754、GRCh38 / hg38:chr3 196708727、GRCh38 / hg38:chr11 95795516、GRCh38 / hg38:chr11 125627607、GRCh38 / hg38:chr15 78111276、GRCh38 / hg38:chr15 78111276、GRCh38 / hg38:chr16 85804941、GRCh38 / hg38:chr10 14939869、GRCh38 / hg38:chr8 90005292、GRCh38 / hg38:chr8 90015541、GRCh38 / hg38:chr5 80649494、GRCh38 / hg38:chr4 106925949、GRCh38 / hg38:chr11 83651930、GRCh38 / hg38:chr8 21910857、GRCh38 / hg38:chr14 72879947、GRCh38 / hg38:chr14 72879947、GRCh38 / hg38:chr18 34757158、GRCh38 / hg38:chr18 34757158、GRCh38 / hg38:chr21 37456130、GRCh38 / hg38:chr11 49206874、GRCh38 / hg38:chr19 49812335、GRCh38 / hg38:chr11 62639110、GRCh38 / hg38:chr17 749909、GRCh38 / hg38:chr17 75243570、GRCh38 / hg38:chr17 46924261、GRCh38 / hg38:chr4 175812249、GRCh38 / hg38:chr7 50710990、GRCh38 / hg38:chr9 121300056、GRCh38 / hg38:chrX 72572109、GRCh38 / hg38:chr6 12020248、GRCh38 / hg38:chr10 69300769、GRCh38 / hg38:chr10 69300769、GRCh38 / hg38:chr6 137215377、GRCh38 / hg38:chr8 42272083、GRCh38 / hg38:chr8 42272083、GRCh38 / hg38:chr8 42272083、GRCh38 / hg38:chr8 42272083、GRCh38 / hg38:chr12 108564060、GRCh3 8 / hg38:chr16 75644462、GRCh38 / hg38:chr16 75644462、GRCh38 / hg38:chr6 24600709、GRCh38 / hg38:chr14 58429363、GRCh38 / hg38:chr14 58429363、GRCh38 / hg38:chr20 21132097、GRCh38 / hg38:chr19 50963549、GRCh38 / hg38:chr1 156126736、GRCh38 / hg38:chr12 25552989、GRCh38 / hg38:chr12 25552989、GRCh38 / hg38:chr1 69716142、GRCh38 / hg38:chr11 72089029、GRCh38 / hg38:chr11 72089029、GRCh38 / hg38:chr11 72089029、GRCh38 / hg38:chr11 72089029、GRCh38 / hg38:chr11 72089029、GRCh38 / hg38:chr11 72089029、GRCh38 / hg38:chr11 72089029、GRCh38 / hg38:chr11 72089029、GRCh38 / hg38:chr11 72089029、GRCh38 / hg38:chr11 72089029、GRCh38 / hg38:chr11 72089029、GRCh38 / hg38:chr3 45838051、GRCh38 / hg38:chr7 78554671、GRCh38 / hg38:chrX 154092307、GRCh38 / hg38:chrX 154092307、GRCh38 / hg38:chr2 111944960、GRCh38 / hg38:chr1 39965211、GRCh38 / hg38:chr3 158592434、GRCh38 / hg38:chr3 158592434、GRCh38 / hg38:chr3 158592434、GRCh38 / hg38:chr3 158592434、GRCh38 / hg38:chr3 158592434、GRCh38 / hg38:chr4 70950700、GRCh38 / hg38:chr12 65308529、GRCh38 / hg38:chr1 161236598、GRCh38 / hg38:chr1 161236598、GRCh38 / hg38:chr1 161236598、GRCh38 / hg38:chr1 161236598、GRCh38 / hg38:chr1 161236598、GRCh38 / hg38:chr1 161236598、GRCh38 / hg38:chr1 161236598、GRCh38 / hg38:chr1 161236598、GRCh38 / hg38:chr1 161236598、GRCh38 / hg38:chr1 161236598、GRCh38 / hg38:chr1 161236598、GRCh38 / hg38:chr1 161236598、GRCh38 / hg38:chr1161236598、GRCh38 / hg38:chr7 33035988、GRCh38 / hg38:chr7 33035988、GRCh38 / hg38:chr15 34345857、GRCh38 / hg38:chr2 26477749、GRCh38 / hg38:chr2 26477749、GRCh38 / hg38:chr10 110876670、GRCh38 / hg38:chr16 2566356、GRCh38 / hg38:chr16 47463899、GRCh38 / hg38:chr16 47463882、GRCh38 / hg38:chrX 15331992、GRCh38 / hg38:chrX 15331992、GRCh38 / hg38:chr3 146124229、GRCh38 / hg38:chr22 37958374、GRCh38 / hg38:chr9 125172001、GRCh38 / hg38:chr6 162262765、GRCh38 / hg38:chr1 151027233、GRCh38 / hg38:chr14 35308914、GRCh38 / hg38:chr17 42573623、GRCh38 / hg38:chr20 50564969、GRCh38 / hg38:chr19 8402086、GRCh38 / hg38:chr4 26320700、GRCh38 / hg38:chr4 26320700、GRCh38 / hg38:chr16 2264760、GRCh38 / hg38:chr16 2264760、GRCh38 / hg38:chr16 2264760、GRCh38 / hg38:chr16 2264760、GRCh38 / hg38:chr1 92833545、 GRCh38 / hg38:chr8 56073768、GRCh38 / hg38:chr9 89325427、GRCh38 / hg38:chr1 151369978、GRCh38 / hg38:chr1 151369978、GRCh38 / hg38:chr4 76995781、GRCh38 / hg38:chr19 38893867、GRCh38 / hg38:chr19 38893867、GRCh38 / hg38:chr19 38893867、 GRCh38 / hg38: chr19 38893867, GRCh38 / hg38: chr19 38893867, GRCh38 / hg38: chr3 66243203, GRCh38 / hg38: chr3 66243203, GRCh38 / hg38: chr17 40644459, GRCh38 / hg38: chrX 53422040, GRCh38 / hg38: chr16 18900044, GRCh38 / hg38: chr13 112382278, GRCh38 / hg38: chr15 38299373, GRCh38 / hg38: chr14 35000936, GRCh38 / hg38: chr7 105268869, GRCh38 / hg38: chr2 218673665, GRCh38 / hg38: chr17 63714108, GRCh38 / hg38: chr17 63714108, GRCh38 / hg38: chr17 63714108, GRCh38 / hg38: chr17 63714108, GRCh38 / hg38: chr17 63714108, GRCh38 / hg38: chr17 63714108, GRCh38 / hg38: chr17 63714108, GRCh38 / hg38: chr17 63714108, GRCh38 / hg38: chr17 63714108, GRCh38 / hg38: chr2 202214429, GRCh38 / hg38: chr3 177065022, GRCh38 / hg38: chr3 177065022, GRCh38 / hg38: chr3 177065022, GRCh38 / hg38: chr3 177065022, GRCh38 / hg38: chrX 12910306, GRCh38 / hg38: chr22 19880945, GRCh38 / hg38: chr15 25408684, GRCh38 / hg38: chr15 25408684, GRCh38 / hg38: chr13 38349999, GRCh38 / hg38: chr10 28535562, GRCh38 / hg38: chr17 1727990, GRCh38 / hg38: chr10 27153281, and GRCh38 / hg38: chr350345232, or up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of a genomic site selected from the group consisting of:

[0018] In some cases, the targeted regions of the pre-mRNA were GRCh38 / hg38:chr14 23071186, GRCh38 / hg38:chr14 68925672, GRCh38 / hg38:chr1 236735635, GRCh38 / hg38:chr4 99143305, GRCh38 / hg38:chr4 99143305, GRCh38 / hg38:chr6 32182698, GRCh38 / hg38:chr10 5077900, GRCh38 / hg38:chr15 58058108, GRCh38 / hg38:chr11 78138767, and GRCh38 / hg38:chr1 109620914, GRCh38 / hg38:chr3 49422257, GRCh38 / hg38:chr3 49422257, GRCh38 / hg38:chr3 49422257, GRCh38 / hg38:chr16 89317078, GRCh38 / hg38:chr16 89317078, GRCh38 / hg38:chr16 89317078, GRCh38 / hg38:chr16 89317075, GRCh38 / hg38:chr16 89317078, GRCh38 / hg38:chr16 89317078, GRCh38 / hg38:chr16 89317075, GRCh38 / hg38:chr16 89317078, GRCh38 / hg38: chr16 89317078、GRCh38 / hg38:chr16 89317075、GRCh38 / hg38:chr16 89317078、GRCh38 / hg38:chr16 89317075、GRCh38 / hg38:chr16 89317078、GRCh38 / hg38:chr16 89317078、GRCh38 / hg38:chr16 4726780、GRCh38 / hg38:chr22 36201796、GRCh38 / hg38:chr3 57230714、GRCh38 / hg38:chr11 118573620、GRCh38 / hg38:chr3 138188455、GRCh38 / hg38:chr3 138188455、GRCh38 / hg38:chr11 13355226、GRCh38 / hg38:chr11 13355226、GRCh38 / hg38:chr3 113249722、GRCh38 / hg38:chr3 113249722、GRCh38 / hg38:chr3 113249722、GRCh38 / hg38:chr3 113249722、GRCh38 / hg38:chr17 43106533、GRCh38 / hg38:chr17 43106533、GRCh38 / hg38:chr1 56959657、GRCh38 / hg38:chr1 56959657、GRCh38 / hg38:chr14 90398991、GRCh38 / hg38:chr19 46608205、GRCh38 / hg38:chr11 105009053、GRCh38 / hg38:chr5 96726754、GRCh38 / hg38:chr3 196708727、GRCh38 / hg38:chr11 95795516、GRCh38 / hg38:chr11 125627607、GRCh38 / hg38:chr15 78111276、GRCh38 / hg38:chr15 78111276、GRCh38 / hg38:chr16 85804941、GRCh38 / hg38:chr10 14939869、GRCh38 / hg38:chr8 90005292、GRCh38 / hg38:chr8 90015541、GRCh38 / hg38:chr5 80649494、GRCh38 / hg38:chr4 106925949、GRCh38 / hg38:chr11 83651930、GRCh38 / hg38:chr8 21910857、GRCh38 / hg38:chr14 72879947、GRCh38 / hg38:chr14 72879947、GRCh38 / hg38:chr18 34757158、GRCh38 / hg38:chr18 34757158、GRCh38 / hg38:chr21 37456130、GRCh38 / hg38:chr11 49206874、GRCh38 / hg38:chr19 49812335、GRCh38 / hg38:chr11 62639110、GRCh38 / hg38:chr17 749909、GRCh38 / hg38:chr17 75243570、GRCh38 / hg38:chr17 46924261、GRCh38 / hg38:chr4 175812249、GRCh38 / hg38:chr7 50710990、GRCh38 / hg38:chr9 121300056、GRCh38 / hg38:chrX 72572109、GRCh38 / hg38:chr6 12020248、GRCh38 / hg38:chr10 69300769、GRCh38 / hg38:chr10 69300769、GRCh38 / hg38:chr6 137215377、GRCh38 / hg38:chr8 42272083、GRCh38 / hg38:chr8 42272083、GRCh38 / hg38:chr8 42272083、GRCh38 / hg38:chr8 42272083、GRCh38 / hg38:chr12 108564060、GRCh38 / hg38:chr16 75644462、GRCh38 / hg38:chr16 75644462、GRCh38 / hg38:chr6 24600709、GRCh38 / hg38:chr14 58429363、GRCh38 / hg38:chr14 58429363、GRCh38 / hg38:chr20 21132097、GRCh38 / hg38:chr19 50963549、GRCh38 / hg38:chr1 156126736、GRCh38 / hg38:chr12 25552989、GRCh38 / hg38:chr12 25552989、GRCh38 / hg38:chr1 69716142、GRCh38 / hg38:chr11 72089029、GRC h38 / hg38:chr11 72089029、GRCh38 / hg38:chr11 72089029、GRCh38 / hg38:chr11 72089029、GRCh38 / hg38:chr11 72089029、GRCh38 / hg38:chr11 72089029、GRCh38 / hg38:chr11 72089029、GRCh38 / hg38:chr11 72089029、GRCh38 / hg38:chr11 72089029、GRCh38 / hg38:chr11 72089029、GRCh38 / hg38:chr11 72089029、GRCh38 / hg38:chr3 45838051、GRCh38 / hg38:chr7 78554671、GRCh38 / hg38:chrX 154092307、GRCh38 / hg38:chrX 154092307、GRCh38 / hg38:chr2 111944960、GRCh38 / hg38:chr1 39965211、GRCh38 / hg38:chr3 158592434、GRCh38 / hg38:chr3 158592434、GRCh38 / hg38:chr3 158592434、GRCh38 / hg38:chr3 158592434、GRCh38 / hg38:chr3 158592434、GRCh38 / hg38:chr4 70950700、GRCh38 / hg38:chr12 65308529、GRCh38 / hg38:chr1 161236598、GRCh38 / hg38:chr1 161236598、GRCh38 / hg38:chr1 161236598、GRCh38 / hg38:chr1 161236598、GRCh38 / hg38:chr1 161236598、GRCh38 / hg38:chr1 161236598、GRCh38 / hg38:chr1 161236598、GRCh38 / hg38:chr1 161236598、GRCh38 / hg38:chr1 161236598、GRCh38 / hg38:chr1 161236598、GRCh38 / hg38:chr1 161236598、GRCh38 / hg38:chr1 161236598、GRCh38 / hg38:chr1 161236598、GRCh38 / hg38:chr733035988、GRCh38 / hg38:chr7 33035988、GRCh38 / hg38:chr15 34345857、GRCh38 / hg38:chr2 26477749、GRCh38 / hg38:chr2 26477749、GRCh38 / hg38:chr10 110876670、GRCh38 / hg38:chr16 2566356、GRCh38 / hg38:chr16 47463899、GRCh38 / hg38:chr16 47463882、GRCh38 / hg38:chrX 15331992、GRCh38 / hg38:chrX 15331992、GRCh38 / hg38:chr3 146124229、GRCh38 / hg38:chr22 37958374、GRCh38 / hg38:chr9 125172001、GRCh38 / hg38:chr6 162262765、GRCh38 / hg38:chr1 151027233、GRCh38 / hg38:chr14 35308914、GRCh38 / hg38:chr17 42573623、GRCh38 / hg38:chr20 50564969、GRCh38 / hg38:chr19 8402086、GRCh38 / hg38:chr4 26320700、GRCh38 / hg38:chr4 26320700、GRCh38 / hg38:chr16 2264760、GRCh38 / hg38:chr16 2264760、GRCh38 / hg38:chr16 2264760、GRCh38 / hg38:chr16 2264760、GRCh38 / hg38:chr1 92833545、GRCh38 / hg38:chr8 56073768、GRCh38 / hg38:chr9 89325427、GRCh38 / hg38:chr1 151369978、GRCh38 / hg38:chr1 151369978、GRCh38 / hg38:chr4 76995781、GRCh38 / hg38:chr19 38893867、GRCh38 / hg38:chr19 38893867、GRCh38 / hg38:chr19 38893867、GRCh38 / hg38:chr19 38893867、GRCh38 / hg38:chr19 38893867、GRCh38 / hg38:chr366243203、GRCh38 / hg38:chr3 66243203、G RCh38 / hg38: chr17 40644459, GRCh38 / hg38: chrX 53422040, GRCh38 / hg38: chr16 18900044, GRCh38 / hg38: chr13 112382278, GRCh38 / hg38: chr15 38299373, GRCh38 / hg38: chr14 35000936, GRCh38 / hg38: chr7 105268869, GRCh38 / hg38: chr2 218673665, GRCh38 / hg38: chr17 63714108, GRCh38 / hg38: chr17 63714108, GRCh38 / hg38: chr17 63714108, GRCh38 / hg38: chr17 63714108, GRCh38 / hg38: chr17 63714108, GRCh38 / hg38: chr17 63714108, GRCh38 / hg38: chr17 63714108, GRCh38 / hg38: chr17 63714108, GRCh38 / hg38: chr17 63714108, GRCh38 / hg38: chr2 202214429, GRCh38 / hg38: chr3 177065022, GRCh38 / hg38: chr3 177065022, GRCh38 / hg38: chr3 177065022, GRCh38 / hg38: chr3 177065022, GRCh38 / hg38: chrX 12910306, GRCh38 / hg38: chr22 19880945, GRCh38 / hg38: chr15 25408684, GRCh38 / hg38: chr15 25408684, GRCh38 / hg38: chr13 38349999, GRCh38 / hg38: chr10 28535562, GRCh38 / hg38: chr17 1727990, GRCh38 / hg38: chr10 27153281, and GRCh38 / hg38: chr350345232.

[0019] In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of a sequence selected from the group consisting of SEQ ID NOs: 130-331. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of a sequence selected from the group consisting of SEQ ID NOs: 130-331.

[0020] In some cases, the targeted regions of the pre-mRNA were GRCh38 / hg38:chr14 23071125, GRCh38 / hg38:chr14 68925558, GRCh38 / hg38:chr1 236735720, GRCh38 / hg38:chr4 99143166, GRCh38 / hg38:chr4 99143166, GRCh38 / hg38:chr6 32182568, GRCh38 / hg38:chr10 5077977, GRCh38 / hg38:chr15 58058012, GRCh38 / hg38:chr11 78138710, and GRCh38 / hg38:chr1 109621266, GRCh38 / hg38:chr3 49422104, GRCh38 / hg38:chr3 49422104, GRCh38 / hg38:chr3 49422104, GRCh38 / hg38:chr16 89316933, GRCh38 / hg38:chr16 89316933, GRCh38 / hg38:ch r16 89316933、GRCh38 / hg38:chr16 89316933、GRCh38 / hg38:chr16 89316933、GRCh38 / hg38:chr16 89316933、GRCh38 / hg38:chr16 89316933、GRCh38 / hg38:chr16 89316933、GRCh38 / hg38:chr16 89316933、GRCh38 / hg38:chr16 89316933、GRCh38 / hg38:chr16 89316933、GRCh38 / hg38:chr16 89316933、GRCh38 / hg38:chr16 89316933、GRCh38 / hg38:chr16 89316933、GRCh38 / hg38:chr16 4726659、GRCh38 / hg38:chr22 36201700、GRCh38 / hg38:chr3 57230767、GRCh38 / hg38:chr11 118573783、GRCh38 / hg38:chr3 138188530、GRCh38 / hg38:chr3 138188530、GRCh38 / hg38:chr11 13355296、GRCh38 / hg38:chr11 13355296、GRCh38 / hg38:chr3 113249899、GRCh38 / hg38:chr3 113249899、GRCh38 / hg38:chr3 113249899、GRCh38 / hg38:chr3 113249899、GRCh38 / hg38:chr17 43106456、GRCh38 / hg38:chr17 43106456、GRCh38 / hg38:chr1 56959529、GRCh38 / hg38:chr1 56959529、GRCh38 / hg38:chr14 90399087、GRCh38 / hg38:chr19 46608340、GRCh38 / hg38:chr11 105008807、GRCh38 / hg38:chr5 96726859、GRCh38 / hg38:chr3 196708528、GRCh38 / hg38:chr11 95795559、GRCh38 / hg38:chr11 125627830、GRCh38 / hg38:chr15 78111165、GRCh38 / hg38:chr15 78111165、GRCh38 / hg38:chr16。 85805104、GRCh38 / hg38:chr10 14939810、GRCh38 / hg38:chr8 90005369、GRCh38 / hg38:chr8 90015666、GRCh38 / hg38:chr5 80649389、GRCh38 / hg38:chr4 106925799、GRCh38 / hg38:chr11 83651839、GRCh38 / hg38:chr8 21910673、GRCh38 / hg38:chr14 72879804、GRCh38 / hg38:chr14 72879804、GRCh38 / hg38:chr18 34757288、GRCh38 / hg38:chr18 34757288、GRCh38 / hg38:chr21 37456308、GRCh38 / hg38:chr11 49206778、GRCh38 / hg38:chr19 49812251、GRCh38 / hg38:chr11 62638983、GRCh38 / hg38:chr17 749814、GRCh38 / hg38:chr17 75243447、GRCh38 / hg38:chr17 46924468、GRCh38 / hg38:chr4 175812191、GRCh38 / hg38:chr7 50710875、GRCh38 / hg38:chr9 121300126、GRCh38 / hg38:chrX 72572057、GRCh38 / hg38:chr6 12020418、GRCh38 / hg38:chr10 69300861、GRCh38 / hg38:chr10 69300861、GRCh38 / hg38:chr6 137215267、GRCh38 / hg38:chr8 42272205、GRCh38 / hg38:chr8 42272205, GRCh38 / hg38:chr8 42272205, GRCh38 / hg38:chr8 42272205, GRCh38 / hg38:chr12 108564155, GRCh38 / hg38:chr16 75644283, GRCh38 / hg38:chr16 75644283, GRCh38 / hg38:chr6 24600619, GRCh38 / hg38:chr14 58429433, GRCh38 / hg38:chr14 58429433, GRCh38 / hg38:chr20 21132159, GRCh 38 / hg38:chr19 50963302、GRCh38 / hg38:chr1 156126915、GRCh38 / hg38:chr12 25552871、GRCh38 / hg38:chr12 25552871、GRCh38 / hg38:chr1 69716218、GRCh38 / hg38:chr11 72089165、GRCh38 / hg38:chr11 72089165、GRCh38 / hg38:chr11 72089165、GRCh38 / hg38:chr11 72089165、GRCh38 / hg38:chr11 72089165、GRCh38 / hg38:chr11 72089165、GRCh38 / hg38:chr11 72089165、GRCh38 / hg38:chr11 72089165、GRCh38 / hg38:chr11 72089165、GRCh38 / hg38:chr11 72089165、GRCh38 / hg38:chr11 72089165、GRCh38 / hg38:chr3 45837927、GRCh38 / hg38:chr7 78554567、GRCh38 / hg38:chrX 154092184、GRCh38 / hg38:chrX 154092184、GRCh38 / hg38:chr2 111945060、GRCh38 / hg38:chr1 39965334、GRCh38 / hg38:chr3 158592581、GRCh38 / hg38:chr3 158592581、GRCh38 / hg38:chr3 158592581、GRCh38 / hg38:chr3 158592581、GRCh38 / hg38:chr3 158592581、GRCh38 / hg38:chr4 70950811、GRCh38 / hg38:chr12 65308655、GRCh38 / hg38:chr1 161236459、GRCh38 / hg38:chr1 161236459、GRCh38 / hg38:chr1 161236459、GRCh38 / hg38:chr1 161236459、GRCh38 / hg38:chr1 161236459、GRCh38 / hg38:chr1 161236459、GRCh38 / hg38:chr1 161236459、GRCh38 / hg38:chr1 161236459、GRCh38 / hg38:chr1 161236459、GRCh38 / hg38:chr1 161236459、GRCh38 / hg38:chr1 161236459、GRCh38 / hg38:chr1 161236459、GRCh38 / hg38:chr1161236459、GRCh38 / hg38:chr7 33035934、GRCh38 / hg38:chr7 33035934、GRCh38 / hg38:chr15 34346035、GRCh38 / hg38:chr2 26477649、GRCh38 / hg38:chr2 26477649、GRCh38 / hg38:chr10 110876753、GRCh38 / hg38:chr16 2566453、GRCh38 / hg38:chr16 47463993、GRCh38 / hg38:chr16 47463993、GRCh38 / hg38:chrX 15331216、GRCh38 / hg38:chrX 15331216、GRCh38 / hg38:chr3 146124138、GRCh38 / hg38:chr22 37958471、GRCh38 / hg38:chr9 125171909、GRCh38 / hg38:chr6 162262525、GRCh38 / hg38:chr1 151027327、GRCh38 / hg38:chr14 35308995、GRCh38 / hg38:chr17 42573478、GRCh38 / hg38:chr20 50565069、GRCh38 / hg38:chr19 8402279、GRCh38 / hg38:chr4 26320815、GRCh38 / hg38:chr4 26320815、GRCh38 / hg38:chr16 2264573、GRCh38 / hg38:chr16 2264573、GRCh38 / hg38:chr16 2264573、GRCh38 / hg38:chr16 2264573、GRCh38 / hg38:chr1 92833660、GRCh38 / hg38:chr8 56073695、GRCh38 / hg38:chr9 89325676、GRCh38 / hg38:chr1 151369713、GRCh38 / hg38:chr1 151369713、GRCh38 / hg38:chr4 76995938、GRCh38 / hg38:chr19 38893819、G RCh38 / hg38: chr19 38893819, GRCh38 / hg38: chr19 38893819, GRCh38 / hg38: chr19 38893819, GRCh38 / hg38: chr19 38893819, GRCh38 / hg38: chr3 66243312, GRCh38 / hg38: chr3 66243312, GRCh38 / hg38: chr17 40644385, GRCh38 / hg38: chrX 53421895, GRCh38 / hg38: chr16 18899987, GRCh38 / hg38: chr13 112382507, GRCh38 / hg38: chr15 38299547, GRCh38 / hg38: chr14 35001020, GRCh38 / hg38: chr7 105268806, GRCh38 / hg38: chr2 218673765, GRCh38 / hg38: chr17 63714006, GRCh38 / hg38: chr17 63714006, GRCh38 / hg38: chr17 63714006, GRCh38 / hg38: chr17 63714006, GRCh38 / hg38: chr17 63714006, GRCh38 / hg38: chr17 63714006, GRCh38 / hg38: chr17 63714006, GRCh38 / hg38: chr17 63714006, GRCh38 / hg38: chr17 63714006, GRCh38 / hg38: chr2 202214357, GRCh38 / hg38: chr3 177064920, GRCh38 / hg38: chr3 177064920, GRCh38 / hg38: chr3 177064920, GRCh38 / hg38: chr3 177064920, GRCh38 / hg38: chrX 12910442, GRCh38 / hg38: chr22 19880856, GRCh38 / hg38: chr15 25408620, GRCh38 / hg38: chr15 25408620, GRCh38 / hg38: chr13 38350227, GRCh38 / hg38: chr10 28nucleotides, about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of a genomic site selected from the group consisting of: 50345124.

[0021] In some cases, the targeted regions of the pre-mRNA were GRCh38 / hg38:chr14 23071125, GRCh38 / hg38:chr14 68925558, GRCh38 / hg38:chr1 236735720, GRCh38 / hg38:chr4 99143166, GRCh38 / hg38:chr4 99143166, GRCh38 / hg38:chr6 32182568, GRCh38 / hg38:chr10 5077977, GRCh38 / hg38:chr15 58058012, GRCh38 / hg38:chr11 78138710, and GRCh38 / hg38:chr1 109621266, GRCh38 / hg38:chr3 49422104, GRCh38 / hg38:chr3 49422104, GRCh38 / hg38:chr3 49422104, GRCh38 / hg38:chr16 89316933, GRCh38 / hg38:chr16 89316933, GRCh38 / hg38:chr16 89316933, GRCh38 / hg38:chr16 89316933, GRCh38 / hg38:chr16 89316933, GRCh38 / hg38:chr16 89316933, GRCh38 / hg38:chr16 89316933, GRCh38 / hg38:chr16 89316933, GRCh38 / hg38:chr16 89316933, GRCh38 / hg38:chr16 89316933, GRCh38 / hg38:chr16 89316933, GRCh38 / hg38:chr16 89316933, GRCh38 / hg38:chr16 89316933, GRCh38 / hg38:chr16 89316933, GRCh38 / hg3 8:chr16 4726659、GRCh38 / hg38:chr22 36201700、GRCh38 / hg38:chr3 57230767、GRCh38 / hg38:chr11 118573783、GRCh38 / hg38:chr3 138188530、GRCh38 / hg38:chr3 138188530、GRCh38 / hg38:chr11 13355296、GRCh38 / hg38:chr11 13355296、GRCh38 / hg38:chr3 113249899、GRCh38 / hg38:chr3 113249899、GRCh38 / hg38:chr3 113249899、GRCh38 / hg38:chr3 113249899、GRCh38 / hg38:chr17 43106456、GRCh38 / hg38:chr17 43106456、GRCh38 / hg38:chr1 56959529、GRCh38 / hg38:chr1 56959529、GRCh38 / hg38:chr14 90399087、GRCh38 / hg38:chr19 46608340、GRCh38 / hg38:chr11 105008807、GRCh38 / hg38:chr5 96726859、GRCh38 / hg38:chr3 196708528、GRCh38 / hg38:chr11 95795559、GRCh38 / hg38:chr11 125627830、GRCh38 / hg38:chr15 78111165、GRCh38 / hg38:chr15 78111165、GRCh38 / hg38:chr16 85805104、GRCh38 / hg38:chr10 14939810、GRCh38 / hg38:chr8 90005369、GRCh38 / hg38:chr8 90015666、GRCh38 / hg38:chr5 80649389、GRCh38 / hg38:chr4 106925799、GRCh38 / hg38:chr11 83651839、GRCh38 / hg38:chr8 21910673、GRCh38 / hg38:chr14 72879804、GRCh38 / hg38:chr14 72879804、GRCh38 / hg38:chr18 34757288、GRCh38 / hg38:chr18 34757288、GRCh38 / hg38:chr21 37456308、GRCh38 / hg38:chr11 49206778、GRCh38 / hg38:chr19 49812251、GRCh38 / hg38:chr11 62638983、GRCh38 / hg38:chr17 749814、GRCh38 / hg38:chr17 75243447、GRCh38 / hg38:chr17 46924468、GRCh38 / hg38:chr4 175812191、GRCh38 / hg38:chr7 50710875、GRCh38 / hg38:chr9 121300126、GRCh38 / hg38:chrX 72572057、GRCh38 / hg38:chr6 12020418、GRCh38 / hg38:chr10 69300861、GRCh38 / hg38:chr10 69300861、GRCh38 / hg38:chr6 137215267、GRCh38 / hg38:chr8 42272205、GRCh38 / hg38:chr8 42272205、GRCh38 / hg38:chr8 42272205、GRCh38 / hg38:chr8 42272205、GRCh38 / hg38:chr12 108564155、GRCh38 / hg38:chr16 75644283、GRCh38 / hg38:chr16 75644283、GRCh38 / hg38:chr6 24600619、GRCh38 / hg38:chr14 58429433、GRCh38 / hg38:chr14 58429433、GRCh38 / hg38:chr20 21132159、GRCh38 / hg38:chr19 50963302、GRCh38 / hg38:chr1 156126915、GRCh38 / hg38:chr12 25552871、GRCh38 / hg38:chr12 25552871、GRCh38 / hg38:chr1 69716218、GRCh38 / hg38:chr11 72089165、GRCh38 / hg38:chr11 72089165、GRCh38 / hg38:chr11 72089165、GRCh38 / hg38:chr11 72089165、GRCh38 / hg38:chr11 72089165、GRCh38 / hg38:chr11 72089165、GRCh38 / hg38:chr11 72089165、G RCh38 / hg38:chr11 72089165、GRCh38 / hg38:chr11 72089165、GRCh38 / hg38:chr11 72089165、GRCh38 / hg38:chr11 72089165、GRCh38 / hg38:chr3 45837927、GRCh38 / hg38:chr7 78554567、GRCh38 / hg38:chrX 154092184、GRCh38 / hg38:chrX 154092184、GRCh38 / hg38:chr2 111945060、GRCh38 / hg38:chr1 39965334、GRCh38 / hg38:chr3 158592581、GRCh38 / hg38:chr3 158592581、GRCh38 / hg38:chr3 158592581、GRCh38 / hg38:chr3 158592581、GRCh38 / hg38:chr3 158592581、GRCh38 / hg38:chr4 70950811、GRCh38 / hg38:chr12 65308655、GRCh38 / hg38:chr1 161236459、GRCh38 / hg38:chr1 161236459、GRCh38 / hg38:chr1 161236459、GRCh38 / hg38:chr1 161236459、GRCh38 / hg38:chr1 161236459、GRCh38 / hg38:chr1 161236459、GRCh38 / hg38:chr1 161236459、GRCh38 / hg38:chr1 161236459、GRCh38 / hg38:chr1 161236459、GRCh38 / hg38:chr1 161236459、GRCh38 / hg38:chr1 161236459、GRCh38 / hg38:chr1 161236459、GRCh38 / hg38:chr1 161236459、GRCh38 / hg38:chr7 33035934、GRCh38 / hg38:chr7 33035934、GRCh38 / hg38:chr15 34346035、GRCh38 / hg38:chr2 26477649、GRCh38 / hg38:chr2 26477649、GRCh38 / hg38:chr10 110876753、GRCh38 / hg38:chr162566453、GRCh38 / hg38:chr16 47463993、GRCh38 / hg38:chr16 47463993、GRCh38 / hg38:chrX 15331216、GRCh38 / hg38:chrX 15331216、GRCh38 / hg38:chr3 146124138、GRCh38 / hg38:chr22 37958471、GRCh38 / hg38:chr9 125171909、GRCh38 / hg38:chr6 162262525、GRCh38 / hg38:chr1 151027327、GRCh38 / hg38:chr14 35308995、GRCh38 / hg38:chr17 42573478、GRCh38 / hg38:chr20 50565069、GRCh38 / hg38:chr19 8402279、GRCh38 / hg38:chr4 26320815、GRCh38 / hg38:chr4 26320815、GRCh38 / hg38:chr16 2264573、GRCh38 / hg38:chr16 2264573、GRCh38 / hg38:chr16 2264573、GRCh38 / hg38:chr16 2264573、GRCh38 / hg38:chr1 92833660、GRCh38 / hg38:chr8 56073695、GRCh38 / hg38:chr9 89325676、GRCh38 / hg38:chr1 151369713、GRCh38 / hg38:chr1 151369713、GRCh38 / hg38:chr4 76995938、GRCh38 / hg38:chr19 38893819、GRCh38 / hg38:chr19 38893819、GRCh38 / hg38:chr19 38893819、GRCh38 / hg38:chr19 38893819、GRCh38 / hg38:chr19 38893819、GRCh38 / hg38:chr3 66243312、GRCh38 / hg38:chr3 66243312、GRCh38 / hg38:chr17 40644385、GRCh38 / hg38:chrX 53421895、GRCh38 / hg38:chr16 18899987、GRCh38 / hg38:chr13 112382507、GRCh38 / hg38:chr1538299547, GRCh38 / hg38:chr14 35001020 , GRCh38 / hg38:chr7 105268806, GRCh38 / hg38:chr2 218673765, GRCh38 / hg38:chr17 63714006, GRCh38 / hg38:chr17 63714006, GRCh38 / hg38:chr17 63714006, GRCh38 / hg38:chr17 63714006, GRCh38 / hg38:chr17 63714006, GRCh38 / hg38:chr17 63714006, GRCh38 / hg38:chr17 63714006, GRCh38 / hg38:chr17 63714006, GRCh38 / hg38:chr17 63714006, GRCh38 / hg38:chr2 202214357, GRCh38 / hg38:chr3 177064920, GRCh38 / hg38:chr3 177064920, GRCh38 / hg38:chr3 177064920, GRCh38 / hg38:chr3 177064920, GRCh38 / hg38:chrX 12910442, GRCh38 / hg38:chr22 19880856, GRCh38 / hg38:chr15 25408620, GRCh38 / hg38:chr15 25408620, GRCh38 / hg38:chr13 38350227, GRCh38 / hg38:chr10 28535757, GRCh38 / hg38:chr17 1728626, GRCh38 / hg38:chr10 27153227, and GRCh38 / hg38:chr3 50345124.

[0022] In some cases, the targeted region of the pre-mRNA is within a sequence selected from the group consisting of SEQ ID NOs: 130-331.In some cases, the targeted regions of the pre-mRNA are GRCh38 / hg38:chr14 23071186 and GRCh38 / hg38:chr14 23071125; GRCh38 / hg38:chr14 68925672 and GRCh38 / hg38:chr14 68925558; GRCh38 / hg38:chr1 236735635 and GRCh38 / hg38:chr1 236735720; GRCh38 / hg38:chr4 99143305 and GRCh38 / hg38:chr4 99143166; GRCh38 / hg38:chr4 99143305 and GRCh38 / hg38:chr4 99143166;GRCh38 / hg38:chr6 32182698 and GRCh38 / hg38:chr6 32182568;GRCh38 / hg38:chr10 5077900 and GRCh38 / hg38:chr10 5077977;GRCh38 / hg38:chr15 58058108 and GRCh38 / hg38:chr15 58058012;GRCh38 / hg38:chr11 78138767 and GRCh38 / hg38:chr11 78138710;GRCh38 / hg38:chr1 109620914 and GRCh38 / hg38:chr1 109621266;GRCh38 / hg38:chr3 49422257, and GRCh38 / hg38:chr3 49422104;GRCh38 / hg38:chr3 49422257, and GRCh38 / hg38:chr3 49422104;GRCh38 / hg38:chr3 49422257, and GRCh38 / hg38:chr3 49422104;GRCh38 / hg38:chr16 89317078, and GRCh38 / hg38:chr16 89316933;GRCh38 / hg38:chr16 89317078, and GRCh38 / hg38:chr16 89316933;GRCh38 / hg38:chr16 89317078, and GRCh38 / hg38:chr16 89316933;GRCh38 / hg38:chr16 89317075, and GRCh38 / hg38:chr16 89316933;GRCh38 / hg38:chr16. 89317078, and GRCh38 / hg38:chr16 89316933;G RCh38 / hg38:chr16 89317078, and GRCh38 / hg38:chr16 89316933;GRCh38 / hg38:chr16 89317075, and GRCh38 / hg38:chr16 89316933;GRCh38 / hg38:chr16 89317078, and GRCh38 / hg38:chr16 89316933;GRCh38 / hg38:chr16 89317078, and GRCh38 / hg38:chr16 89316933;GRCh38 / hg38:chr16 89317075, and GRCh38 / hg38:chr16 89316933;GRCh38 / hg38:chr16 89317078, and GRCh38 / hg38:chr16 89316933;GRCh38 / hg38:chr16 89317075, and GRCh38 / hg38:chr16 89316933;GRCh38 / hg38:chr16 89317078, and GRCh38 / hg38:chr16 89316933;GRCh38 / hg38:chr16 89317078, and GRCh38 / hg38:chr16 89316933;GRCh38 / hg38:chr16 4726780, and GRCh38 / hg38:chr16 4726659; GRCh38 / hg38:chr22 36201796, and GRCh38 / hg38:chr22 36201700; GRCh38 / hg38:chr3 57230714, and GRCh38 / hg38:chr3 57230767; GRCh38 / hg38:chr11 118573620, and GRCh38 / hg38:chr11 118573783; GRCh38 / hg38:chr3 138188455, and GRCh38 / hg38:chr3 138188530; GRCh38 / hg38:chr3 138188455, and GRCh38 / hg38:chr3 138188530;GRCh38 / hg38:chr11 13355226, and GRCh38 / hg38:chr11 13355296;GRCh38 / hg38:chr11 13355226, and GRCh38 / hg38:chr11 13355296;GRCh38 / hg38:chr3 113249722, and GRCh38 / hg38:chr3 113249899;GRCh38 / hg38:chr3 113249722, and GRCh38 / hg38:chr3 113249899;GRCh38 / hg38:chr3 113249722, and GRCh38 / hg38:chr3 113249899;GRCh38 / hg38:chr17 43106533, and GRCh38 / hg38:chr17 43106456;GRCh38 / hg38:chr1 56959657, and GRCh38 / hg38:chr1 56959529;GRCh38 / hg38:chr1 56959657, and GRCh38 / hg38:chr1 56959529;GRCh38 / hg38:chr14 90398991, and GRCh38 / hg38:chr14 90399087;GRCh38 / hg38:chr19 46608205, and GRCh38 / hg38:chr19 46608340;GRCh38 / hg38:chr11 105009053 and GRCh38 / hg38:chr11 105008807; GRCh38 / hg38:chr5 96726754 and GRCh38 / hg38:chr5 96726859; GRCh38 / hg38:chr3 196708727 and GRCh38 / hg38:chr3 196708528; GRCh38 / hg38:chr11 95795516 and GRCh38 / hg38:chr11 95795559; GRCh38 / hg38:chr11 125627607 and GRCh38 / hg38:chr11 125627830;GRCh38 / hg38:chr15 78111276, and GRCh38 / hg38:chr15 78111165;GRCh38 / hg38:chr15 78111276, and GRCh38 / hg38:chr15 78111165;GRCh38 / hg38:chr16 85804941, and GRCh38 / hg38:chr16 85805104;GRCh38 / hg38:chr10 14939869, and GRCh38 / hg38:chr1; 0 14939810;GRCh38 / hg38:chr8 90005292 and GRCh38 / hg38:chr8 90005369;GRCh38 / hg38:chr8 90015541 and GRCh38 / hg38:chr8 90015666;GRCh38 / hg38:chr5 80649494 and GRCh38 / hg38:chr5 80649389;GRCh38 / hg38:chr4 106925949 and GRCh38 / hg38:chr4 106925799;GRCh38 / hg38:chr11 83651930 and GRCh38 / hg38:chr11 83651839;GRCh38 / hg38:chr8 21910857, and GRCh38 / hg38:chr8 21910673;GRCh38 / hg38:chr14 72879947, and GRCh38 / hg38:chr14 72879804;GRCh38 / hg38:chr14 72879947, and GRCh38 / hg38:chr14 72879804;GRCh38 / hg38:chr18 34757158, and GRCh38 / hg38:chr18 34757288;GRCh38 / hg38:chr18 34757158, and GRCh38 / hg38:chr18 34757288;GRCh38 / hg38:chr21 37456130 and GRCh38 / hg38:chr21 37456308;GRCh38 / hg38:chr11 49206874 and GRCh38 / hg38:chr11 49206778;GRCh38 / hg38:chr19 49812335 and GRCh38 / hg38:chr19 49812251;GRCh38 / hg38:chr11 62639110 and GRCh38 / hg38:chr11 62638983;GRCh38 / hg38:chr17 749909 and GRCh38 / hg38:chr17 749814;GRCh38 / hg38:chr17 75243570, and GRCh38 / hg38:chr17 75243447;GRCh38 / hg38:chr17 46924261, and GRCh38 / hg38:chr17 46924468;GRCh38 / hg38:chr4 175812249 and GRCh38 / hg38:chr4 175812191; GRCh38 / hg38:chr7 50710990 and GRCh38 / hg38:chr7 50710875; GRCh38 / hg38:chr9 121300056 and GRCh38 / hg38:chr9 121300126; GRCh38 / hg38:chrX 72572109 and GRCh38 / hg38:chrX 72572057; GRCh38 / hg38:chr6 12020248 and GRCh38 / hg38:chr6 12020418;GRCh38 / hg38:chr10 69300769, and GRCh38 / hg38:chr10 69300861;GRCh38 / hg38:chr10 69300769, and GRCh38 / hg38:chr10 69300861;GRCh38 / hg38:chr6 137215377, and GRCh38 / hg38:chr6 137215267;GRCh38 / hg38:chr8 42272083, and GRCh38 / hg38:chr8 42272205;GRCh38 / hg38:chr8 42272083, and GRCh38 / hg38:chr8 42272205;GRCh38 / hg38:chr8 42272083, and GRCh38 / hg38:chr8 42272205;GRCh38 / hg38:chr8 42272083, and GRCh38 / hg38:chr8 42272205;GRCh38 / hg38:chr12 108564060, and GRCh38 / hg38:chr12 108564155;GRCh38 / hg38:chr16 75644462, and GRCh38 / hg38:chr16 75644283;GRCh38 / hg38:chr16 75644462, and GRCh38 / hg38:chr16 75644283;GRCh38 / hg38:chr6 24600709, and GRCh38 / hg38:chr6 24600619;GRCh38 / hg38:chr14 58429363, and GRCh38 / hg38:chr14 58429433;GRCh38 / hg38:chr14 58429363, and GRCh38 / hg38:chr14 58429433;GRCh38 / hg38:chr20 21132097, and GRCh38 / hg38:chr20 21132159; ;GRCh38 / hg38:chr19 50963549, and GRCh38 / hg38:chr19 50963302;GRCh38 / hg38:chr1 156126736, and GRCh38 / hg38:chr1 156126915;GRCh38 / hg38:chr12 25552989, and GRCh38 / hg38:chr12 25552871;GRCh38 / hg38:chr1 25552989, and GRCh38 / hg38:chr12 25552871;GRCh38 / hg38:chr1 69716142, and GRCh38 / hg38:chr1 69716218;GRCh38 / hg38:chr11 72089029, and GRCh38 / hg38:chr11 72089165;GRCh38 / hg38:chr11 72089029, and GRCh38 / hg38:chr11 72089165;GRCh38 / hg38:chr11 72089029, and GRCh38 / hg38:chr11 72089165;GRCh38 / hg38:chr11 72089029, and GRCh38 / hg38:chr11 72089165;GRCh38 / hg38:chr11 72089029, and GRCh38 / hg38:chr11 72089165;GRCh38 / hg38:chr11 72089029, and GRCh38 / hg38:chr11 72089165;GRCh38 / hg38:chr11 72089029, and GRCh38 / hg38:chr11 72089165;GRCh38 / hg38:chr11 72089029, and GRCh38 / hg38:chr11 72089165;GRCh38 / hg38:chr11 72089029, and GRCh38 / hg38:chr11 72089165;GRCh38 / hg38:chr11 72089029, and GRCh38 / hg38:chr11 72089165; GRCh38 / hg38:chr11 72089029, and GRCh38 / hg38:chr11 72089165; GRCh38 / hg38:chr3 45838051, and GRCh38 / hg38:chr3 45837927; GRCh38 / hg38:chr7 78554671, and GRCh38 / hg38:chr7 78554567; GRCh38 / hg38:chrX 154092307, and GRCh38 / hg38:chrX 154092184; GRCh38 / hg38:chrX 154092307, and GRCh38 / hg38:chrX 154092184;GRCh38 / hg38:chr2 111944960, and GRCh38 / hg38:chr2 111945060;GRCh38 / hg38:chr1 39965211, and GRCh38 / hg38:chr1 39965334;GRCh38 / hg38:chr3 158592434, and GRCh38 / hg38:chr3 158592581;GRCh38 / hg38:chr3 158592434, and GRCh38 / hg38:chr3 158592581;GRCh38 / hg38:chr3 158592434, and GRCh38 / hg38:chr3 158592581;GRCh38 / hg38:chr3 158592434, and GRCh38 / hg38:chr3 158592581;GRCh38 / hg38:chr3 158592434 and GRCh38 / hg38:chr3 158592581;GRCh38 / hg38:chr4 70950700 and GRCh38 / hg38:chr4 70950811;GRCh38 / hg38:chr12 65308529 and GRCh38 / hg38:chr12 65308655;GRCh38 / hg38:chr1 161236598 and GRCh38 / hg38:chr1 161236459;GRCh38 / hg38:chr1 161236598 and GRCh38 / hg38:chr1 161236459;GRCh38 / hg38:chr1 161236598, and GRCh38 / hg38:chr1 161236459;GRCh38 / hg38:chr1 161236598, and GRCh38 / hg38:chr1 161236459;GRCh38 / hg38:chr1 161236598, and GRCh38 / hg38:chr1 161236459;GRCh38 / hg38:chr1 161236598, and GRCh38 / hg38:chr1 161236459;GRCh38 / hg38:chr1 161236598, and GRCh38 / hg38:chr1 161 236459;GRCh38 / hg38:chr1 161236598, and GRCh38 / hg38:chr1 161236459;GRCh38 / hg38:chr1 161236598, and GRCh38 / hg38:chr1 161236459;GRCh38 / hg38:chr1 161236598, and GRCh38 / hg38:chr1 161236459;GRCh38 / hg38:chr1 161236598, and GRCh38 / hg38:chr1 161236459;GRCh38 / hg38:chr1 161236598, and GRCh38 / hg38:chr1 161236459;GRCh38 / hg38:chr1 161236598, and GRCh38 / hg38:chr1 161236459;GRCh38 / hg38:chr7 33035988, and GRCh38 / hg38:chr7 33035934;GRCh38 / hg38:chr7 33035988, and GRCh38 / hg38:chr7 33035934;GRCh38 / hg38:chr15 34345857, and GRCh38 / hg38:chr15 34346035;GRCh38 / hg38:chr2 26477749, and GRCh38 / hg38:chr2 26477649;GRCh38 / hg38:chr2 26477749, and GRCh38 / hg38:chr2 26477649;GRCh38 / hg38:chr10 110876670, and GRCh38 / hg38:chr10 110876753;GRCh38 / hg38:chr16 2566356, and GRCh38 / hg38:chr16 2566453;GRCh38 / hg38:chr16 47463899, and GRCh38 / hg38:chr16 47463993;GRCh38 / hg38:chr16 47463882, and GRCh38 / hg38:chr16 47463993; GRCh38 / hg38:chrX 15331992, and GRCh38 / hg38:chrX 15331216; GRCh38 / hg38:chrX 15331992, and GRCh38 / hg38:chrX 15331216; GRCh38 / hg38:chr3 146124229, and GRCh38 / hg38:chr3 146124138; GRCh38 / hg38:chr22 37958374, and GRCh38 / hg38:chr22 37958471; GRCh38 / hg38:chr9 125172001, and GRCh38 / hg38:chr9 125171909;GRCh38 / hg38:chr6 162262765, and GRCh38 / hg38:chr6 162262525; GRCh38 / hg38:chr1 151027233 and GRCh38 / hg38:chr1 151027327; GRCh38 / hg38:chr14 35308914 and GRCh38 / hg38:chr14 35308995; GRCh38 / hg38:chr17 42573623 and GRCh38 / hg38:chr17 42573478; GRCh38 / hg38:chr20 50564969 and GRCh38 / hg38:chr20 50565069; GRCh38 / hg38:chr19 8402086 and GRCh38 / hg38:chr19 8402279;GRCh38 / hg38:chr4 26320700, and GRCh38 / hg38:chr4 26320815;GRCh38 / hg38:chr4 26320700, and GRCh38 / hg38:chr4 26320815;GRCh38 / hg38:chr16 2264760, and GRCh38 / hg38:chr16 2264573;GRCh38 / hg38:chr16 2264760, and GRCh38 / hg38:chr16 2264573;GRCh38 / hg38:chr16 2264760, and GRCh38 / hg38:chr16 2264573;GRCh38 / hg38:chr1 92833545, and GRCh38 / hg38:chr1 92833660;GRCh38 / hg38:chr8 56073768, and GRCh38 / hg38:chr8 56073695;GRCh38 / hg38:chr9 89325427, and GRCh38 / hg38:chr9 89325676;GRCh38 / hg38:chr1 151369978, and GRCh38 / hg38:chr1 151369713;GRCh38 / h g38:chr1 151369978, and GRCh38 / hg38:chr1 151369713;GRCh38 / hg38:chr4 76995781, and GRCh38 / hg38:chr4 76995938;GRCh38 / hg38:chr19 38893867, and GRCh38 / hg38:chr19 38893819;GRCh38 / hg38:chr19 38893867, and GRCh38 / hg38:chr19 38893819;GRCh38 / hg38:chr19 38893867, and GRCh38 / hg38:chr19 38893819;GRCh38 / hg38:chr19 38893867, and GRCh38 / hg38:chr19 38893819;GRCh38 / hg38:chr3 66243203, and GRCh38 / hg38:chr3 66243312;GRCh38 / hg38:chr3 66243203, and GRCh38 / hg38:chr3 66243312; GRCh38 / hg38:chr17 40644459 and GRCh38 / hg38:chr17 40644385; GRCh38 / hg38:chrX 53422040 and GRCh38 / hg38:chrX 53421895; GRCh38 / hg38:chr16 18900044 and GRCh38 / hg38:chr16 18899987; GRCh38 / hg38:chr13 112382278 and GRCh38 / hg38:chr13 112382507; GRCh38 / hg38:chr15 38299373 and GRCh38 / hg38:chr15 38299547;GRCh38 / hg38:chr14 35000936, and GRCh38 / hg38:chr14 35001020;GRCh38 / hg38:chr7 105268869, and GRCh38 / hg38:chr7 105268806;GRCh38 / hg38:chr2 218673665, and GRCh38 / hg38:chr2 218673765;GRCh38 / hg38:chr17 63714108, and GRCh38 / hg38:chr17 63714006;GRCh38 / hg38:chr17 63714108, and GRCh38 / hg38:chr17 63714006;GRCh38 / hg38:chr17 63714108, and GRCh38 / hg38:chr17 63714006;GRCh38 / hg38:chr17 63714108, and GRCh38 / hg38:chr17 63714006;GRCh38 / hg38:chr17 63714108, and GRCh38 / hg38:chr17 63714006;GRCh38 / hg38:chr17 63714108, and GRCh38 / hg38:chr17 63714006;GRCh38 / hg38:chr17 63714108, and GRCh38 / hg38:chr17 63714006;GRCh38 / hg38:chr17 63714108, and GRCh38 / hg38:chr17 63714006;GRCh38 / hg38:chr17 63714108, and GRCh38 / hg38:chr17 63714006;GRCh38 / hg38:chr2 202214429, and GRCh38 / hg38:chr2 202214357;GRCh38 / hg38:chr3 177065022, and GRCh38 / hg38:chr3 177064920;GRCh38 / hg38:chr3 177065022, and GRCh38 / hg38:chr3 177064920;GRCh38 / hg38:chr3 177065022 and GRCh38 / hg38:chr3 177064920;GRCh38 / hg38:chr3 177065022 and GRCh38 / hg38:chr3 177064920;GRCh38 / hg38:chrX 12910306 and GRCh38 / hg38:chrX 12910442;GRCh38 / hg38:chr22 19880945 and GRCh38 / hg38:chr22 19880856;GRCh38 / hg38:chr15 25408684 and GRCh38 / hg38:chr15 25408620;GRCh38 / hg38:chr15 25408684, and GRCh38 / hg38:chr15 25408620;GRCh38 / hg38:chr13 38349999, and GRCh38 / hg38:chr13 38350227; within the sequence between a pair of genomic sites selected from the group consisting of GRCh38 / hg38:chr10 28535562 and GRCh38 / hg38:chr10 28535757; GRCh38 / hg38:chr17 1727990 and GRCh38 / hg38:chr17 1728626; GRCh38 / hg38:chr10 27153281 and GRCh38 / hg38:chr10 27153227; GRCh38 / hg38:chr3 50345232 and GRCh38 / hg38:chr3 50345124.

[0023] In some cases, the therapeutic agent is an antisense oligomer complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 130-331. In some cases, the therapeutic agent is an antisense oligomer complementary to a sequence having 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 130-331. In some cases, the therapeutic agent is an antisense oligomer having a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 534-8095. In some cases, the therapeutic agent is an antisense oligomer having a sequence having 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 534-8095.

[0024] In some cases, the disease or condition is intellectual disability; colorectal cancer; bleeding disorder, platelet type, 15; autosomal dominant macrothrombocytopenia; hypertrophic cardiomyopathy; cardiomyopathy, dilated, 1AA; cardiomyopathy, familial hypertrophic, 23, with or without myocardial noncompaction; familial dilated cardiomyopathy; Charcot-Marie-Tooth disease; cardiac conduction disorder; cardiomyopathy, dilated; alcohol use disorder; alcohol abuse; alcoholism, chronic; alcohol use disorder; Alcohol abuse; Chronic alcoholism; Schizophrenia; Bipolar disorder; Chronic alcoholism; Congenital glycosylation disorders; Epileptic encephalopathy; Depressive disorder; Congenital glycosylation disorder type 1H; Pontocerebellar hypoplasia type 9; Epileptic encephalopathy; Ataxia, hereditary; Spastic paraplegia 63, autosomal recessive; Cerebellar hypoplasia; Spastic paraplegia, hereditary; Nonketotic hyperglycinemia; Transient neonatal hyperglycinemia; Glycine encephalopathy; KBG syndrome; 16q24.3 microdeletion syndrome;Situs inversus;Malignant neoplasm of the breast;Maturity-onset diabetes mellitus of the young;Maturity-onset diabetes mellitus type 14;Microcephaly;Polydactyly;Ciliopathy;Mental depression;Seasonal affective disorder;Bipolar disorder;Mood disorders;Depressive disorders;Malignant neoplasm of the breast;Cytopenias;Gastrointestinal neoplasms;Depressive disorders;Prostate cancer, familial;Primary peritoneal cancer;Ovarian cancer, familial, susceptibility, 1;Breast cancer, familial male;Malignant neoplasm;Pancreatic neoplasm;Breast cancer, familial;Breast neoplasm of uncertain or unknown nature;Ovarian carcinoma;Prostate adenocarcinoma;Ovarian neoplasm of uncertain or unknown nature;Malignant neoplasm of the pancreas;Pancreatic cancer;Malignant neoplasm of the ovary;Congenital anemia;Hematologic tumors;Breast adenocarcinoma;Breast cancer, ovarian cancer, familial, susceptibility, 1;Splenic cancer, familial;Benign tumor of the pancreas;Breast carcinoma;Breast cancer cancer), familial, susceptibility, 1; ovarian neoplasm; hereditary breast and ovarian cancer syndrome; psychological depression; ovarian epithelial cancer; malignant neoplasm of the breast; sporadic breast cancer; breast and ovarian cancer, familial, 1; splenic cancer, susceptibility, 4; C8 deficiency type II; ventricular tachycardia, catecholamine-induced polymorphism, 4; ventricular tachycardia, catecholamine-induced polymorphism, 1; long QT syndrome; Romano-Ward syndrome; long Qt syndrome 14; peeling skin syndrome; peeling skin with nail plate leukosis, acral punctate keratosis, cheilitis, and knuckle pads; erythrokeratoderma; palmoplantar keratoderma; morbid obesity and spermatogenesis imperfecta; Warbleton-Enyan-Yeboiasis syndrome; mosaic variegated aneuploidy syndrome; familial breast cancer; malignant ovarian neoplasm; mitochondrial disease; severe combined immunodeficiency with sensitivity to ionizing radiation; partial severe combined immunodeficiency; familial reticuloendotheliosis with eosinophilia; Omenn's syndrome; Athabascan severe combined immunodeficiency; severe combined immunodeficiency, Athabascan type; cocaine abuse; congenital anemia; cytopenias; neurodegeneration due to cerebral folate transport deficiency; megaloblastic anemia due to dihydrofolate reductase deficiency; chronic alcoholism; bipolar disorder; unipolar depression; major depressive disorder; schizophrenia and related disorders. ;Left ventricular noncompaction;Left ventricular noncompaction;Familial Meniere's disease;Charcot-Marie-Tooth disease;Left ventricular noncompaction, familial isolated, autosomal dominant 1;Primary microcephaly;Microcephaly;Epileptic encephalopathy;Mental retardation, autosomal dominant 7;Colorectal cancer;Depressive disorder;Mental depression;Caudal regression syndrome;Arnold-Chiari malformation;Caudal dysplasia syndrome;Chiari malformation type II;Sacral hypoplasia syndrome;Sacral hypoplasia;Clarino triad;Spina bifida manifesta of the cervical spine;Neural tube defects;Polycystic kidney disease, autosomal dominant;Polycystic kidney disease 3, autosomal dominant;Alcoholism, chronic;Malignant breast neoplasm ;Ataxia, hereditary;Epilepsy, progressive myoclonus, 6;Epileptic encephalopathy;Lattice corneal degeneration type II;Meretja syndrome;Malignant neoplasm of the breast;Periodic fever syndrome;Familial amyloid polyneuropathy type IV;Cerebral amyloid angiopathy, Gsn-related;Corneal abnormalities;Amyloidosis, Finnish type;Primary microcephaly;Cornelia de Lange syndrome 5;Clant hand;Cornelia de Lange syndrome;Wilson-Turner X-linked mental retardation syndrome;Congenital anemia;Retinitis pigmentosa 79;Charcot-Marie-Tooth disease;Cytopenia;Hexokinase Nonspherocytic hemolytic anemia due to deficiency; Neuropathy, hereditary motor and sensory, Russe type; Interferon gamma receptor 1 deficiency; Immunodeficiency 27a; Immunodeficiency 27b; H. pylori infection, susceptibility; Tuberculosis infection, protection against it; Immunodeficiency 27A, mycobacteriosis, AR; Immunodeficiency 27B, mycobacteriosis, AD; Hepatitis B virus infection, susceptibility; Tuberculosis, susceptibility; Malignant neoplasms of the breast; Lymphoma, non-Hodgkin's; Immunodeficiency 15; Congenital myopathy; Arthrogryposis; Rhabdomyolysis; Myopathy with exercise intolerance, Swedish type; Lactic acidosis Myopathy with dysplasia, hereditary; Charcot-Marie-Tooth disease, recessive intermediate type B; Charcot-Marie-Tooth disease; Hearing loss, autosomal recessive 89; Hearing loss, autosomal recessive 89; Dyslexia, susceptibility, 2; Joubert syndrome 23; Polydactyly; Familial cerebellar vermis hypoplasia; Joubert syndrome with Jeune asphyxiating thoracic dysplasia; Hydrocephalus; Ciliopathy; Short-rib thoracic dysplasia with polydactyly 14; Retinitis pigmentosa; Retinitis pigmentosa 69; Muscular dystrophy, limb-girdle type, type 1B; Hypertrophic cardiomyopathy; Left ventricular noncompaction; Osteogenesis imperfecta; Charcot-Marie-Tooth disease; Cardiomyopathy, familial idiopathic;Familial partial lipodystrophy type 1; Left ventricular noncompaction; Mandibulofacial dysostosis; Muscular dystrophy, congenital, Lmna-related; Congenital myopathy; Arthrogryposis; Arrhythmogenic right ventricular dysplasia; Muscular dystrophy, limb-girdle type; Malouf syndrome; Najjar syndrome; Charcot-Marie-Tooth disease type 2B1; Emery-Dreifuss muscular dystrophy 3; Lethal tension cutis contracture syndrome; Familial partial lipodystrophy type 2; Cardiac conduction disorders; Cardiomyopathy, dilated type; Progeria syndrome, childhood onset; Atypical Werner syndrome; Congenital muscular dystrophy; Autosomal recessive Emery-Dreifuss muscular dystrophy; Heart-hand syndrome, Slovenian type; Progeria; Autosomal dominant Emery-Dreifuss Ifs muscular dystrophy; Cardiomyopathy, dilated type, 1A; Mandibular acromegaly dysplasia; Muscular dystrophy, limb-girdle type, type 1B; Emery-Dreifuss muscular dystrophy 2, AD; Malouf syndrome; Fatal restrictive cutis; Emery-Dreifuss muscular dystrophy 3, AR; Heart-hand syndrome, Slovenian type; Charcot-Marie-Tooth disease type 2B1; Hutchinson-Gilford progeria; Lipodystrophy, familial partial type, type 2; Muscular dystrophy, congenital; Malignant neoplasm of the breast; Hearing loss, autosomal recessive type 63; Bardet-Biedl syndrome; Polydactyly; Ciliopathy; Bardet-Biedl syndrome 17; Major affective disorder 2; Bipolar disorder; Epileptic encephalopathy; Rett syndrome, speech-preserving variant; Lubs X-linked mental retardation syndrome; neonatal severe encephalopathy due to Mecp2 mutation; mental retardation with psychosis, pyramidal signs, and macroorchidism; mental retardation, X-linked, with spasticity; Xq28 trisomy; mental retardation, X-linked 16; epileptic encephalopathy; mental retardation, X-linked, syndromic 13; mental retardation, X-linked 1; Rett syndrome, atypical; mental retardation, X-linked 79; microcephaly; Ppm-X syndrome; Rett syndrome, Zappella variant; Rett syndrome T syndrome; autism susceptibility, X-linked 3; benign neoplasm of the adrenal gland; retinitis pigmentosa; conventional (clear cell) renal cell carcinoma; squamous cell carcinoma of the head and neck; malignant neoplasm of the aortic body and other paragangliomas; retinitis pigmentosa 38; malignant adrenal medullary neoplasm; benign neoplasm of the aortic body and other paragangliomas; primary microcephaly; microcephaly 15, primary, autosomal recessive; autosomal recessive primary microcephaly; microcephaly; leukemia, acute myeloid; deafness, autosomal recessive 74; cytopenias;Uridine 5'-monophosphate hydrolase; Protein deficiency and resulting hemolytic anemia; congenital anemia; midline nucleoprotein (NUT) tumor; malignant neoplasm of the breast; hearing loss, autosomal recessive; hearing loss, autosomal recessive 9; auditory neuropathy, nonsyndromic recessive; auditory neuropathy, autosomal recessive 1; malignant neoplasm of the breast; breast cancer; breast neoplasm of uncertain or unknown nature; breast adenocarcinoma; ketotic hypoglycemia; rhabdomyolysis; glycogen storage disease IXB; liver and muscle phosphorylase kinase deficiency, autosomal recessive; congenital anemia; congenital glycosylation disorders; cytopenias; epileptic encephalopathy; paroxysmal nocturnal hemoglobinuria; paroxysmal nocturnal hemoglobinuria Globinuria 1;West syndrome;Congenital multiple malformations-hypotonia-convulsion syndrome 2;Congenital anemia;Congenital glycosylation disorders;Cytopenia;Epileptic encephalopathy;Paroxysmal nocturnal hemoglobinuria;Paroxysmal nocturnal hemoglobinuria 1;West syndrome;Congenital multiple malformations-hypotonia-convulsion syndrome 2;Bruck syndrome 2;Osteogenesis imperfecta;Bruck syndrome 1;Arthrogryposis;Bruck syndrome;Cutaneous melanoma;Melanoma;Parkinson's disease 2, autosomal recessive, juvenile;Parkinson's disease;Juvenile-onset Parkinson's disease;Parkinson's disease, late-onset;Leprosy, susceptible;Adenocarcinoma, ovarian, somatic Sexuality; lung adenocarcinoma, somatic; primary microcephaly; neurodevelopmental disorders with microcephaly, hypotonia, and various brain malformations; myocardial infarction, susceptible; pure gonadal dysgenesis, 46,XX; ovarian dysgenesis, 3; insulin resistance, susceptible; leukodystrophy; epileptic encephalopathy; Adams-Oliver syndrome, 3; Adams-Oliver syndrome; mood disorders; congenital anemia; hematologic tumors; Diamond-Blackfan anemia; cytopenia; Ose-Smith syndrome, 2; radial club hand; precursor T-cell lymphoblastic leukemia-lymphoma; Diamond-Blackfan anemia, 6; hereditary nonpolyposis colorectal cancer syndrome; Familial colorectal cancer type X; hereditary nonpolyposis colorectal cancer; hereditary nonpolyposis colorectal neoplasia; thyroid hormone metabolism disorders; thyroid hormone insensitivity syndrome; bipolar disorder; mood disorders; combined oxidative phosphorylation deficiency 28; Coffin-Siris syndrome 5; Coffin-Siris syndrome; meningioma; meningiomas, multiple; meningiomas, familial, susceptible; primary microcephaly; congenital anemia; osteogenesis imperfecta; cytopenia; epileptic encephalopathy; radial club hand; Cornelia de Lange syndrome; growth failure and mental retardation with facial dysmorphism; congenital myometrial hypertrophy-encephalopathy syndrome;Cornelia de Lange syndrome 2; invasive ductal carcinoma in women; colorectal cancer; neurofibromatosis 1; neurofibromatosis type 1-like syndrome; Regius syndrome; Schwachman syndrome; glioblastoma multiforme; ovarian serous adenocarcinoma; Polynesian bronchiectasis; Kartagener syndrome; polyhydramnios, megalencephaly, and symptomatic epilepsy; hydrocephalus; epileptic encephalopathy; partial anodontia; hypodontia; orofacial clefts 10; malignant neoplasm of the bladder; acute promyelocytic leukemia; colorectal adenocarcinoma; bladder neoplasm; epileptic encephalopathy; bladder neoplasm of uncertain or unknown nature; mental retardation, autosomal dominant 41; benign neoplasm of the bladder; lymphoma, non-Hodgkin's; intraepithelial carcinoma of the bladder; central nervous system lymphoma; carcinoma of the bladder; plantar lipomatosis, dysfacies, and and developmental delay; Pierpont syndrome; X-linked adrenal hypoplasia; depression; familial dilated cardiomyopathy; familial glucocorticoid deficiency type 1; cardiac conduction disorders; cardiomyopathy, dilated; Angelman syndrome; epileptic encephalopathy; microcephaly; 15q11-q13 duplication syndrome; leukodystrophy, hypomyelination; chromosome 10p12-p11 deletion syndrome; colorectal cancer; Descente-Sinawi syndrome; ataxia, hereditary; cerebellar ataxia, mental retardation, and disproportion syndrome; hydrocephalus; cerebellar hypoplasia; disproportion syndrome; optic atrophy; Polynesian bronchiectasis; ciliary dyskinesia, primary; Kartagener syndrome; and ciliopathy.

[0025] In some cases, the disease or condition is caused by an insufficient amount or activity of a functional target protein, and the first protein comprising the target peptide sequence is at least partially functionally equivalent to the functional target protein. In some cases, the disease or condition is caused by an insufficient amount or activity of the target peptide sequence. In some cases, the therapeutic agent increases the level of the first processed mRNA in the cell. In some cases, the level of the first processed mRNA in the cell contacted with the therapeutic agent is about 1.1 to about 10-fold, about 1.5 to about 10-fold, about 2 to about 10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1 to about 5-fold, about 1.1 to about 6-fold, about 1.1 to about 7-fold, about 1.1 to about 8-fold, about 1.1 to about 9-fold, about The increase is 2 to about 5 times, about 2 to about 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.

[0026] In some cases, a therapeutic agent increases expression of a target peptide sequence in a cell. In some cases, the level of the target peptide sequence in a cell contacted with a therapeutic agent increases by 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, about 1.1 to about 8 times, about 1.1 to about 9 times, about 2 to about 5 times, or about 2 to about 6 times compared to the level of the target peptide sequence in a control cell. , 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.

[0027] In some cases, the therapeutic agent is an antisense oligonucleotide, and the therapeutic agent comprises a backbone modification comprising a phosphorothioate linkage or a phosphorodiamidate linkage. In some cases, the therapeutic agent is an antisense oligonucleotide, and the therapeutic agent comprises a phosphorodiamidate morpholino, a locked nucleic acid, a peptide nucleic acid, a 2'-O-methyl, a 2'-fluoro, or a 2'-O-methoxyethyl moiety. In some cases, the therapeutic agent is an antisense oligonucleotide, and the therapeutic agent comprises at least one modified sugar moiety. In some cases, each sugar moiety is a modified sugar moiety. In some cases, the therapeutic agent is an antisense oligonucleotide, and the therapeutic agent may be an antisense oligonucleotide having from 8 to 50 nucleobases, from 8 to 40 nucleobases, from 8 to 35 nucleobases, from 8 to 30 nucleobases, from 8 to 25 nucleobases, from 8 to 20 nucleobases, from 8 to 15 nucleobases, from 9 to 50 nucleobases, from 9 to 40 nucleobases, from 9 to 35 nucleobases, from 9 to 30 nucleobases, from 9 to 25 nucleobases, from 9 to 20 nucleobases, from 9 to 15 nucleobases, from 10 to 50 nucleobases, from 10 to 40 nucleobases, from 10 to 35 nucleobases consisting of acid bases, 10-30 nucleobases, 10-25 nucleobases, 10-20 nucleobases, 10-15 nucleobases, 11-50 nucleobases, 11-40 nucleobases, 11-35 nucleobases, 11-30 nucleobases, 11-25 nucleobases, 11-20 nucleobases, 11-15 nucleobases, 12-50 nucleobases, 12-40 nucleobases, 12-35 nucleobases, 12-30 nucleobases, 12-25 nucleobases, 12-20 nucleobases, or 12-15 nucleobases.

[0028] In some cases, the method further comprises assessing the level of mRNA encoding the target peptide sequence or the expression level of the target peptide sequence.

[0029] In some cases, the subject is a human. In some cases, the subject is a non-human animal. In some cases, the subject is a fetus, embryo, or child. In some cases, the cell(s) are ex vivo, or in a tissue, or organ ex vivo.

[0030] In some cases, the therapeutic agent is administered to the subject by intraventricular injection, intraperitoneal injection, intramuscular injection, intrathecal injection, subcutaneous injection, oral administration, synovial injection, intravitreal administration, subretinal injection, topical application, implantation, or intravenous injection.

[0031] In some aspects, disclosed herein are therapeutic agents for use in the methods disclosed herein.

[0032] In some aspects, a therapeutic agent described herein and a pharmaceutically acceptable excipient are Disclosed herein is a pharmaceutical composition comprising:

[0033] In some aspects, disclosed herein are methods of treating a subject in need thereof, comprising administering to the subject a pharmaceutical composition described herein by intraventricular injection, intraperitoneal injection, intramuscular injection, intrathecal injection, subcutaneous injection, oral administration, synovial injection, intravitreal administration, subretinal injection, topical application, implantation, or intravenous injection.

[0034] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0035] The novel features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings, in which: [Brief explanation of the drawings]

[0036] [Figure 1] Schematic diagram of MECP2 pre-mRNA splicing isoforms (A) and protein domains (B). [Figure 2] FIG. 1 is a schematic diagram showing a targeting strategy for modulating alternative splicing of MECP2 pre-mRNA. [Figure 3] RT-PCR analysis performed to confirm exon 2 inclusion events during MECP2 mRNA processing is shown. [Figure 4] ASO walk of the MECP2 exon 2 region is shown. [Figure 5] RT-PCR analysis performed to evaluate the ASO walk across the MECP2 exon 2 region is shown. [Figure 6] The effects of selected ASOs on MECP2 exon 2 inclusion (A) and MECP2 protein expression (B) are shown. [Figure 7] Quantification of total MECP2 mRNA (e1+e2) is shown. [Figure 8] Figure 1 shows the dose-dependent effect of selected ASO Mecp2 exon 2 inclusion in mouse embryonic fibroblast (MEF) cells. [Figure 9] RT-PCR analysis performed to evaluate the ASO microwalk in the regions of ASOs 31–33 and 37–38 is shown. DETAILED DESCRIPTION OF THE INVENTION

[0037] Alternative splicing in certain genes can result in non-productive or less productive mRNA transcripts, which can then downregulate protein expression.Therapeutic agents that can target the alternative splicing events in these genes can regulate the expression level of protein.Such therapeutic agents can be used to treat conditions caused by protein deficiency.

[0038] One of the alternative splicing events that can result in non-productive or less productive mRNA transcripts can be the inclusion of exons that contain inefficiently translated regions, which can result in inefficient translation of mRNA transcripts.In some cases, mRNA transcripts that have inefficiently translated regions have significantly lower translation efficiency than corresponding mRNA transcripts that are otherwise identical but do not have inefficient translated regions.

[0039] In one aspect, the present disclosure provides a method for the alternative splicing of genes that can have pre-mRNAs with exons that are efficiently translated and have inefficiently translated regions to increase production of mRNAs that encode target peptide sequences and, therefore, translated target peptide sequences. The present disclosure provides compositions and methods for modulating exon skipping. The compositions and methods include antisense oligomers (ASOs) that can induce exon skipping and promote the production of mRNA that can be efficiently translated. In various examples, target peptide sequences can be augmented using the methods of the present disclosure to treat conditions caused by deficiencies in the target peptide sequence or associated protein.

[0040] In some embodiments, methods are described herein for modulating expression of a target peptide sequence by a cell having a pre-mRNA that encodes the target peptide sequence and includes an inefficiently translated region, the methods comprising contacting the cell with a therapeutic agent that binds to a targeted region of the pre-mRNA encoding the target peptide sequence, thereby modulating splicing of the inefficiently translated region from the pre-mRNA encoding the target peptide sequence, thereby modulating the level of a first processed mRNA that does not include the inefficiently translated region and encodes the target peptide sequence, thereby modulating expression of the target peptide sequence in the cell, the processed mRNA having a higher translation efficiency for producing the target peptide sequence in the cell compared to a second processed mRNA that includes the inefficiently translated region. In some cases, the second processed mRNA is identical to the first processed mRNA except for including the inefficiently translated region. In some cases, both the first processed mRNA and the second processed mRNA are spliced ​​products of the same pre-mRNA. In some cases, the subject therapeutic agent modulates splicing of the pre-mRNA, thereby modulating the balance between the first processed mRNA and the second processed mRNA in the cell.

[0041] In some embodiments, one alternative splicing event that can result in a non-productive or less productive mRNA transcript is the inclusion of an exon containing a premature termination codon (PTC) followed by an alternative start codon. In these cases, the pre-mRNA has a first start codon, a second start codon (alternative start codon), and a PTC located downstream of the first start codon and upstream of the second start codon. Without wishing to be bound by any particular theory, motifs or exons containing PTCs and alternative start codons may contribute to low productivity of mRNA transcripts. In some embodiments, motifs or exons containing PTCs and alternative start codons result in inefficient translation of downstream exon sequences. In some embodiments, motifs or exons containing PTCs and alternative start codons result in less stable protein products expressed due to defects in downstream exon sequences or post-translational modifications, or some other process at the molecular or cellular level, which may result in defects in protein expression or function. Without wishing to be bound by any particular theory, the presence of alternative start codons may contribute to the lack of nonsense-mediated decay (NMD) of mRNA transcripts because the translating ribosome may resume translation at the alternative start codon immediately after encountering the PTC rather than triggering the recruitment of the NMD machinery, which may ultimately lead to degradation of the mRNA transcript.

[0042] In one aspect, the present disclosure provides compositions and methods for modulating alternative splicing of genes that may have pre-mRNAs with exons containing PTCs followed by alternative start codons to increase production of mature mRNAs encoding the target peptide sequence, and thus the translated target peptide sequence. In some cases, the compositions include ASOs that can cause exon skipping and promote the production of mRNAs that can be efficiently translated. In various examples, the target peptide sequence can be increased using the methods of the present disclosure to treat conditions caused by deficiencies in the target peptide sequence or related proteins.

[0043] In some embodiments, a target peptide sequence is encoded by a first start codon, a second start codon, and a sequence downstream of the first start codon and upstream of the second start codon. Described herein are methods for modulating expression of a target peptide sequence by a cell having a pre-mRNA that includes a premature termination codon (PTC), the method comprising contacting the cell with a therapeutic agent that binds to a targeted portion of the pre-mRNA that encodes the target peptide sequence, thereby modulating splicing of the PTC and second start codon from the pre-mRNA, thereby modulating the level of a first processed mRNA that does not include the PTC and second start codon and encodes the target peptide sequence, thereby modulating expression of the target peptide sequence in the cell.

[0044] RNA splicing Intervening sequences, or introns, are removed by a large and highly dynamic RNA-protein complex called the spliceosome, which orchestrates complex interactions between the primary transcript, small nuclear RNAs (snRNAs), and numerous proteins. The spliceosome begins with recognition of the 5' splice site (5'ss) by the U1 snRNA or the 3' splice site (3'ss) by the U2 pathway. The spliceosome then assembles opportunistically on each intron in an ordered manner, involving binding of U2 accessory factors (U2AFs) to the 3'ss region and promoting U2 binding to the branch point sequence (BPS). U2AF is a stable heterodimer consisting of a 65-kD subunit (U2AF65) encoded by U2AF2, which binds to the polypyrimidine tract (PPT), and a 35-kD subunit (U2AF35) encoded by U2AF1, which interacts with a highly conserved AG dinucleotide at the 3'ss and stabilizes U2AF65 binding. In addition to the BPS / PPT units and 3'ss / 5'ss, accurate splicing requires auxiliary sequences or structures that activate or repress splice site recognition, known as intronic or exonic splicing enhancers or silencers. These elements enable true splice sites to be recognized among the vast excess of cryptic or pseudosites in the genomes of higher eukaryotes, which share the same sequence but outnumber the original sites by an order of magnitude. Although they often have regulatory functions, the precise mechanisms of their activation or repression are poorly understood.

[0045] The decision to splice or not to splice can typically be modeled as a stochastic rather than a deterministic process, as even the most well-defined splicing signals can occasionally be misspliced. However, under normal conditions, pre-mRNA splicing can proceed with surprisingly high fidelity. This may be due, in part, to the activity of adjacent cis-acting auxiliary exonic and intronic splicing regulatory elements (ESRs or ISRs). Typically, these functional elements are classified as either exonic or intronic splicing enhancers (ESEs or ISEs) or silencers (ESSs or ISSs) based on their ability to stimulate or inhibit splicing, respectively. While there is now evidence that some auxiliary cis-acting elements can act by influencing the dynamics of spliceosome assembly, such as the positioning of the complex between the U1 snRNP and the 5' ss, it seems highly likely that many elements function in concert with trans-acting RNA-binding proteins (RBPs). For example, the serine- and arginine-rich family of RBPs (SR proteins) is a conserved family of proteins that play a key role in defining exons. SR proteins promote exon recognition by recruiting components of the pre-spliceosome to adjacent splice sites or by antagonizing the effects of ESSs in the vicinity. The repressive effect of ESSs can be mediated by members of the heterogeneous nuclear ribonucleoprotein (hnRNP) family, which can alter the recruitment of core splicing factors to adjacent splice sites. In addition to their role in splicing regulation, silencer elements are suggested to have a role in the suppression of pseudoexons, which are sets of decoy intronic splice sites with the typical spacing of an exon but without a functional open reading frame. ESEs and ESSs are involved in the suppression of their cognate transactivities. Together with RBPs, they represent key components in the splicing regulatory chain that specifies how, where, and when mRNAs are assembled from their precursors.

[0046] Sequences marking exon-intron boundaries are degenerate signals of varying strength that frequently occur within human genes. In multi-exon genes, different pairs of splice sites can be linked together in many different combinations, generating a diverse array of transcripts from a single gene. This is commonly referred to as alternative pre-mRNA splicing. While most mRNA isoforms produced by alternative splicing can be exported from the nucleus and translated into functional polypeptides, different mRNA isoforms from a single gene can vary greatly in their translation efficiency. These mRNA isoforms with a premature termination codon (PTC) at least 50 bp upstream of the exon junction complex are likely to be targeted for degradation by the nonsense-mediated mRNA decay (NMD) pathway. However, in some embodiments, an alternative start codon following the PTC can prevent the induction of NMD events, as exemplified in the case of the MECP2 e2 mRNA isoform (discussed below). Mutations in conventional (BPS / PPT / 3'ss / 5'ss) and auxiliary splicing motifs can cause aberrant splicing, such as exon skipping or cryptic (or pseudo) exon inclusion or splice site activation, and contribute significantly to human morbidity and mortality. Both aberrant and alternative splicing patterns can be influenced by natural DNA variants in exons and introns.

[0047] In some embodiments, compositions and methods use cryptic splice sites to regulate alternative splicing to generate desired splice isoforms for regulating the expression level of a target peptide sequence. Cryptic (or pseudo) splice sites can have the same splicing recognition sequence as true splice sites, but are not used in the splicing reaction. They outnumber true splice sites in the human genome by an order of magnitude and are typically suppressed by molecular mechanisms that are poorly understood. Cryptic 5' splice sites have the consensus NNN / GUNNNN or NNN / GCNNNN, where N is any nucleotide and / or is the exon-intron boundary. Cryptic 3' splice sites have the consensus NAG / N. Their activation is positively influenced by surrounding nucleotides that make them more similar to the optimal consensus of the original splice site, i.e., MAG / GURAGU and YAG / G, where M is C or A, R is G or A, and Y is C or U, respectively.

[0048] Splice sites and their regulatory sequences can be readily identified by one skilled in the art using suitable publicly available algorithms, for example, those listed in Kralovicova, J. and Vorechovsky, I. (2007) Global control of aberrant splice site activation by auxiliary splicing sequences: evidence for a gradient in exon and intron definition. Nucleic Acids Res., 35, 6399-6413, (available at www.ncbi.nlm.nih.gov / pmc / articles / PMC2095810 / pdf / gkm680.pdf).

[0049] Cryptic splice sites or splicing regulatory sequences can compete for RNA-binding proteins such as U2AF. In some embodiments, an agent can bind to a cryptic splice site or splicing regulatory sequence, thereby preventing binding of the RNA-binding protein and thereby favoring binding of the RNA-binding protein to the desired splice site.

[0050] MECP2 mRNA splicing In some embodiments, the disclosed methods utilize alternative splicing of pre-mRNA transcribed from the MECP2 gene. MECP2 pre-mRNA can have four exons and can be alternatively spliced ​​(Figure 1). Exemplary MECP2 pre-mRNA sequences include SEQ ID NOS: 2-27. In some embodiments, MECP2 pre-mRNA can be spliced ​​into two isoforms, which can result in the production of MeCP2α or e1 protein isoforms and MeCP2β or e2 isoforms, respectively. Skipping exon 2 can result in the production of the predominant MeCP2α or e1 isoform, while inclusion of exon 2 can give rise to the MeCP2β or e2 isoforms. MeCP2-e1 and e2 isoforms can have unique N-terminal sequences of 21 aa and 9 aa, respectively. The relative expression levels of these isoforms can vary between tissues, with MeCP2-e1 being more predominant in the adult brain. MeCP2-e2 is more abundantly expressed in the placenta, liver, and skeletal muscle. Furthermore, in some cases, deletion of MeCP2-e2 by disrupting exon 2 does not result in RTT-related phenotypes in mice. Exon 2 is an out-of-frame exon. It has both a PTC and an alternative start codon. Translation from the downstream start codon can be highly inefficient. Mutagenesis studies have shown that the presence of two start codons in the full-length (e2) transcript dramatically reduces the translation efficiency of the downstream open reading frame. Eliminating the ATG upstream of exon 1 can significantly increase MeCP2-e2 translation. In some embodiments, skipping (splicing out) exon 2 from the full-length (e2) MECP2 transcript can reduce the nonproductive transcript pool and result in increased translation of MeCP2-e1 protein. In adult human brains, approximately 50% of transcripts are identified by RNA-seq (Lister PMID). As determined by NIH / NIH / 23828890, the isoform may include exon 2. In some cases, exon 2-containing isoforms may be dispensable in the adult brain, and as a result, exon 2 skipping induced by a therapeutic agent (e.g., an ASO) may be a viable therapeutic strategy for increasing MeCP2 expression in patients suffering from MeCP2 protein deficiency, e.g., Rett syndrome patients.

[0051] In some embodiments, a therapeutic agent targets a sequence about 4 to about 300 nucleotides upstream (or 5') from the 5' end of an inefficiently translated region, e.g., exon 2 region of MECP2 pre-mRNA. In some embodiments, a therapeutic agent targets a sequence about 1 to about 20 nucleotides, about 20 to about 50 nucleotides, about 50 to about 100 nucleotides, about 100 to about 150 nucleotides, about 150 to about 200 nucleotides, about 200 to about 250 nucleotides, or about 250 to about 300 nucleotides upstream (or 5') from the 5' end of an inefficiently translated region. In some embodiments, a therapeutic agent may target a sequence more than 300 nucleotides upstream from the 5' end of an inefficiently translated region. In some embodiments, a therapeutic agent targets a sequence about 4 to about 300 nucleotides downstream (or 3') from the 3' end of an inefficiently translated region. In some embodiments, a therapeutic agent targets a sequence about 1 to about 20 nucleotides, about 20 to about 50 nucleotides, about 50 to about 100 nucleotides, about 100 to about 150 nucleotides, about 150 to about 200 nucleotides, about 200 to about 250 nucleotides, or about 250 to about 300 nucleotides downstream from the 3' end of the inefficiently translated region. In some embodiments, a therapeutic agent targets a sequence more than 300 nucleotides downstream from the 3' end of the inefficiently translated region.

[0052] In some embodiments, the therapeutic agent targets a sequence about 4 to about 300 nucleotides upstream (or 5') from the 5' end of an exon that includes a PTC and a second start codon (alternative start codon), e.g., exon 2 region of the MECP2 pre-mRNA. In some embodiments, the therapeutic agent targets a sequence about 1 to about 20 nucleotides upstream (or 5') from the 5' end of an exon that includes a PTC and a second start codon (alternative start codon), e.g., exon 2 region of the MECP2 pre-mRNA. The therapeutic agent targets a sequence about 20 to about 50 nucleotides, about 50 to about 100 nucleotides, about 100 to about 150 nucleotides, about 150 to about 200 nucleotides, about 200 to about 250 nucleotides, or about 250 to about 300 nucleotides upstream (or 5'). In some embodiments, the therapeutic agent may target a sequence more than 300 nucleotides upstream from the 5' end of the exon containing the PTC and alternative start codon. In some embodiments, the therapeutic agent targets a sequence about 4 to about 300 nucleotides downstream (or 3') from the 3' end of the exon containing the PTC and alternative start codon. In some embodiments, the therapeutic agent targets a sequence about 1 to about 20 nucleotides, about 20 to about 50 nucleotides, about 50 to about 100 nucleotides, about 100 to about 150 nucleotides, about 150 to about 200 nucleotides, about 200 to about 250 nucleotides, or about 250 to about 300 nucleotides downstream from the 3' end of the exon containing the PTC and alternative start codon. In some embodiments, the therapeutic agent targets a sequence more than 300 nucleotides downstream from the 3' end of the exon containing the PTC and alternative start codon.

[0053] In some embodiments, a pre-mRNA transcript that can be targeted by a method or composition provided herein is encoded by a gene sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 1. In some embodiments, a pre-mRNA transcript that can be targeted by a method or composition provided herein comprises a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to any one of SEQ ID NOs: 2-27.

[0054] In some embodiments, a therapeutic agent targets intron 1, exon 2, or intron 2 of the MECP2 pre-mRNA. In some embodiments, a therapeutic agent targets an exon sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to any selected from the group consisting of SEQ ID NOs: 28-31. In some embodiments, a therapeutic agent targets exon 2 of the MECP2 pre-mRNA. In some embodiments, a therapeutic agent targets an exon sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 28.

[0055] In some embodiments, a therapeutic agent targets a sequence that is about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream (or 5') from the 5' end of exon 2 of the MECP2 pre-mRNA. In some embodiments, a therapeutic agent targets a sequence that is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream (or 5') from the 5' end of exon 2 of the MECP2 pre-mRNA.

[0056] In some embodiments, a therapeutic agent targets a sequence about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream (or 3') from the 3' end of exon 2 of the MECP2 pre-mRNA. In some embodiments, a therapeutic agent targets a sequence about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream (or 3') from the 3' end of exon 2 of the MECP2 pre-mRNA. The target sequence is about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream (or 3').

[0057] In some embodiments, the therapeutic agent is an ASO, and the ASO has a sequence complementary to a targeted portion of a pre-mRNA according to SEQ ID NOs: 2-27. In some embodiments, the ASO has a sequence complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to any one selected from the group consisting of SEQ ID NOs: 28-31. In some embodiments, the ASO has a sequence complementary to a sequence having 100% sequence identity to any one selected from the group consisting of SEQ ID NOs: 28-31. In some embodiments, the ASO has a sequence complementary to a sequence having 100% sequence identity to SEQ ID NO: 28.

[0058] In some embodiments, the ASO targets a sequence comprising an exon-intron boundary (or junction).

[0059] In some embodiments, the methods and compositions of the disclosure are used to increase expression of MeCP2 by inducing exon skipping of exon 2 of the MECP2 pre-mRNA.

[0060] In some cases, the target peptide sequence is a portion of the MECP2 protein. In some cases, the therapeutic agent increases the level of a first processed mRNA encoding a protein having the sequence of SEQ ID NO: 8204 and decreases the level of a second processed mRNA encoding a protein having the sequence of SEQ ID NO: 440. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 238. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 238. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chrX 154092307. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chrX 154092307.In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, or about 60 nucleotides of SEQ ID NO:238. , about 50 nucleotides downstream. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 238. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chrX 154092184. In some cases, the targeted region of the pre-mRNA is located at the genomic site GRCh38 / hg38:chrX The targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of 154092184. In some cases, the targeted region of the pre-mRNA is within the sequence of SEQ ID NO: 238. In some cases, the targeted region of the pre-mRNA is within the sequence between the pair of genomic sites GRCh38 / hg38:chrX 154092307 and GRCh38 / hg38:chrX 154092184. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 238. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having 100% sequence identity to SEQ ID NO: 238. In some cases, the therapeutic agent increases the level of a first processed mRNA encoding a protein having the sequence of SEQ ID NO: 8205 and decreases the level of a second processed mRNA encoding a protein having the sequence of SEQ ID NO: 441. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 239. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 239.In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chrX 154092307. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chrX 154092307. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, or about 500 nucleotides of SEQ ID NO:239. The targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 239. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 239. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chrX 154092184. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chrX 154092184. In some cases, the targeted region of the pre-mRNA is within the sequence of SEQ ID NO: 239. In some cases, the targeted region of the pre-mRNA is within the sequence between the pair of genomic sites GRCh38 / hg38:chrX 154092307 and GRCh38 / hg38:chrX 154092184. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:239.In some cases, the therapeutic agent is an antisense oligomer complementary to a sequence having 100% sequence identity to SEQ ID NO: 239. In some cases, the therapeutic agent is an antisense oligomer having a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 4548-4611. In some cases, the therapeutic agent is an antisense oligomer having a sequence selected from the group consisting of SEQ ID NOs: 4548-4611. In some cases, the target peptide sequence is a portion of the MECP2 protein, and the method treats a disease or condition comprising intellectual disability; Rett syndrome, speech-preserving variant; Lubs X-linked mental retardation syndrome; severe neonatal encephalopathy due to MeCP2 mutations; mental retardation with psychosis, pyramidal signs, and macroorchidism; mental retardation, X-linked, with spasticity; Xq28 trisomy; mental retardation, X-linked 16; epileptic encephalopathy; mental retardation, X-linked, syndromic 13; mental retardation, X-linked 1; Rett syndrome, atypical; mental retardation, X-linked 79; microcephaly; Ppm-X syndrome; Rett syndrome, Zappella variant; Rett syndrome; or autism susceptibility, X-linked 3.

[0061] Protein expression In some embodiments, the methods described herein are used to increase production of a functional protein, e.g., an MeCP2 protein, having a target peptide sequence. As used herein, the term "functional" refers to the amount of protein activity or function necessary to eliminate any one or more symptoms of a treated condition or disease, e.g., Rett Syndrome. In some embodiments, the methods are used to increase production of a partially functional MeCP2 protein. As used herein, the term "partially functional" refers to any amount of protein activity or function that is less than the amount of activity or function necessary to eliminate or prevent any one or more symptoms of a disease or condition, e.g., Rett Syndrome. In some embodiments, a partially functional protein is at least 10%, at least 20%, or at least 30% of a fully functional protein. , at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% less activity.

[0062] In some embodiments, the method is for increasing expression of a target peptide sequence by cells of a subject having a pre-mRNA encoding the target peptide sequence, wherein the subject has a disease or condition caused by an insufficient amount or activity of a functional target protein to which the target peptide sequence is at least functionally equivalent. In such embodiments, the subject has a first allele encoding a functional target protein that is not produced. In another such embodiment, the subject has a first allele encoding a functional target protein and a second allele encoding a non-functional target protein. In another such embodiment, the subject has a first allele encoding a functional target protein and a second allele encoding a partially functional target protein. In some of these embodiments, the antisense oligomer binds to a target portion of a pre-mRNA transcribed from the second allele that encodes the target peptide sequence and includes an exon containing an inefficiently translated region, thereby inducing skipping of the inefficiently translated region from the pre-mRNA, resulting in an increase in the level of mature mRNA encoding the target peptide sequence and increased expression of the target peptide sequence in the subject's cells. In some of these embodiments, the antisense oligomer binds to a target portion of a pre-mRNA transcribed from a second allele that encodes the target peptide sequence and contains an exon containing a PTC followed by an alternative start codon, thereby inducing skipping of the PTC and start codon from the pre-mRNA, resulting in increased levels of mature mRNA encoding the target peptide sequence and increased expression of the target peptide sequence in cells of the subject.

[0063] In some embodiments, a target peptide sequence as described herein can be a fully functional protein. In some embodiments, the target peptide sequence is a portion of a full-length protein, for example, the N-terminal portion of the full-length protein or the C-terminal portion of the full-length protein. In the case of MeCP2, the target peptide sequence can be the C-terminal portion of MeCP2. In some embodiments, the target peptide sequence is translated from a sequence selected from the group consisting of SEQ ID NOs: 32-34. In some embodiments, the target peptide sequence is translated from a sequence having SEQ ID NOs: 32 or 33 and 34. In some embodiments, the target peptide sequence is encoded by a portion of the pre-mRNA downstream of an inefficiently translated region or an alternative start codon. In some embodiments, the target peptide sequence is encoded by a portion of the pre-mRNA upstream of an inefficiently translated region or an alternative start codon. The target peptide sequence may comprise at least about 10 amino acids (aa), 20 aa, 30 aa, 40 aa, 50 aa, 60 aa, 70 aa, 80 aa, 90 aa, 100 aa, 120 aa, 150 aa, 200 aa, 300 aa, 400 aa, 500 aa, 600 aa, 700 aa, 800 aa, 100 aa, 1500 aa, or 2000 aa. The target peptide sequence can comprise about 10 amino acids (aa), 20 aa, 30 aa, 40 aa, 50 aa, 60 aa, 70 aa, 80 aa, 90 aa, 100 aa, 120 aa, 150 aa, 200 aa, 300 aa, 400 aa, 500 aa, 600 aa, 700 aa, 800 aa, 100 aa, 1500 aa, or 2000 aa.

[0064] In some embodiments, the method is for increasing expression of a functional target protein having a target peptide sequence, e.g., the MeCP2-e1 isoform encoded by exons 1, 3, and 4 of the MECP2 gene, by cells of a subject having a pre-mRNA encoding the target peptide sequence, and the subject has a disease or condition caused by an insufficient amount of active MeCP2 protein. In such embodiments, the subject has alleles encoding a partially functional MeCP2, e.g., a hypomorphic allele. In such embodiments, the subject has a first allele encoding a functional MeCP2 protein. The subject has a gene and a second allele encoding a partially functional MeCP2 protein. In some of these embodiments, the antisense oligomer binds to a target portion of a pre-mRNA transcribed from the second allele that encodes MeCP2 and includes exon 2 of MECP2, thereby inducing skipping of at least a portion of MECP2 exon 2 from the pre-mRNA, resulting in an increase in the level of mature mRNA encoding the MeCP2-e1 isoform and increased expression of the MeCP2-e1 isoform in cells of the subject. Without wishing to be bound by any particular theory, X inactivation may result in a subject having cells with a wild-type allele and a mutant allele, e.g., a hypomorphic allele, that encodes a partially functional MeCP2, having approximately 50% of the cells with the mutant allele that express the wild-type allele but not the mutant allele, and approximately 50% of the cells with the mutant allele that express the mutant allele but not the wild-type allele. In some cases, the methods and compositions provided herein can increase expression of a functional target protein having a target peptide sequence from a mutant hypomorphic allele, e.g., the MeCP2-e1 isoform encoded by exons 1, 3, and 4 of the MECP2 gene, in cells having pre-mRNA transcripts from the hypomorphic allele. In some cases, the methods and compositions provided herein can increase expression of the MeCP2-e1 isoform in cells having about 50% of the hypomorphic allele in a subject. In some cases, the methods and compositions restore MeCP2 function, e.g., function equivalent to a level of function as having a normal amount of WT MeCP2 protein, in cells having about 50% of the hypomorphic allele in a subject.

[0065] In some embodiments, a method is for increasing expression of a target protein by cells of a subject having a pre-mRNA encoding the target protein and including an exon with an inefficiently translated region or PTC followed by an alternative start codon, wherein the subject has a disease or condition caused by insufficient amounts or activity of the target protein due to autosomal recessive inheritance. In some embodiments, a method is for increasing expression of a target protein by cells of a subject having a pre-mRNA encoding the target protein and including an exon with an inefficiently translated region or PTC followed by an alternative start codon, wherein the subject has a disease or condition caused by insufficient amounts or activity of the target protein due to autosomal dominant inheritance. In some embodiments, the disease or condition is caused by or associated with haploinsufficiency of a target gene encoding the target protein. In some embodiments, a method is for increasing expression of a target protein by cells of a subject having a pre-mRNA encoding the target protein and including an exon with an inefficiently translated region or PTC followed by an alternative start codon, wherein the subject has a disease or condition caused by insufficient amounts or activity of the target protein due to X-linked dominant mutations. For example, the method can be a method of increasing expression of the MeCP2-e1 isoform by a cell (e.g., a brain cell, e.g., a neuron or glial cell) of a subject having a pre-mRNA that encodes MeCP2 and includes exon 2, and the subject has Rett syndrome caused by insufficient amounts or activity of MeCP2 caused by an X-linked dominant mutation.

[0066] In some embodiments, pre-mRNA transcripts encoding proteins that cause a disease or condition are targeted by the ASOs described herein. In some embodiments, pre-mRNA transcripts encoding proteins that are not disease-causing are targeted by the ASOs. For example, a disease resulting from a mutation or deficiency in a first protein in a particular pathway can be ameliorated by targeting a pre-mRNA (e.g., containing a target peptide sequence) encoding a second protein, thereby increasing production of the second protein. In some embodiments, the function of the second protein can also compensate for the mutation or deficiency in the first protein (causing the disease or condition). do.

[0067] In some embodiments, the methods and compositions include: (a) (i) the target protein is produced at a reduced level compared to production from a wild-type allele; (ii) the target protein is produced in a form that has reduced function compared to the equivalent wild-type protein, or (iii) a first mutant allele in which the target protein is not produced; and (b) (i) the target protein is produced at a reduced level compared to production from a wild-type allele; (ii) the target protein is produced in a form that has reduced function compared to the equivalent wild-type protein, or (iii) It is applicable to treat subjects who have a second mutant allele in which the target protein is not produced.

[0068] In some embodiments, the level of a first processed mRNA encoding a first protein comprising a target peptide sequence in cells contacted with a therapeutic agent provided herein is increased compared to the level of the first processed mRNA in otherwise identical control cells not contacted with the therapeutic agent. In some embodiments, the level of a first processed mRNA encoding a first protein comprising a target peptide sequence in cells contacted with a therapeutic agent provided herein is increased by about 1.1 to about 10-fold, about 1.5 to about 10-fold, about 2 to about 10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1 to about 5-fold, about 1.1 to about 6-fold, about 1.1 to about 7-fold, about 1.1 to about 8-fold, or about The level of a second processed mRNA encoding a second protein comprising a target peptide sequence in cells contacted with a therapeutic agent provided herein is increased by 1.1 to about 9-fold, about 2 to about 5-fold, about 2 to about 6-fold, about 2 to about 7-fold, about 2 to about 8-fold, about 2 to about 9-fold, about 3 to about 6-fold, about 3 to about 7-fold, about 3 to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold, about 4 to about 8-fold, about 4 to about 9-fold, at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 5-fold, or at least about 10-fold. In some embodiments, the level of a second processed mRNA encoding a second protein comprising an inefficiently translated region and comprising a target peptide sequence in cells contacted with a therapeutic agent provided herein is reduced compared to the level of the second processed mRNA in otherwise identical control cells not contacted with the therapeutic agent.In some embodiments, the level of a second processed mRNA that comprises an inefficiently translated region and encodes a second protein that comprises a target peptide sequence in cells contacted with a therapeutic agent provided herein is about 1.1 to about 10-fold, about 1.5 to about 10-fold, about 2 to about 10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1 to about 5-fold, about 1.1 to about 6-fold, about 1.1 to about 7-fold, about 1.1 to about 8-fold, about 1.1 to about 9-fold, about 1.1 to about 10-fold, about 1.1 to about 11-fold, about 1.1 to about 12-fold, about 1.1 to about 13-fold, about 1.1 to about 14-fold, about 1.1 to about 15-fold, about 1.1 to about 16-fold, about 1.1 to about 17-fold, about 1.1 to about 18-fold, about 1.1 to about 19-fold, about 1.1 to about 20-fold, about 1.1 to about 21-fold, about 1.1 to about 22-fold, about 1.1 to about 23-fold, about 1.1 to about 24-fold, about 1.1 to about 25-fold, about 1.1 to about 26-fold, about 1.1 to about 27-fold, about 1.1 to about 28-fold, about 1.1 to about 29-fold, about 1.1 to about 30-fold, about 1.1 to about 31-fold, about 1.1 to about 32-fold, about 1.1 to about 33-fold, about 1.1 to about 34-fold, about 1.1 to about 35-fold, about 1.1 to about 36-fold The reduction may be at least about 1.1 to about 8 times, at least about 1.1 to about 9 times, at least about 2 to about 5 times, at least about 2 to about 6 times, at least about 2 to about 7 times, at least about 2 to about 8 times, at least about 2 to about 9 times, at least about 3 to about 6 times, at least about 3 to about 7 times, at least about 3 to about 8 times, at least about 3 to about 9 times, at least about 4 to about 7 times, at least about 4 to about 8 times, at least 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.

[0069] In some embodiments, the therapeutic agents provided herein increase the expression of a target peptide sequence in a cell. In some embodiments, the level of the target peptide sequence in a cell contacted with a therapeutic agent is increased compared to the level of the target peptide sequence in an otherwise identical control cell that is not contacted with the therapeutic agent. In some embodiments, the level of the target peptide sequence in a cell contacted with a therapeutic agent is increased compared to the level of the target peptide sequence in the control cell. The level of the peptide sequence is increased by about 1.1 to about 10-fold, about 1.5 to about 10-fold, about 2 to about 10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1 to about 5-fold, about 1.1 to about 6-fold, about 1.1 to about 7-fold, about 1.1 to about 8-fold, about 1.1 to about 9-fold, about 2 to about 5-fold, about 2 to about 6-fold, about 2 to about 7-fold, about 2 to about 8-fold, about 2 to about 9-fold, about 3 to about 6-fold, about 3 to about 7-fold, about 3 to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold, about 4 to about 8-fold, about 4 to about 9-fold, at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 5-fold, or at least about 10-fold.

[0070] Inefficient translation areas As described herein, an inefficiently translated region can refer to any region in an mRNA transcript that contributes to the inefficient translation of a target peptide sequence encoded by the mRNA transcript in such a manner that a corresponding mRNA transcript without the inefficiently translated region has a higher translation efficiency for producing the target peptide sequence compared to an mRNA transcript with the inefficiently translated region. An inefficiently translated region can reduce the translation efficiency of an mRNA transcript of a target peptide sequence at the stage of translation initiation, elongation, termination, or any combination thereof. In some embodiments, an mRNA transcript with an inefficiently translated region has a translation efficiency that is approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% lower than a corresponding mRNA transcript without the inefficiently translated region. In some embodiments, an mRNA transcript having an inefficiently translated region has a higher mRNA transcript length than a corresponding mRNA transcript without an inefficiently translated region by about 1.2, 1.5, 1.8, 2, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 9, 10, 11, 12, 15, 18, 20, 22, 25, 28, 30, 35, 40, 50, 60, 70, 80, 90, 100, 120, 150, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 5000, 10 ... 4 , 10 5In some embodiments, an mRNA transcript with an inefficiently translated region has a translation efficiency that is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% less than a corresponding mRNA transcript without the inefficiently translated region. In some embodiments, an mRNA transcript having an inefficiently translated region has a nucleotide sequence that is at least about 1.2, 1.5, 1.8, 2, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 9, 10, 11, 12, 15, 18, 20, 22, 25, 28, 30, 35, 40, 50, 60, 70, 80, 90, 100, 120, 150, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 5000, 10 ... 4 , or 10 5 It has a 2-fold lower translation efficiency.

[0071] In some embodiments, the inefficiently translated region comprises a PTC followed by an alternative start codon. Without wishing to be bound by any particular theory, a motif or exon containing a PTC and an alternative start codon may contribute to inefficient translation of a downstream sequence because the PTC induces premature termination of translation of an upstream open reading frame in an mRNA, while the proximity of the alternative start codon to the PTC can prevent nonsense-mediated decay from initiating translation of the downstream open reading frame rather than reinitiation. In this regard, the efficiency of translation initiation of a downstream open reading frame may be relatively much lower than that of a canonical open reading frame starting from a canonical start codon (e.g., upstream of a downstream open reading frame). As exemplified in the case of MECP2 mRNA processing, removal of exon 2 containing the PTC and alternative start codon can result in increased production of the MeCP2-e1 isoform; however, the relative mature mRNA level may remain stable, and the MECP2 e1 mRNA isoform that does not contain exon 2 containing the PTC and alternative start codon may be significantly lower than that containing exon 2. This suggests that MECP2 e2 mRNA isoform has higher translation efficiency than MECP2 e2 mRNA isoform. In some embodiments, the distance between the PTC and the downstream start codon in the inefficiently translated region is short, for example, at most 75 nucleotides (nt), 70 nt, 60 nt, 55 nt, 50 nt, 45 nt, 40 nt, 35 nt, 30 nt, 27 nt, 24 nt, 21 nt, 18 nt, 15 nt, 12 nt, 10 nt, 9 nt, 6 nt, 3 nt, or 2 nt. In some embodiments, the distance between the PTC and the downstream start codon in the inefficiently translated region is about 3 nt, 6 nt, 9 nt, 10 nt, 12 nt, 15 nt, 18 nt, 21 nt, 24 nt, 27 nt, 30 nt, 35 nt, 40 nt, 45 nt, 50 nt, 55 nt, 60 nt, 70 nt, or 75 nt. In some cases, the distance between the PTC and the downstream start codon in the inefficiently translated region is at least 2 nt, 3 nt, 6 nt, 9 nt, 10 nt, 12 nt, 15 nt, 18 nt, 21 nt, 24 nt, 27 nt, 30 nt, 35 nt, 40 nt, 45 nt, 50 nt, or 55 nt. In some cases, the distance between the PTC and the downstream start codon in the inefficiently translated region is 2 nt to 75 nt, 5 nt to 70 nt, 10 nt to 65 nt, 15 nt to 60 nt, 20 nt to 55 nt, 25 nt to 50 nt, 30 nt to 45 nt, 40 nt to 50 nt, 45 nt to 55 nt, 50 nt to 60 nt, 55 nt to 70 nt, or 60 nt to 75 nt.

[0072] In some embodiments, the inefficiently translated region comprises a region encoding a proline-rich peptide sequence. Without wishing to be bound by a particular theory, the mRNA sequence encoding a proline-rich peptide sequence may, for example, contribute to the inefficient translation of the mRNA transcript containing it, for example, inefficient translation elongation. In some embodiments, the inefficiently translated region encodes a peptide sequence having at least about 5, 8, 10, 12, 15, 16, 18, 20, 22, 24, 26, 28, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 95 or 100 prolines. In some embodiments, the inefficiently translated region encodes a peptide sequence having a consecutive peptide sequence consisting of at least about 5, 8, 10, 12, 15, 16, 18, 20, 22, 24, 26, 28, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 95, or 100 prolines. In some embodiments, the inefficiently translated region encodes a peptide sequence having at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% prolines.

[0073] The inefficiently translated region can be any length. In some embodiments, the inefficiently translated region can be 5 to 10 nucleotides, 10 to 15 nucleotides, 15 to 20 nucleotides, 20 to 25 nucleotides, 25 to 30 nucleotides, 30 to 35 nucleotides, 35 to 40 nucleotides, 40 to 45 nucleotides, 45 to 50 nucleotides, 50 to 55 nucleotides, 55 to 60 nucleotides, 60 to 65 nucleotides, 65 to 70 nucleotides, 70 to 75 nucleotides, 75 to 80 nucleotides, 80 to 85 nucleotides, 85 to 90 nucleotides, 90 to 95 nucleotides, or 95 to 100 nucleotides in length. In some embodiments, the inefficiently translated region can be at least 10 nucleotides, at least 20 nucleotides, at least 30 nucleotides, at least 40 nucleotides, at least 50 nucleotides, at least 60 nucleotides, at least 70 nucleotides, at least 80 nucleotides in length, at least 90 nucleotides in length, or at least 100 nucleotides in length. In some embodiments, the inefficiently translated region can be 100-200 nucleotides in length, 200-300 nucleotides in length, 300-400 nucleotides in length, 400-500 nucleotides in length, 500-600 nucleotides in length, 600-700 nucleotides in length, 700-800 nucleotides in length, 80 It can be 0 to 900 nucleotides in length, or 900 to 1,000 nucleotides in length, In some embodiments, the inefficiently translated region can be longer than 1,000 nucleotides in length.

[0074] Regulation of translation of various targets In embodiments, the methods, compositions, and kits are applicable to modulating the translation of various targets, for example, for target peptide sequences whose translation is regulated by an inefficiently translated region present in a processed mRNA transcript encoding the target peptide sequence. In some cases, the inefficiently translated region comprises at least a portion of an exon comprising a PTC followed by an alternative start codon. Table 1 below lists exemplary target genes and their corresponding pre-mRNA transcripts that can be processed into mRNA transcripts having exons comprising a PTC followed by an alternative start codon. The sequences of the exons (and SEQ ID NOs) and their corresponding genomic coordinates are listed in the table. In some cases, the subject methods, compositions, and kits are applicable to modulating the translation of target peptide sequences encoded by the target genes listed in Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11]

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

[0075] ACIN1 In some cases, the target peptide sequence is a peptide encoding ACIN1 (apoptotic chromatin condensation inhibitor). Inducer 1) is a portion of a protein. In some cases, the therapeutic agent increases the level of a first processed mRNA encoding a protein having the sequence of SEQ ID NO: 8096 and decreases the level of a second processed mRNA encoding a protein having the sequence of SEQ ID NO: 332. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 130. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 130. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr14 23071186. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr14 23071186.In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 130. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 130. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr14 23071125. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr14 23071125. In some cases, the targeted region of the pre-mRNA is within the sequence of SEQ ID NO: 130. In some cases, the targeted region of the pre-mRNA is within the sequence between the pair of genomic sites GRCh38 / hg38:chr14 23071186 and GRCh38 / hg38:chr14 23071125.In some cases, the therapeutic agent is at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 10% identical to SEQ ID NO:130. In some cases, the therapeutic agent is an antisense oligomer complementary to a sequence having 0% sequence identity. In some cases, the therapeutic agent is an antisense oligomer complementary to a sequence having 100% sequence identity to SEQ ID NO: 130. In some cases, the therapeutic agent is an antisense oligomer having a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 534-584. In some cases, the therapeutic agent is an antisense oligomer having a sequence selected from the group consisting of SEQ ID NOs: 534-584. In some cases, the target peptide sequence is a portion of the ACIN1 protein, and the method treats a disease or condition, including intellectual disability; or colorectal cancer.

[0076] ACTN1 In some cases, the target peptide sequence is a portion of the ACTN1 protein. In some cases, the therapeutic agent increases the level of a first processed mRNA encoding a protein having the sequence of SEQ ID NO: 8097 and decreases the level of a second processed mRNA encoding a protein having the sequence of SEQ ID NO: 333. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 131. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 131. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr14 68925672. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr14 68925672.In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 131. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 131. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, or about 70 nucleotides of the genomic site GRCh38 / hg38:chr14 68925558. nucleotides, about 60 nucleotides, or about 50 nucleotides downstream. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr14 68925558. In some cases, the targeted region of the pre-mRNA is within the sequence of SEQ ID NO: 131. In some cases, the targeted region of the pre-mRNA is within the sequence between the pair of genomic sites GRCh38 / hg38:chr14 68925672 and GRCh38 / hg38:chr14 68925558. In some cases, the therapeutic agent is an antisense oligomer complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 131. In some cases, the therapeutic agent is an antisense oligomer complementary to a sequence having 100% sequence identity to SEQ ID NO: 131. In some cases, the therapeutic agent is an antisense oligomer having a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 585-646. In some cases, the therapeutic agent is an antisense oligomer having a sequence selected from the group consisting of SEQ ID NOs: 585-646. In some cases, the target peptide sequence is a portion of the ACTN1 protein and the method treats a disease or condition, including a bleeding disorder, platelet type 15; or autosomal dominant macrothrombocytopenia.

[0077] ACTN2 In some cases, the target peptide sequence is a portion of the ACTN2 protein. In some cases, the therapeutic agent increases the level of a first processed mRNA encoding a protein having the sequence of SEQ ID NO: 8098 and decreases the level of a second processed mRNA encoding a protein having the sequence of SEQ ID NO: 334. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 132. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 132. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr1 236735635. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of the genomic site GRCh38 / hg38:chr1 236735635.In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides of SEQ ID NO:132. nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 132. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 132. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr1 236735720. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr1 The targeted region of the pre-mRNA is at least about 1500, 1000, 800, 700, 600, 500, 400, 300, 200, 100, 80, 70, 60, or 50 nucleotides downstream of 236735720. In some cases, the targeted region of the pre-mRNA is within the sequence of SEQ ID NO: 132. In some cases, the targeted region of the pre-mRNA is within the sequence between the pair of genomic sites GRCh38 / hg38:chr1 236735635 and GRCh38 / hg38:chr1 236735720. In some cases, the therapeutic agent is an antisense oligomer complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 132. In some cases, the therapeutic agent is an antisense oligomer complementary to a sequence having 100% sequence identity to SEQ ID NO: 132. In some cases, the therapeutic agent is an antisense oligomer having a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 647-702. In some cases, the therapeutic agent is an antisense oligomer having a sequence selected from the group consisting of SEQ ID NOs: 647-702. In some cases, the target peptide sequence is a portion of the ACTN2 protein, and the method treats a disease or condition including hypertrophic cardiomyopathy; cardiomyopathy, dilated, 1AA; cardiomyopathy, familial hypertrophic, 23, with or without noncompaction; familial dilated cardiomyopathy; Charcot-Marie-Tooth disease; cardiac conduction disorders; or cardiomyopathy, dilated.

[0078] ADH4 In some cases, the target peptide sequence is a portion of the ADH4 protein. In some cases, the therapeutic agent increases the level of a first processed mRNA encoding a protein having the sequence of SEQ ID NO: 8099 and decreases the level of a second processed mRNA encoding a protein having the sequence of SEQ ID NO: 335. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 133. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 1500 nucleotides of SEQ ID NO: 133. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr4 99143305. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr4 99143305. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 133. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 133.In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr4 99143166. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr4 99143166. In some cases, the targeted region of the pre-mRNA is within the sequence of SEQ ID NO: 133. In some cases, the targeted region of the pre-mRNA is within the sequence between the pair of genomic sites GRCh38 / hg38:chr4 99143305 and GRCh38 / hg38:chr4 99143166. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 133. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having 100% sequence identity to SEQ ID NO: 133. In some cases, the therapeutic agent increases the level of a first processed mRNA encoding a protein having the sequence of SEQ ID NO: 8100 and decreases the level of a second processed mRNA encoding a protein having the sequence of SEQ ID NO: 336.In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 134. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, or about 500 nucleotides upstream of SEQ ID NO: 134. nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of the target region of the pre-mRNA. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of the genomic site GRCh38 / hg38:chr4 99143305. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr4 99143305. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 134. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 134.In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr4 99143166. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr4 99143166. In some cases, the targeted region of the pre-mRNA is within the sequence of SEQ ID NO: 134. In some cases, the targeted region of the pre-mRNA is within the sequence between the pair of genomic sites GRCh38 / hg38:chr4 99143305 and GRCh38 / hg38:chr4 99143166. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 134. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having 100% sequence identity to SEQ ID NO: 134. In some cases, the therapeutic agent is an antisense oligomer having a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 703-769. In some cases, the therapeutic agent is an antisense oligomer having a sequence selected from the group consisting of SEQ ID NOs: 703-769.In some cases, the target peptide sequence is a portion of the ADH4 protein and the method treats a disease or condition, including alcohol use disorder; alcohol abuse; or alcoholism, chronic.

[0079] AGER In some cases, the target peptide sequence is a portion of the AGER protein. In some cases, the therapeutic agent increases the level of a first processed mRNA encoding a protein having the sequence of SEQ ID NO: 8101 and decreases the level of a second processed mRNA encoding a protein having the sequence of SEQ ID NO: 337. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 135. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 135. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr6 32182698. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr6 32182698.In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 135. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 135. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr6 32182568. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr6 32182568. In some cases, the targeted region of the pre-mRNA is within the sequence of SEQ ID NO: 135. In some cases, the targeted region of the pre-mRNA is within the sequence between the pair of genomic sites GRCh38 / hg38:chr6 32182698 and GRCh38 / hg38:chr6 32182568. In some cases, a therapeutic agent. is an antisense oligomer complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 135. In some cases, the therapeutic agent is an antisense oligomer complementary to a sequence having 100% sequence identity to SEQ ID NO: 135. In some cases, the therapeutic agent is an antisense oligomer having a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 8031-8095. In some cases, the therapeutic agent is an antisense oligomer having a sequence selected from the group consisting of SEQ ID NOs: 8031-8095. In some cases, the target peptide sequence is a portion of an AGER protein, and the method treats a disease or condition, including schizophrenia.

[0080] AKR1C3 In some cases, the target peptide sequence is a portion of the AKR1C3 protein. In some cases, the therapeutic agent increases the level of a first processed mRNA encoding a protein having the sequence of SEQ ID NO: 8102 and decreases the level of a second processed mRNA encoding a protein having the sequence of SEQ ID NO: 338. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 136. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 136. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr10 5077900. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr10 5077900.In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 136. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 136. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, or about 300 nucleotides of the genomic site GRCh38 / hg38:chr10 5077977. The targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of the genomic site GRCh38 / hg38:chr10 5077977. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of the genomic site GRCh38 / hg38:chr10 5077977. In some cases, the targeted region of the pre-mRNA is within the sequence of SEQ ID NO: 136. In some cases, the targeted region of the pre-mRNA is within the sequence between the pair of genomic sites GRCh38 / hg38:chr10 5077900 and GRCh38 / hg38:chr10 5077977. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 136. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having 100% sequence identity to SEQ ID NO: 136. In some cases, the therapeutic agent is an antisense oligomer having a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 770-824. In some cases, the therapeutic agent is an antisense oligomer having a sequence selected from the group consisting of SEQ ID NOs: 770 to 824. In some cases, the target peptide sequence is a portion of the AKR1C3 protein and the method treats a disease or condition, including bipolar disorder; or alcoholism, chronic.

[0081] ALDH1A2 In some cases, the target peptide sequence is a portion of the ALDH1A2 protein. In some cases, the therapeutic agent increases the level of a first processed mRNA encoding a protein having the sequence of SEQ ID NO: 8103 and decreases the level of a second processed mRNA encoding a protein having the sequence of SEQ ID NO: 339. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 137. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 137. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr15 58058108. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr15 58058108.In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, of SEQ ID NO:137. The targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 137. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 137. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr15 58058012. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr15 58058012. In some cases, the targeted region of the pre-mRNA is within the sequence of SEQ ID NO: 137. In some cases, the targeted region of the pre-mRNA is within the sequence between the pair of genomic sites GRCh38 / hg38:chr15 58058108 and GRCh38 / hg38:chr15 58058012.In some cases, the therapeutic agent is an antisense oligomer complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 137. In some cases, the therapeutic agent is an antisense oligomer complementary to a sequence having 100% sequence identity to SEQ ID NO: 137. In some cases, the therapeutic agent is an antisense oligomer having a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 825-882. In some cases, the therapeutic agent is an antisense oligomer having a sequence selected from the group consisting of SEQ ID NOs: 825-882. In some cases, the target peptide sequence is a portion of the ALDH1A2 protein, and the method treats a disease or condition, including schizophrenia.

[0082] ALG8 In some cases, the target peptide sequence is a portion of an ALG8 protein. In some cases, the therapeutic agent increases the level of a first processed mRNA encoding a protein having the sequence of SEQ ID NO: 8104 and decreases the level of a second processed mRNA encoding a protein having the sequence of SEQ ID NO: 340. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 138. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 138. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr11 78138767. At most about 1500, 1000, 800, 700, 600, 500, 400, 300, 200, 100, 80, 70, 60, or 50 nucleotides upstream. In some cases, the targeted region of the pre-mRNA is at least about 1500, 1000, 800, 700, 600, 500, 400, 300, 200, 100, 80, 70, 60, or 50 nucleotides upstream of genomic site GRCh38 / hg38:chr11 78138767. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 138. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 138. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr11 78138710.In some cases, the targeted region of the pre-mRNA is the genomic site GRCh38 / hg38:chr11. The targeted region of the pre-mRNA is at least about 1500, 1000, 800, 700, 600, 500, 400, 300, 200, 100, 80, 70, 60, or 50 nucleotides downstream of 78138710. In some cases, the targeted region of the pre-mRNA is within the sequence of SEQ ID NO: 138. In some cases, the targeted region of the pre-mRNA is within the sequence between the pair of genomic sites GRCh38 / hg38:chr11 78138767 and GRCh38 / hg38:chr11 78138710. In some cases, the therapeutic agent is an antisense oligomer complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 138. In some cases, the therapeutic agent is an antisense oligomer complementary to a sequence having 100% sequence identity to SEQ ID NO: 138. In some cases, the therapeutic agent is an antisense oligomer having a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 883-933. In some cases, the therapeutic agent is an antisense oligomer having a sequence selected from the group consisting of SEQ ID NOs: 883-933. In some cases, the target peptide sequence is a portion of the ALG8 protein and the method treats a disease or condition, including intellectual disability; a congenital glycosylation disorder; an epileptic encephalopathy; a depressive disorder; or a congenital glycosylation disorder type 1H.

[0083] AMPD2 In some cases, the target peptide sequence is a portion of the AMPD2 protein. In some cases, the therapeutic agent increases the level of a first processed mRNA encoding a protein having the sequence of SEQ ID NO: 8105, and a protein having the sequence of SEQ ID NO: 341.In some cases, the level of the second processed mRNA encoding SEQ ID NO: 139 is reduced. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 139. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 139. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr1 109620914. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr1 109620914.In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 139. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 139. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr1 109621266. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr1. The targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of 109621266. In some cases, the targeted region of the pre-mRNA is within the sequence of SEQ ID NO: 139. In some cases, the targeted region of the pre-mRNA is within the sequence between the pair of genomic sites GRCh38 / hg38:chr1 109620914 and GRCh38 / hg38:chr1 109621266. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 139. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having 100% sequence identity to SEQ ID NO: 139. In some cases, the therapeutic agent is an antisense oligomer having a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 934-1043. In some cases, the therapeutic agent is an antisense oligomer having a sequence selected from the group consisting of SEQ ID NOs: 934-1043. In some cases, the target peptide sequence is a portion of the AMPD2 protein, and the method treats a disease or condition, including intellectual disability; pontocerebellar hypoplasia type 9; epileptic encephalopathy; ataxia, hereditary; spastic paraplegia 63, autosomal recessive; cerebellar hypoplasia; or spastic paraplegia, hereditary.

[0084] AMT In some cases, the target peptide sequence is a portion of the AMT protein. In some cases, the therapeutic agent increases the level of a first processed mRNA encoding a protein having the sequence of SEQ ID NO: 8106 and decreases the level of a second processed mRNA encoding a protein having the sequence of SEQ ID NO: 342. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 140. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 140. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr3 49422257. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr3 49422257.In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 140. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 140. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr3 49422104. The targeted region of the RNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr3 49422104. In some cases, the targeted region of the pre-mRNA is within the sequence of SEQ ID NO: 140. In some cases, the targeted region of the pre-mRNA is within the sequence between the pair of genomic sites GRCh38 / hg38:chr3 49422257 and GRCh38 / hg38:chr3 49422104. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 140. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having 100% sequence identity to SEQ ID NO: 140. In some cases, the therapeutic agent increases the level of a first processed mRNA encoding a protein having the sequence of SEQ ID NO: 8107 and decreases the level of a second processed mRNA encoding a protein having the sequence of SEQ ID NO: 343. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO:141.In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 141. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr3 49422257. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr3 49422257. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 141.In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 141. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, or about 200 nucleotides downstream of genomic site GRCh38 / hg38:chr3 49422104. The targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr3 49422104. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr3 49422104. In some cases, the targeted region of the pre-mRNA is within the sequence of SEQ ID NO: 141. In some cases, the targeted region of the pre-mRNA is within the sequence between the pair of genomic sites GRCh38 / hg38:chr3 49422257 and GRCh38 / hg38:chr3 49422104. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 141. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having 100% sequence identity to SEQ ID NO: 141. In some cases, the therapeutic agent increases the level of a first processed mRNA encoding a protein having the sequence of SEQ ID NO: 8108 and decreases the level of a second processed mRNA encoding a protein having the sequence of SEQ ID NO: 344. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO:142.In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 142. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr3 49422257. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr3 49422257. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 142.In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 142. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, or about 1500 nucleotides of genomic site GRCh38 / hg38:chr3 49422104. The targeted region of the pre-mRNA is about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of the genomic site GRCh38 / hg38:chr3 49422104. In some cases, the targeted region of the pre-mRNA is within the sequence of SEQ ID NO: 142. In some cases, the targeted region of the pre-mRNA is within the sequence between the pair of genomic sites GRCh38 / hg38:chr3 49422257 and GRCh38 / hg38:chr3 49422104. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 142. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having 100% sequence identity to SEQ ID NO: 142. In some cases, the therapeutic agent is an antisense oligomer having a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 1044-1113. In some cases, the therapeutic agent is an antisense oligomer having a sequence selected from the group consisting of SEQ ID NOs: 1044 to 1113. In some cases, the target peptide sequence is a portion of an AMT protein, and the method treats a disease or condition, including nonketotic hyperglycinemia; transient neonatal hyperglycinemia; or glycine encephalopathy.

[0085] ANKRD11 In some cases, the target peptide sequence is a portion of the ANKRD11 protein. In some cases, the therapeutic agent increases the level of a first processed mRNA encoding a protein having the sequence of SEQ ID NO: 8109 and decreases the level of a second processed mRNA encoding a protein having the sequence of SEQ ID NO: 345. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 143. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 143. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr16 89317078. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, about 75 nucleotides, about 80 nucleotides, about 90 nucleotides, about 95 nucleotides, about 100 nucleotides, about 150 ... 0 nucleotides, or about 50 nucleotides upstream. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 143. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 143. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr16 89316933. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr16 89316933. In some cases, the targeted region of the pre-mRNA is within the sequence of SEQ ID NO: 143. In some cases, the targeted region of the pre-mRNA is within the sequence between the pair of genomic sites GRCh38 / hg38:chr16 89317078 and GRCh38 / hg38:chr16 89316933.In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 143. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having 100% sequence identity to SEQ ID NO: 143. In some cases, the therapeutic agent increases the level of a first processed mRNA encoding a protein having the sequence of SEQ ID NO: 8110 and decreases the level of a second processed mRNA encoding a protein having the sequence of SEQ ID NO: 346. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 144. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 144. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr16 89317078.In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, or about 600 nucleotides of genomic site GRCh38 / hg38:chr16 89317078. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 60 nucleotides, about 50 nucleotides upstream of SEQ ID NO: 144. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 144. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 144. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr16 89316933. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr16 89316933. In some cases, the targeted region of the pre-mRNA is within the sequence of SEQ ID NO: 144.In some cases, the targeted region of the pre-mRNA is within the sequence between the pair of genomic sites GRCh38 / hg38:chr16 89317078 and GRCh38 / hg38:chr16 89316933. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 144. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having 100% sequence identity to SEQ ID NO: 144. In some cases, the therapeutic agent increases the level of a first processed mRNA encoding a protein having the sequence of SEQ ID NO: 8111 and decreases the level of a second processed mRNA encoding a protein having the sequence of SEQ ID NO: 347. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 145. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 145. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr16 89317078.In some cases, the targeted region of the pre-mRNA is the genomic site GRCh38 / h. g38:chr16 89317078. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 145. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 145. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr16 89316933.In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr16 89316933. In some cases, the targeted region of the pre-mRNA is within the sequence of SEQ ID NO: 145. In some cases, the targeted region of the pre-mRNA is within the sequence between the pair of genomic sites GRCh38 / hg38:chr16 89317078 and GRCh38 / hg38:chr16 89316933. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 145. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having 100% sequence identity to SEQ ID NO: 145. In some cases, the therapeutic agent increases the level of a first processed mRNA encoding a protein having the sequence of SEQ ID NO: 8112 and decreases the level of a second processed mRNA encoding a protein having the sequence of SEQ ID NO: 348. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO:146.In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 146. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, or about 80 nucleotides upstream of genomic site GRCh38 / hg38:chr16 89317075. In some cases, the targeted region of the pre-mRNA is at least about 1500, about 1000, about 800, about 700, about 600, about 500, about 400, about 300, about 200, about 100, about 80, about 70, about 60, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr16 89317075. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 146. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 146. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr16 89316933. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr16 The targeted region of the pre-mRNA is at least about 1500, 1000, 800, 700, 600, 500, 400, 300, 200, 100, 80, 70, 60, or 50 nucleotides downstream of 89316933. In some cases, the targeted region of the pre-mRNA is within the sequence of SEQ ID NO: 146. In some cases, the targeted region of the pre-mRNA is within the sequence between the pair of genomic sites GRCh38 / hg38:chr16 89317075 and GRCh38 / hg38:chr16 89316933. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 146. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having 100% sequence identity to SEQ ID NO: 146. In some cases, the therapeutic agent increases the level of a first processed mRNA encoding a protein having the sequence of SEQ ID NO: 8113 and decreases the level of a second processed mRNA encoding a protein having the sequence of SEQ ID NO: 349. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 147. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 147.In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, or about 700 nucleotides of genomic site GRCh38 / hg38:chr16 89317078. nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr16 89317078. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 147. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 147. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr16 89316933. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr16 89316933. In some cases, the targeted region of the pre-mRNA is within the sequence of SEQ ID NO: 147. In some cases, the targeted region of the pre-mRNA is within the genomic site GRCh38 / hg38:chr16 89317078, and GRCh38 / hg38:chr16 89316933. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 147. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having 100% sequence identity to SEQ ID NO: 147. In some cases, the therapeutic agent increases the level of a first processed mRNA encoding a protein having the sequence of SEQ ID NO: 8114 and decreases the level of a second processed mRNA encoding a protein having the sequence of SEQ ID NO: 350. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 148. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 148. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr16 89317078. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr16 89317078. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 148. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 148.In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr16 89316933. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr16 89316933. In some cases, the targeted region of the pre-mRNA is within the sequence of SEQ ID NO: 148. In some cases, the targeted region of the pre-mRNA is within the sequence between the pair of genomic sites GRCh38 / hg38:chr16 89317078 and GRCh38 / hg38:chr16 89316933. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 148. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having 100% sequence identity to SEQ ID NO: 148. In some cases, the therapeutic agent increases the level of a first processed mRNA encoding a protein having the sequence of SEQ ID NO: 8115 and decreases the level of a second processed mRNA encoding a protein having the sequence of SEQ ID NO: 351.In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 149. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 40 nucleotides upstream of SEQ ID NO: 149. 0 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr16 89317075. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr16 89317075. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 149. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 149.In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr16 89316933. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr16 89316933. In some cases, the targeted region of the pre-mRNA is within the sequence of SEQ ID NO: 149. In some cases, the targeted region of the pre-mRNA is within the sequence between the pair of genomic sites GRCh38 / hg38:chr16 89317075 and GRCh38 / hg38:chr16 89316933. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 149. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having 100% sequence identity to SEQ ID NO: 149. In some cases, the therapeutic agent increases the level of a first processed mRNA encoding a protein having the sequence of SEQ ID NO: 8116 and decreases the level of a second processed mRNA encoding a protein having the sequence of SEQ ID NO: 352.In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 150. In some cases, the targeted region of the pre-mRNA is SEQ ID NO: 1. 50 at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr16 89317078. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr1 nucleotides, about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 150. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 150. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 150. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr16 89316933.In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr16 89316933. In some cases, the targeted region of the pre-mRNA is within the sequence of SEQ ID NO: 150. In some cases, the targeted region of the pre-mRNA is within the sequence between the pair of genomic sites GRCh38 / hg38:chr16 89317078 and GRCh38 / hg38:chr16 89316933. In some cases, the therapeutic agent is an antisense oligomer complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 150. In some cases, the therapeutic agent is an antisense oligomer complementary to a sequence having 100% sequence identity to SEQ ID NO: 150. In some cases, the therapeutic agent increases the level of a first processed mRNA encoding a protein having the sequence of SEQ ID NO: 8117 and decreases the level of a second processed mRNA encoding a protein having the sequence of SEQ ID NO: 353. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, or about 500 nucleotides of SEQ ID NO: 151. The targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 151. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 151. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr16 89317078. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr16 The targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of 89317078. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 151. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 151. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr16 89316933.In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr16 89316933. In some cases, the targeted region of the pre-mRNA is within the sequence of SEQ ID NO: 151. In some cases, the targeted region of the pre-mRNA is within the sequence between the pair of genomic sites GRCh38 / hg38:chr16 89317078 and GRCh38 / hg38:chr16 89316933. In some cases, the therapeutic agent is an antisense oligomer complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 151. In some cases, the therapeutic agent is an antisense oligomer complementary to a sequence having 100% sequence identity to SEQ ID NO: 151. In some cases, the therapeutic agent increases the level of a first processed mRNA encoding a protein having the sequence of SEQ ID NO: 8118 and decreases the level of a second processed mRNA encoding a protein having the sequence of SEQ ID NO: 354. In some cases, the therapeutic agent targets pre-mRNA. The targeted region is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 152. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 152. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr16 89317075. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr16 89317075.In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 152. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 152. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr16 89316933. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr16 89316933. In some cases, the targeted region of the pre-mRNA is within the sequence of SEQ ID NO: 152. In some cases, the targeted region of the pre-mRNA is within the sequence between the pair of genomic sites GRCh38 / hg38:chr16 89317075 and GRCh38 / hg38:chr16 89316933. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 152. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having 100% sequence identity to SEQ ID NO: 152. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a protein having the sequence of SEQ ID NO: 8119. and decreases the level of a second processed mRNA encoding a protein having the sequence of SEQ ID NO: 355. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 153. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 153. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr16 89317078. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr16 89317078.In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 153. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 153. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr16 89316933. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr16 89316933. In some cases, the targeted region of the pre-mRNA is within the sequence of SEQ ID NO: 153. In some cases, the targeted region of the pre-mRNA is within the sequence between the pair of genomic sites GRCh38 / hg38:chr16 89317078 and GRCh38 / hg38:chr16 89316933.In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 153. In some cases, the therapeutic agent is a sequence. an antisense oligomer complementary to a sequence having 100% sequence identity to SEQ ID NO: 153. In some cases, the therapeutic agent increases the level of a first processed mRNA encoding a protein having the sequence of SEQ ID NO: 8120 and decreases the level of a second processed mRNA encoding a protein having the sequence of SEQ ID NO: 356. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 154. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 154. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr16 89317075. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr16 89317075.In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 154. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 154. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr16 89316933. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr16 89316933. In some cases, the targeted region of the pre-mRNA is within the sequence of SEQ ID NO: 154. In some cases, the targeted region of the pre-mRNA is within the sequence between the pair of genomic sites GRCh38 / hg38:chr16 89317075 and GRCh38 / hg38:chr16 89316933.In some cases, the therapeutic agent has a sequence similar to SEQ ID NO:154 but at least about 80%, 85%, 90%. , 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 154. In some cases, the therapeutic agent is an antisense oligomer complementary to a sequence having 100% sequence identity to SEQ ID NO: 154. In some cases, the therapeutic agent increases the level of a first processed mRNA encoding a protein having the sequence of SEQ ID NO: 8121 and decreases the level of a second processed mRNA encoding a protein having the sequence of SEQ ID NO: 357. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 155. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, or about 300 nucleotides of SEQ ID NO: 155. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of the genomic site GRCh38 / hg38:chr16 89317078. The targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr16 89317078. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr16 89317078. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 155. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 155. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr16 89316933.In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, or about 80 nucleotides of genomic site GRCh38 / hg38:chr16 89316933. The targeted region of the pre-mRNA is about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream. In some cases, the targeted region of the pre-mRNA is within the sequence of SEQ ID NO: 155. In some cases, the targeted region of the pre-mRNA is within the sequence between the pair of genomic sites GRCh38 / hg38:chr16 89317078 and GRCh38 / hg38:chr16 89316933. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 155. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having 100% sequence identity to SEQ ID NO: 155. In some cases, the therapeutic agent increases levels of a first processed mRNA encoding a protein having the sequence of SEQ ID NO: 8122 and decreases levels of a second processed mRNA encoding a protein having the sequence of SEQ ID NO: 358. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 156. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 156.In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr16 89317078. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr16 89317078. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 156. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 156.In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr16 89316933. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, or about 700 nucleotides downstream of genomic site GRCh38 / hg38:chr16 89316933. The targeted region of the pre-mRNA is about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream. In some cases, the targeted region of the pre-mRNA is within the sequence of SEQ ID NO: 156. In some cases, the targeted region of the pre-mRNA is within the sequence between the pair of genomic sites GRCh38 / hg38:chr16 89317078 and GRCh38 / hg38:chr16 89316933. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 156. In some cases, the therapeutic agent is an antisense oligomer complementary to a sequence having 100% sequence identity to SEQ ID NO: 156. In some cases, the therapeutic agent is an antisense oligomer having a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 1114-1181. In some cases, the therapeutic agent is an antisense oligomer having a sequence selected from the group consisting of SEQ ID NOs: 1114-1181. In some cases, the target peptide sequence is a portion of the ANKRD11 protein, and the method treats a disease or condition comprising intellectual disability; KBG syndrome; or 16q24.3 microdeletion syndrome.

[0086] ANKS3 In some cases, the target peptide sequence is a portion of the ANKS3 protein. In some cases, the therapeutic agent increases the level of a first processed mRNA encoding a protein having the sequence of SEQ ID NO: 8123 and decreases the level of a second processed mRNA encoding a protein having the sequence of SEQ ID NO: 359. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 157. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 157. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr16 4726780. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr16 4726780.In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 157. In some cases, the targeted region of the pre-mRNA is , or at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 157. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr16 4726659. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr16 4726659. In some cases, the targeted region of the pre-mRNA is within the sequence of SEQ ID NO: 157. In some cases, the targeted region of the pre-mRNA is within the sequence between the pair of genomic sites GRCh38 / hg38:chr16 4726780 and GRCh38 / hg38:chr16 4726659. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 157. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having 100% sequence identity to SEQ ID NO: 157.In some cases, the therapeutic agent is an antisense oligomer having a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 1182-1244. In some cases, the therapeutic agent is an antisense oligomer having a sequence selected from the group consisting of SEQ ID NOs: 1182-1244. In some cases, the target peptide sequence is a portion of an ANKS3 protein, and the method treats a disease or condition involving situs inversus.

[0087] APOL4 In some cases, the target peptide sequence is a portion of the APOL4 protein. In some cases, the therapeutic agent increases the level of a first processed mRNA encoding a protein having the sequence of SEQ ID NO: 8124 and decreases the level of a second processed mRNA encoding a protein having the sequence of SEQ ID NO: 360. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 158. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 158. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr22 36201796. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr22 36201796. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 158. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 158. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr22 36201700.In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr22 36201700. In some cases, the targeted region of the pre-mRNA is within the sequence of SEQ ID NO: 158. In some cases, the targeted region of the pre-mRNA is within the sequence between the pair of genomic sites GRCh38 / hg38:chr22 36201796 and GRCh38 / hg38:chr22 36201700. In some cases, the therapeutic agent is an antisense oligomer complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 158. In some cases, the therapeutic agent is an antisense oligomer complementary to a sequence having 100% sequence identity to SEQ ID NO: 158. In some cases, the therapeutic agent is an antisense oligomer having a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 1245-1302. In some cases, the therapeutic agent is an antisense oligomer having a sequence selected from the group consisting of SEQ ID NOs: 1245-1302. In some cases, the target peptide sequence is a portion of an APOL4 protein, and the method treats a disease or condition, including schizophrenia.

[0088] APPL1 In some cases, the target peptide sequence is a portion of the APPL1 protein. In some cases, the therapeutic agent increases the level of a first processed mRNA encoding a protein having the sequence of SEQ ID NO: 8125 and decreases the level of a second processed mRNA encoding a protein having the sequence of SEQ ID NO: 361. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 80 nucleotides, about 90 nucleotides, about 100 nucleotides, about 15 ... In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 159. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr3 57230714. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr3 57230714. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 159.In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 159. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr3 57230767. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr3 57230767. In some cases, the targeted region of the pre-mRNA is within the sequence of SEQ ID NO: 159. In some cases, the targeted region of the pre-mRNA is within the sequence between the pair of genomic sites GRCh38 / hg38:chr3 57230714 and GRCh38 / hg38:chr3 57230767. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 159. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having 100% sequence identity to SEQ ID NO: 159.In some cases, the therapeutic agent is an antisense oligomer having a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 1303-1352. In some cases, the therapeutic agent is an antisense oligomer having a sequence selected from the group consisting of SEQ ID NOs: 1303-1352. In some cases, the target peptide sequence is an APPL1 protein. The method is part of a method for treating diseases or conditions including malignant neoplasms of the breast; maturity-onset diabetes of the young; or maturity-onset diabetes of the young type 14.

[0089] ARCN1 In some cases, the target peptide sequence is a portion of the ARCN1 protein. In some cases, the therapeutic agent increases the level of a first processed mRNA encoding a protein having the sequence of SEQ ID NO: 8126 and decreases the level of a second processed mRNA encoding a protein having the sequence of SEQ ID NO: 362. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 160. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 160. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr11 118573620. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr11 118573620.In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 160. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 160. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr11 118573783. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of the genomic site GRCh38 / hg38:chr11 118573783. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of the genomic site GRCh38 / hg38:chr11 118573783. The region is within the sequence of SEQ ID NO: 160. In some cases, the targeted region of the pre-mRNA is within the sequence between the pair of genomic sites GRCh38 / hg38:chr11 118573620 and GRCh38 / hg38:chr11 118573783. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 160. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having 100% sequence identity to SEQ ID NO: 160. In some cases, the therapeutic agent is an antisense oligomer having a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 1353-1424. In some cases, the therapeutic agent is an antisense oligomer having a sequence selected from the group consisting of SEQ ID NOs: 1353-1424. In some cases, the target peptide sequence is a portion of the ARCN1 protein and the method treats a disease or condition including intellectual disability; or microcephaly.

[0090] ARMC8 In some cases, the target peptide sequence is a portion of the ARMC8 protein. In some cases, the therapeutic agent increases the level of a first processed mRNA encoding a protein having the sequence of SEQ ID NO: 8127 and decreases the level of a second processed mRNA encoding a protein having the sequence of SEQ ID NO: 363. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 161. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 161. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr3 138188455. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr3 138188455.In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 161. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 161. 0 nucleotides downstream. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of the genomic site GRCh38 / hg38:chr3 138188530. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of the genomic site GRCh38 / hg38:chr3 The targeted region of the pre-mRNA is at least about 1500, 1000, 800, 700, 600, 500, 400, 300, 200, 100, 80, 70, 60, or 50 nucleotides downstream of 138188530. In some cases, the targeted region of the pre-mRNA is within the sequence of SEQ ID NO: 161. In some cases, the targeted region of the pre-mRNA is within the sequence between the pair of genomic sites GRCh38 / hg38:chr3 138188455 and GRCh38 / hg38:chr3 138188530. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 161. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having 100% sequence identity to SEQ ID NO: 161. In some cases, the therapeutic agent increases the level of a first processed mRNA encoding a protein having the sequence of SEQ ID NO: 8128 and decreases the level of a second processed mRNA encoding a protein having the sequence of SEQ ID NO: 364. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 162. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 162.In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr3 138188455. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr3 138188455. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 162. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, or about 500 nucleotides of SEQ ID NO:162. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr3 138188530. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr3 138188530. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr3 138188530. In some cases, the targeted region of the pre-mRNA is within the sequence of SEQ ID NO: 162. In some cases, the targeted region of the pre-mRNA is within the sequence between the pair of genomic sites GRCh38 / hg38:chr3 138188455 and GRCh38 / hg38:chr3 138188530. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 162. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having 100% sequence identity to SEQ ID NO: 162. In some cases, the therapeutic agent is an antisense oligomer that has a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 1425-1478.In some cases, the therapeutic agent is an antisense oligomer having a sequence selected from the group consisting of SEQ ID NOs: 1425 to 1478. In some cases, the target peptide sequence is a portion of an ARMC8 protein and the method treats a disease or condition, including polydactyly; or ciliopathies.

[0091] ARNTL In some cases, the target peptide sequence is a portion of the ARNTL protein. In some cases, the therapeutic agent increases the level of a first processed mRNA encoding a protein having the sequence of SEQ ID NO: 8129 and decreases the level of a second processed mRNA encoding a protein having the sequence of SEQ ID NO: 365. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 163. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 163. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr11 13355226. In some cases, the targeted region of the pre-mRNA is located at the genomic site GRCh38 / h g38:chr11 13355226. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 163. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 163. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr11 13355296.In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr11 13355296. In some cases, the targeted region of the pre-mRNA is within the sequence of SEQ ID NO: 163. In some cases, the targeted region of the pre-mRNA is within the sequence between the pair of genomic sites GRCh38 / hg38:chr11 13355226 and GRCh38 / hg38:chr11 13355296. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 163. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having 100% sequence identity to SEQ ID NO: 163. In some cases, the therapeutic agent increases the level of a first processed mRNA encoding a protein having the sequence of SEQ ID NO: 8130 and decreases the level of a second processed mRNA encoding a protein having the sequence of SEQ ID NO: 366. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 164.In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 164. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, or about 80 nucleotides upstream of genomic site GRCh38 / hg38:chr11 13355226. In some cases, the targeted region of the pre-mRNA is at least about 1500, about 1000, about 800, about 700, about 600, about 500, about 400, about 300, about 200, about 100, about 80, about 70, about 60, or about 50 nucleotides upstream of the genomic site GRCh38 / hg38:chr11 13355226. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 164. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 164. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr11 13355296. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr11 The targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of 13355296. In some cases, the targeted region of the pre-mRNA is within the sequence of SEQ ID NO: 164. In some cases, the targeted region of the pre-mRNA is within the sequence between the pair of genomic sites GRCh38 / hg38:chr11 13355226 and GRCh38 / hg38:chr11 13355296. In some cases, the therapeutic agent is an antisense oligomer complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 164. In some cases, the therapeutic agent is an antisense oligomer complementary to a sequence having 100% sequence identity to SEQ ID NO: 164. In some cases, the therapeutic agent is an antisense oligomer having a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 1479-1531. In some cases, the therapeutic agent is an antisense oligomer having a sequence selected from the group consisting of SEQ ID NOs: 1479-1531. In some cases, the target peptide sequence is a portion of the ARNTL protein, and the method treats a disease or condition comprising psychiatric depression; seasonal affective disorder; bipolar disorder; mood disorder; or depression. In some cases, the method treats a cancer associated with the ARNTL protein.

[0092] BOC In some cases, the target peptide sequence is a portion of a BOC protein. In some cases, the therapeutic agent increases the level of a first processed mRNA encoding a protein having the sequence of SEQ ID NO: 8131 and decreases the level of a second processed mRNA encoding a protein having the sequence of SEQ ID NO: 367. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides of SEQ ID NO: 165, about 10 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 165. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 165. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr3 113249722. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr3 113249722. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 165.In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 165. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr3 113249899. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr3 113249899. In some cases, the targeted region of the pre-mRNA is within the sequence of SEQ ID NO: 165. In some cases, the targeted region of the pre-mRNA is within the sequence between the pair of genomic sites GRCh38 / hg38:chr3 113249722 and GRCh38 / hg38:chr3 113249899. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 165. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having 100% sequence identity to SEQ ID NO: 165.In some cases, the therapeutic agent increases the level of a first processed mRNA encoding a protein having a sequence of SEQ ID NO: 8132, and a second processed mRNA encoding a protein having a sequence of SEQ ID NO: 368. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 166. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 166. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr3 113249722. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr3 113249722.In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 166. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 166. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr3 113249899. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genomic site GRCh38 / hg38:chr3 113249899. In some cases, the targeted region of the pre-mRNA is within the sequence of SEQ ID NO: 166. In some cases, the targeted region of the pre-mRNA is within the sequence between the pair of genomic sites GRCh38 / hg38:chr3 113249722 and GRCh38 / hg38:chr3 113249899.In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 166. In some cases, the therapeutic agent is an antisense oligomer that is complementary to a sequence having 100% sequence identity to SEQ ID NO: 166. In this case, the therapeutic agent increases the level of a first processed mRNA encoding a protein having the sequence of SEQ ID NO: 8133 and decreases the level of a second processed mRNA encoding a protein having the sequence of SEQ ID NO: 369. In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 167. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of SEQ ID NO: 167. about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr3 113249722. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides upstream of genomic site GRCh38 / hg38:chr3 113249722. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 167. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of SEQ ID NO: 167.In some cases, the targeted region of the pre-mRNA is up to about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, or about 50 nucleotides downstream of genom...

Claims

1. A pharmaceutical composition comprising a therapeutic agent or a vector encoding said therapeutic agent and a pharma- ceutically acceptable excipient, the therapeutic agent binds to a targeted region of a pre-mRNA in a cell; the pre-mRNA encodes a target peptide sequence and comprises a first start codon, a second start codon, and a premature termination codon (PTC) located downstream of the first start codon and upstream of the second start codon; splicing of the PTC and the second start codon from the pre-mRNA is regulated such that the level of a first processed mRNA, which does not contain the PTC and the second start codon and encodes a first protein comprising the target peptide sequence, is regulated and expression of the target peptide sequence is regulated in the cell; the cell has a second processed mRNA that includes the sequence of the first processed mRNA, the PTC, and the second start codon and encodes a second protein that includes the target peptide sequence; and The pharmaceutical composition, wherein the first processed mRNA and the second processed mRNA are both splicing products of the pre-mRNA.

2. 2. The pharmaceutical composition of claim 1, wherein the therapeutic agent is an antisense oligomer (ASO) that is complementary to the targeted region of the pre-mRNA.

3. 3. The pharmaceutical composition of claim 1 or 2, wherein the therapeutic agent is an ASO that is at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% complementary to the targeted region of the pre-mRNA encoding the target peptide sequence.

4. The pharmaceutical composition of any one of claims 1 to 3, wherein at least a portion of the targeted region of the pre-mRNA is upstream of an exon containing the PTC and the second start codon.

5. The pharmaceutical composition of any one of claims 1 to 3, wherein at least a portion of the targeted region of the pre-mRNA is downstream of an exon that contains the PTC and the second start codon.

6. The pharmaceutical composition of any one of claims 1 to 3, wherein at least a portion of the targeted region of the pre-mRNA is within an exon that contains the PTC and the second start codon.

7. The pharmaceutical composition of any one of claims 1 to 6, wherein the PTC and the second start codon have a distance of 2 nucleotides (nt) to 75 nt on the pre-mRNA.

8. 8. The pharmaceutical composition of claim 1, wherein the first protein comprising the target peptide sequence is translated starting from the first start codon on the first processed mRNA, and the second protein is translated starting from the second start codon on the second processed mRNA.

9. 9. The pharmaceutical composition of any one of claims 1 to 8, wherein the first processed mRNA has a higher translation efficiency to produce the first protein compared to the translation efficiency of the second processed mRNA to produce the second protein.

10. The pharmaceutical composition of any one of claims 1 to 9, wherein the therapeutic agent increases the level of the first processed mRNA encoding the target peptide sequence in the cell.

11. The pharmaceutical composition of any one of claims 1 to 10, wherein the therapeutic agent increases the level of the target peptide sequence in the cell.

12. The pharmaceutical composition of any one of claims 1 to 11, wherein the target peptide sequence is a portion of a full-length protein.

13. The pharmaceutical composition of any one of claims 1 to 11, wherein the target peptide sequence produced is a fully functional protein.

14. The pharmaceutical composition according to any one of claims 1 to 12, wherein the target peptide sequence is the N-terminal or C-terminal portion of a full-length protein.

15. 15. The pharmaceutical composition of any one of claims 1 to 14, wherein the therapeutic agent is an antisense oligomer having a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 35-129.

16. The target peptide sequence is selected from the group consisting of ACIN1, ACTN1, ACTN2, ADH4, AKR1C3, ALDH1A2, ALG8, AMPD2, AMT, ANKRD11, ANKS3, APOL4, APPL1, ARCN1, ARMC8, ARNTL, BOC, BRCA1, C8B, CALM1, CALM3, CASP5, CAST, CEP19, CEP57, CHEK1, CIB2, COX4I1, DCLRE1C, DECR 1, DHFR, DKK2, DLG2, DOK2, DPF3, DTNA, DYRK1A, FOLH1, FUZ, GANAB, GEMIN4, GGA3, GOSR2, GPM6A, GRB10, GSN, HDAC8 , HIVEP1, HK1, IFNGR1, IKBKB, ISCU, KARS, KIAA0319, KIAA0586, KIZ, KLK6, LMNA, LMNTD1, LRRC7, LRTOMT, LZTFL1, M AGI2, MECP2, MERTK, MFSD2A, MLF1, MOB1B, MSRB3, NR1I3, NT5C3A, NUTM1, OTOF, PDCD4, PDPK1, PHKB, PIGA, PLOD2, P OLR2F, PPP6C, PRKN, PRUNE1, PSMA6, PSMC3IP, PTPN1, RAB11B, RBPJ, RNPS1, RPL5, RPS20, SECISBP2, SELENBP1, SEP The pharmaceutical composition of any one of claims 1 to 15, which is a portion of a protein selected from the group consisting of T11, SIRT2, SLC25A26, SMARCE1, SMC1A, SMG1, SPACA7, SPRED1, SRP54, SRPK2, STK36, STRADA, SUMO1, TBL1XR1, TLR8, TXNRD2, UBE3A, UFM1, WAC, WDR81, YME1L1, and ZMYND10.

17. 17. The pharmaceutical composition of claim 16, wherein the therapeutic agent increases the level of the first processed mRNA encoding the first protein having a sequence selected from the group consisting of SEQ ID NOs: 8096-8297 and decreases the level of the second processed mRNA encoding the second protein having a sequence selected from the group consisting of SEQ ID NOs: 332-533.

18. 18. The pharmaceutical composition of claim 16 or 17, wherein the targeted region of the pre-mRNA is up to about 1500, 1000, 800, 700, 600, 500, 400, 300, 200, 100, 80, 70, 60, or 50 nucleotides upstream of a sequence selected from the group consisting of SEQ ID NOs: 130-331.

19. The targeted region of the pre-mRNA is located at GRCh38 / hg38: chr14 23071186, GRCh38 / hg38: chr14 68925672, GRCh38 / hg38: chr1 236735635, GRCh38 / hg38: chr4 99143305, GRCh38 / hg38: chr4 99143305, GRCh38 / hg38: chr6 32182698, GRCh38 / hg38: chr10 5077900, GRCh38 / hg38: chr15 58058108, GRCh38 / hg38: chr11 78138767, GRCh38 / hg38: chr1 109620914, GRCh38 / hg38: chr3 49422257, GRCh38 / hg38: chr3 49422257, GRCh38 / hg38: chr3 49422257, GRCh38 / hg38: chr16 89317078, GRCh38 / hg38: chr16 89317078, GRCh38 / hg38: chr16 89317078, GRCh38 / hg38: chr16 89317075, GRCh38 / hg38: chr16 89317078, GRCh38 / hg38: chr16 89317078, GRCh38 / hg38: chr16 89317075, GRCh38 / hg38: chr16 89317078, GRCh38 / hg38: chr16 89317078, GRCh38 / hg38: chr16 89317075, GRCh38 / hg38: chr16 89317078, GRCh38 / hg38: chr16 89317075, GRCh38 / hg38: chr16 89317078, GRCh38 / hg38: chr16 89317078, GRCh38 / hg38: chr16 4726780, GRCh38 / hg38: chr22 36201796, GRCh38 / hg38: chr3 57230714, GRCh38 / hg38: chr11 118573620, GRCh38 / hg38: chr3 138188455, GRCh38 / hg38: chr3 138188455, GRCh38 / hg38: chr11 13355226, GRCh38 / hg38: chr11 13355226, GRCh38 / hg38: chr3113249722、GRCh38 / hg38:chr3 113249722、GRCh38 / hg38:chr3 113249722、GRCh38 / hg38:chr3 113249722、GRCh38 / hg38:chr17 43106533、GRCh38 / hg38:chr17 43106533、GRCh38 / hg38:chr1 56959657、GRCh38 / hg38:chr1 56959657、GRCh38 / hg38:chr14 90398991、GRCh38 / hg38:chr19 46608205、GRCh38 / hg38:chr11 105009053、GRCh38 / hg38:chr5 96726754、GRCh38 / hg38:chr3 196708727、GRCh38 / hg38:chr11 95795516、GRCh38 / hg38:chr11 125627607、GRCh38 / hg38:chr15 78111276、GRCh38 / hg38:chr15 78111276、GRCh38 / hg38:chr16 85804941、GRCh38 / hg38:chr10 14939869、GRCh38 / hg38:chr8 90005292、GRCh38 / hg38:chr8 90015541、GRCh38 / hg38:chr5 80649494、GRCh38 / hg38:chr4 106925949、GRCh38 / hg38:chr11 83651930、GRCh38 / hg38:chr8 21910857、GRCh38 / hg38:chr14 72879947、GRCh38 / hg38:chr14 72879947、GRCh38 / hg38:chr18 34757158、GRCh38 / hg38:chr18 34757158、GRCh38 / hg38:chr21 37456130、GRCh38 / hg38:chr11 49206874、GRCh38 / hg38:chr19 49812335、GRCh38 / hg38:chr11 62639110、GRCh38 / hg38:chr17 749909、GRCh38 / hg38:chr17 75243570、GRCh38 / hg38:chr17 46924261、GRCh38 / hg38:chr4 175812249、GRCh38 / hg38:chr750710990、GRCh38 / hg38:chr9 121300056、GRCh38 / hg38:chrX 72572109、GRCh38 / hg38:chr6 12020248、GRCh38 / hg38:chr10 69300769、GRCh38 / hg38:chr10 69300769、GRCh38 / hg38:chr6 137215377、GRCh38 / hg38:chr8 42272083、GRCh38 / hg38:chr8 42272083、GRCh38 / hg38:chr8 42272083、GRCh38 / hg38:chr8 42272083、GRCh38 / hg38:chr12 108564060、GRCh38 / hg38:chr16 75644462、GRCh38 / hg38:chr16 75644462、GRCh38 / hg38:chr6 24600709、GRCh38 / hg38:chr14 58429363、GRCh38 / hg38:chr14 58429363、GRCh38 / hg38:chr20 21132097、GRCh38 / hg38:chr19 50963549、GRCh38 / hg38:chr1 156126736、GRCh38 / hg38:chr12 25552989、GRCh38 / hg38:chr12 25552989、GRCh38 / hg38:chr1 69716142、GRCh38 / hg38:chr11 72089029、GRCh38 / hg38:chr11 72089029、GRCh38 / hg38:chr11 72089029、GRCh38 / hg38:chr11 72089029、GRCh38 / hg38:chr11 72089029、GRCh38 / hg38:chr11 72089029、GRCh38 / hg38:chr11 72089029、GRCh38 / hg38:chr11 72089029、GRCh38 / hg38:chr11 72089029、GRCh38 / hg38:chr11 72089029、GRCh38 / hg38:chr11 72089029、GRCh38 / hg38:chr3 45838051、GRCh38 / hg38:chr7 78554671、GRCh38 / hg38:chrX 154092307、GRCh38 / hg38:chrX154092307、GRCh38 / hg38:chr2 111944960、GRCh38 / hg38:chr1 39965211、GRCh38 / hg38:chr3 158592434、GRCh38 / hg38:chr3 158592434、GRCh38 / hg38:chr3 158592434、GRCh38 / hg38:chr3 158592434、GRCh38 / hg38:chr3 158592434、GRCh38 / hg38:chr4 70950700、GRCh38 / hg38:chr12 65308529、GRCh38 / hg38:chr1 161236598、GRCh38 / hg38:chr1 161236598、GRCh38 / hg38:chr1 161236598、GRCh38 / hg38:chr1 161236598、GRCh38 / hg38:chr1 161236598、GRCh38 / hg38:chr1 161236598、GRCh38 / hg38:chr1 161236598、GRCh38 / hg38:chr1 161236598、GRCh38 / hg38:chr1 161236598、GRCh38 / hg38:chr1 161236598、GRCh38 / hg38:chr1 161236598、GRCh38 / hg38:chr1 161236598、GRCh38 / hg38:chr1 161236598、GRCh38 / hg38:chr7 33035988、GRCh38 / hg38:chr7 33035988、GRCh38 / hg38:chr15 34345857、GRCh38 / hg38:chr2 26477749、GRCh38 / hg38:chr2 26477749、GRCh38 / hg38:chr10 110876670、GRCh38 / hg38:chr16 2566356、GRCh38 / hg38:chr16 47463899、GRCh38 / hg38:chr16 47463882、GRCh38 / hg38:chrX 15331992、GRCh38 / hg38:chrX 15331992、GRCh38 / hg38:chr3 146124229、GRCh38 / hg38:chr22 37958374、GRCh38 / hg38:chr9 125172001、GRCh38 / hg38:chr6162262765、GRCh38 / hg38:chr1 151027233、GRCh38 / hg38:chr14 35308914、GRCh38 / hg38:chr17 42573623、GRCh38 / hg38:chr20 50564969、GRCh38 / hg38:chr19 8402086、GRCh38 / hg38:chr4 26320700、GRCh38 / hg38:chr4 26320700、GRCh38 / hg38:chr16 2264760、GRCh38 / hg38:chr16 2264760、GRCh38 / hg38:chr16 2264760、GRCh38 / hg38:chr16 2264760、GRCh38 / hg38:chr1 92833545、GRCh38 / hg38:chr8 56073768、GRCh38 / hg38:chr9 89325427、GRCh38 / hg38:chr1 151369978、GRCh38 / hg38:chr1 151369978、GRCh38 / hg38:chr4 76995781、GRCh38 / hg38:chr19 38893867、GRCh38 / hg38:chr19 38893867、GRCh38 / hg38:chr19 38893867、GRCh38 / hg38:chr19 38893867、GRCh38 / hg38:chr19 38893867、GRCh38 / hg38:chr3 66243203、GRCh38 / hg38:chr3 66243203、GRCh38 / hg38:chr17 40644459、GRCh38 / hg38:chrX 53422040、GRCh38 / hg38:chr16 18900044、GRCh38 / hg38:chr13 112382278、GRCh38 / hg38:chr15 38299373、GRCh38 / hg38:chr14 35000936、GRCh38 / hg38:chr7 105268869、GRCh38 / hg38:chr2 218673665、GRCh38 / hg38:chr17 63714108、GRCh38 / hg38:chr17 63714108、GRCh38 / hg38:chr17 63714108、GRCh38 / hg38:chr17 63714108、GRCh38 / hg38:chr1763714108、GRCh38 / hg38:chr17 63714108、GRCh38 / hg38:chr17 63714108、GRCh38 / hg38:chr17 63714108、GRCh38 / hg38:chr17 63714108、GRCh38 / hg38:chr2 202214429、GRCh38 / hg38:chr3 177065022, GRCh38 / hg38chr 3 177065022, GRCh38 / hg38:chr3 177065022, GRCh38 / hg38:chr3 177065022, GRCh38 / hg38:chrX 12910306, GRCh38 / hg38:chr22 19880945, GRCh38 / hg38:chr15 25408684, GRCh38 / hg38:chr15 25408684, GRCh38 / hg38:chr13 38349999, GRCh38 / hg38:chr10 28535562, GRCh38 / hg38:chr17 18. The pharmaceutical composition of claim 16 or 17, wherein the genomic site is up to about 1500, 1000, 800, 700, 600, 500, 400, 300, 200, 100, 80, 70, 60, 50 nucleotides upstream of a genomic site selected from the group consisting of GRCh38 / hg38:chr10 27153281, GRCh38 / hg38:chr3 50345232.

20. 20. The pharmaceutical composition of any one of claims 16-19, wherein the therapeutic agent is an antisense oligomer that is complementary to a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 130-331.

21. 20. The pharmaceutical composition of any one of claims 16 to 19, wherein the therapeutic agent is an antisense oligomer having a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 534-8095.

22. The level of the first treated mRNA in the cells contacted with the therapeutic agent is about 1.1 to about 10 fold, about 1.5 to about 10 fold, about 2 to about 10 fold, about 3 to about 10 fold, about 4 to about 10 fold, about 1.1 to about 5 fold, about 1.1 to about 6 fold, about 1.1 to about 7 fold, about 1.1 to about 8 fold, about 1.1 to about 9 fold, about 2 to about 5 fold, about 2 to about 6 fold, about 2 to about 7 fold, about 2 22. The pharmaceutical composition of any one of claims 1 to 21, wherein the amount of IgG1 is increased by up to about 8-fold, about 2- to about 9-fold, about 3- to about 6-fold, about 3- to about 7-fold, about 3- to about 8-fold, about 3- to about 9-fold, about 4- to about 7-fold, about 4- to about 8-fold, about 4- to about 9-fold, at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 5-fold, or at least about 10-fold.

23. the level of the target peptide sequence in the cells contacted with the therapeutic agent is about 1.1 to about 10 fold, about 1.5 to about 10 fold, about 2 to about 10 fold, about 3 to about 10 fold, about 4 to about 10 fold, about 1.1 to about 5 fold, about 1.1 to about 6 fold, about 1.1 to about 7 fold, about 1.1 to about 8 fold, about 1.1 to about 9 fold, about 2 to about 5 fold, about 2 to about 6 fold, about 2 to about 7 fold, about 2 to about 8 fold, 23. The pharmaceutical composition of any one of claims 1 to 22, wherein the affinity of the antibody to the antibody is increased by 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.

24. 24. The pharmaceutical composition of any one of claims 1 to 23, wherein the therapeutic agent is an antisense oligonucleotide, and the therapeutic agent comprises a backbone modification comprising a phosphorothioate or phosphorodiamidate linkage.

25. 25. The pharmaceutical composition of any one of claims 1 to 24, wherein the therapeutic agent is an antisense oligonucleotide, and the therapeutic agent comprises a phosphorodiamidate morpholino, locked nucleic acid, peptide nucleic acid, 2'-O-methyl, 2'-fluoro, or 2'-O-methoxyethyl moiety.

26. The pharmaceutical composition of any one of claims 1 to 25, wherein the therapeutic agent is an antisense oligonucleotide, and the therapeutic agent comprises at least one modified sugar moiety.

27. 27. The pharmaceutical composition of claim 26, wherein each sugar moiety is a modified sugar moiety.

28. The therapeutic agent is an antisense oligonucleotide, and the therapeutic agent is selected from the group consisting of 8 to 50 nucleobases, 8 to 40 nucleobases, 8 to 35 nucleobases, 8 to 30 nucleobases, 8 to 25 nucleobases, 8 to 20 nucleobases, 8 to 15 nucleobases, 9 to 50 nucleobases, 9 to 40 nucleobases, 9 to 35 nucleobases, 9 to 30 nucleobases, 9 to 25 nucleobases, 9 to 20 nucleobases, 9 to 15 nucleobases, 10 to 50 nucleobases, 10 to 40 nucleobases, 10 to 35 nucleobases, 10 to 30 nucleobases, 10 to 28. The pharmaceutical composition of any one of claims 1 to 27, which is 25 nucleobases, 10 to 20 nucleobases, 10 to 15 nucleobases, 11 to 50 nucleobases, 11 to 40 nucleobases, 11 to 35 nucleobases, 11 to 30 nucleobases, 11 to 25 nucleobases, 11 to 20 nucleobases, 11 to 15 nucleobases, 12 to 50 nucleobases, 12 to 40 nucleobases, 12 to 35 nucleobases, 12 to 30 nucleobases, 12 to 25 nucleobases, 12 to 20 nucleobases, or 12 to 15 nucleobases in length.

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