Methods for modifying RNA splicing
Described herein is an intronic recognition element for splicing modifier (iREMS) that can be recognized by a small molecule splicing modifier compound of Formula (I) provided herein or a form thereof, wherein W, X, A and B are as defined herein. In one aspect, methods for modifying RNA splicing to modulate the amount of a product of a gene, wherein a precursor RNA transcript transcribed from the gene that contains an intronic REMS is modified utilizing a splicing modifier compound of Formula (I), are described herein. In another aspect, methods for modifying RNA splicing to modulate the amount of an RNA transcript or protein product encoded by a gene, wherein a precursor RNA transcript transcribed from the gene is modified to comprise an intronic REMS utilizing a splicing modifier compound of Formula (I), are described herein.
1. A method for modifying RNA splicing in order to produce a mature mRNA transcript having an intronic exon (iExon), the method comprising contacting 5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenol having the formula
or a form thereof with a cell containing a pre-mRNA transcript in cell culture or with a cell lysate containing a pre-mRNA transcript, wherein the pre-mRNA transcript comprises two exons and an intron, wherein a first exon is upstream of the intron and a second exon is downstream of the intron, wherein the intron comprises in 5′ to 3′ order: a first 5′ splice site, a first branch point, a first 3′ splice site, an intronic recognition element for splicing modifier (iREMS), a second branch point, and a second 3′ splice site, wherein the iREMS comprises an RNA sequence GAgurngn, wherein r is adenine or guanine and n is any nucleotide, and
wherein the pre-mRNA transcript is a pre-mRNA transcript of a gene selected from the group consisting of:
(a) ADAL, ADAM23, ADAMTS19, AGPS, AKAP8L, ANKRD13C, ANXA11, ARL15, ARSJ, BECN1, BIN3, BTBD10, C11orf30, C12orf4, C1orf27, C2orf47, CACNB1, CACNB4, CADM2, CDH18, CEP162, CEP170, CEP192, CHEK1, CHRM2, CMAHP, CNRIP1, CNTN1, CUX1, DAAM1, DCAF17, DCUN1D4, DDX42, DET1, DENND1A, DENND4A, DENND5A, DGKI, DHFR, DIAPH3, DLG5, DYRK1A, DZIP1L, ELMO2, ENAH, ENOX1, EVC, FAM162A, FAM174A, FAM208B, FAM69B, FBXL16, FGD4, FHOD3, GALC, GOLGB1, GTSF1, GXYLT1, HDAC5, HDX, HTT, IFT57, INO80, INVS, KDM6A, KIDINS220, KIF21A, L3MBTL2, LINCR-0002, LINGO2, LOC400927, LPHN1, LRRC1, LRRC42, LYRM1, MACROD2, MAPK10, MARCH8, MDN1, MEAF6, MEMO1, MFN2, MLLT10, MRPL39, MRPL45, MRPS28, MTMR3, MYB, MYCBP2, NSUN4, NUPL1, OSBPL3, PAPD4, PCDH10, PDE3A, PDE7A, PDXDC1, PDXDC2P, PELI1, PITPNB, PMS1, POMT2, PSMA4, RAB23, RAF1, RCOR3, RERE, RNF130, RNF144A, RNF213, RPF2, RPS10, SCO1, SENP6, SF3B3, SGMS1, SGPL1, SLC25A16, SLC25A17, SNX24, SNX7, SORCS1, SPIDR, SPRYD7, SREK1, SSBP1, STRADB, SUPT20H, TAF2, TARBP1, TASP1, TBCA, TCF4, TET1, TIAM1, TJP2, TMEM214, TNRC6A, TRAF3, TRIM65, TSPAN7, UBN2, URGCP-MRPS24, UVRAG, WDR27, WDR90, WNK1, XRN2, ZFP82, ZMIZ2, ZNF138, ZNF208, ZNF212, ZNF280D, ZNF37BP, ZNF426, ZNF618, ZNF680, ZNF730, ZNF836, and ZSCAN25;
(b) ADAL, ADAM23, ADAMTS19, AGPS, AKAP8L, ANKRD13C, ANXA11, ARL15, ARSJ, BECN1, BIN3, BTBD10, C11orf30, C12orf4, C1orf27, C2orf47, CACNB1, CACNB4, CADM2, CDH18, CENPI, CEP162, CEP170, CEP192, CHEK1, CHRM2, CMAHP, CNRIP1, CNTN1, CRYBG3, CUX1, DAAM1, DCAF17, DCUN1D4, DDX42, DENND1A, DENND4A, DENND5A, DET1, DGKI, DHFR, DIAPH3, DLG5, DYRK1A, DZIP1L, ELMO2, ENAH, ENOX1, ERC2, EVC, FAM162A, FAM174A, FAM195B, FAM208B, FAM69B, FBXL16, FGD4, FHOD3, GALC, GLCE, GOLGB1, GXYLT1, HDAC5, HDX, HTT, IFT57, INO80, INVS, KDM6A, KIDINS220, KIF21A, L3MBTL2, LINCR-0002, LINGO2, LOC400927, LPHN1, LRRC1, LRRC42, LYRM1, MACROD2, MAPK10, 44628, MDN1, MEAF6, MEMO1, MFN2, MLLT10, MRPL39, MRPL45, MRPS28, MTMR3, MYB, MYCBP2, MYLK, NLGN1, NSUN4, NUPL1, OSBPL3, PAPD4, PCDH10, PDE3A, PDE7A, PDXDC1, PDXDC2P, PELI1, PITPNB, PMS1, POMT2, PSMA4, RAB23, RAF1, RASIP1, RCOR3, RERE, RNF130, RNF144A, RNF213, RPF2, RPS10, SCO1, SENP6, SF3B3, SGMS1, SGPL1, SLC25A16, SLC25A17, SNX24, SNX7, SORCS1, SPIDR, SPRYD7, SREK1, SSBP1, STRADB, STXBP4, SUPT20H, TAF2, TARBP1, TASP1, TBCA, TCF4, TEKT4P2, TET1, TIAM1, TJP2, TMEM214, TNRC6A, TRAF3, TRIM65, TSPAN7, UBN2, URGCP-MRPS24, UVRAG, WDR27, WDR90, WNK1, XRN2, ZFP82, ZMIZ2, ZNF138, ZNF208, ZNF212, ZNF280D, ZNF37BP, ZNF426, ZNF618, ZNF680, ZNF730, ZNF836, and ZSCAN25, or
(c) ABHD10, ADAM17, AGPAT4, AGPS, AKT1, ANKRD13C, ANXA11, APIP, APPL2, ARHGAP1, ARHGAP5, ARL15, ARL5B, ASAP1, ATF6, BECN1, BHMT2, BIN3, BNC2, BTBD10, C10orf76, C11orf30, C11orf73, C12orf4, C1orf27, C1QTNF9B-AS1, CCNL2, CDH18, CENPI, CEP57, CMSS1, CNOT7, COPS7B, CRISPLD2, CUX1, DCAF17, DDX42, DENND4A, DENND5A, DET1, DLG5, DMXL1, DNAJA4, DNMBP, ENAH, EP300, ERC1, EVC, EXOC3, EXOC6B, FAM162A, FAM174A, FAM208B, FAM49B, FBN2, GBP1, GNG12, GXYLT1, HDX, HMGXB4, HOXB3, HSD17B4, IFT57, IKBKAP, INO80, INPP4B, ITCH, IVD, KDM6A, KDSR, KIAA1524, KIAA1715, KIDINS220, L3MBTL2, LGALS3, LOC400927, LRRC42, LYRM1, MACROD2, MANEA, MARCH7, MARCH8, MEAF6, MEMO1, MFN2, MMS19, MORF4L1, MRPL39, MRPL45, MRPS28, MYCBP2, MYLK, MZT1, NEDD4, NFASC, NGF, NIPA1, NLN, NREP, NUPL1, OSBPL3, PAPD4, PBX3, PDE7A, PIGN, PITPNB, PNISR, POMT2, PPARG, PPFIBP1, PRPF31, PSMA4, PXK, RAB23, RAF1, RAPGEF1, RBBP8, RERE, RGL1, RPF2, SAMD4A, SCO1, SENP6, SF3B3, SGIP1, SH2B3, SKP1, SLC12A2, SLC25A17, SMOX, SNAP23, SNX24, SNX7, SOCS6, SOGA2, SPIDR, SSBP1, STRADB, STXBP6, SUPT20H, TAF2, TASP1, TBCA, TBL1XR1, TCF4, TJAP1, TJP2, TMEM214, TMX3, TNRC6A, TXNL4B, UBE2D3, UBE2L3, UNC13B, URGCP-MRPS24, VDAC2, WHSC2, WNK1, XRN2, ZFP82, ZNF138, ZNF350, ZNF37BP, ZNF618, ZNF680, ZNF777, ZNF804A, and ZSCAN25.
2. A method for modifying RNA splicing in order to modulate the amount of a mature mRNA transcript produced from a pre-mRNA transcript, the method comprising contacting 5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenol having the formula
or a form thereof with a cell containing a pre-mRNA transcript in cell culture or with a cell lysate containing a pre-mRNA transcript, wherein the pre-mRNA transcript comprises two exons and an intron, wherein a first exon is upstream of the intron and a second exon is downstream of the intron, wherein the intron comprises in 5′ to 3′ order: an intronic recognition element for splicing modifier (iREMS), a branch point, and a 3′ splice site, wherein the iREMS comprises an RNA sequence GAgurngn, wherein r is adenine or guanine and n is any nucleotide, and wherein the pre-mRNA transcript is a pre-mRNA transcript of a gene selected from the group consisting of:
(a) ADAL, ADAM23, ADAMTS19, AGPS, AKAP8L, ANKRD13C, ANXA11, ARL15, ARSJ, BECN1, BIN3, BTBD10, C11orf30, C12orf4, C1orf27, C2orf47, CACNB1, CACNB4, CADM2, CDH18, CEP162, CEP170, CEP192, CHEK1, CHRM2, CMAHP, CNRIP1, CNTN1, CUX1, DAAM1, DCAF17, DCUN1D4, DDX42, DET1, DENND1A, DENND4A, DENND5A, DGKI, DHFR, DIAPH3, DLG5, DYRK1A, DZIP1L, ELMO2, ENAH, ENOX1, EVC, FAM162A, FAM174A, FAM208B, FAM69B, FBXL16, FGD4, FHOD3, GALC, GOLGB1, GTSF1, GXYLT1, HDAC5, HDX, HTT, IFT57, INO80, INVS, KDM6A, KIDINS220, KIF21A, L3MBTL2, LINCR-0002, LINGO2, LOC400927, LPHN1, LRRC1, LRRC42, LYRM1, MACROD2, MAPK10, MARCH8, MDN1, MEAF6, MEMO1, MFN2, MLLT10, MRPL39, MRPL45, MRPS28, MTMR3, MYB, MYCBP2, NSUN4, NUPL1, OSBPL3, PAPD4, PCDH10, PDE3A, PDE7A, PDXDC1, PDXDC2P, PELI1, PITPNB, PMS1, POMT2, PSMA4, RAB23, RAF1, RCOR3, RERE, RNF130, RNF144A, RNF213, RPF2, RPS10, SCO1, SENP6, SF3B3, SGMS1, SGPL1, SLC25A16, SLC25A17, SNX24, SNX7, SORCS1, SPIDR, SPRYD7, SREK1, SSBP1, STRADB, SUPT20H, TAF2, TARBP1, TASP1, TBCA, TCF4, TET1, TIAM1, TJP2, TMEM214, TNRC6A, TRAF3, TRIM65, TSPAN7, UBN2, URGCP-MRPS24, UVRAG, WDR27, WDR90, WNK1, XRN2, ZFP82, ZMIZ2, ZNF138, ZNF208, ZNF212, ZNF280D, ZNF37BP, ZNF426, ZNF618, ZNF680, ZNF730, ZNF836, and ZSCAN25,
(b) ADAL, ADAM23, ADAMTS19, AGPS, AKAP8L, ANKRD13C, ANXA11, ARL15, ARSJ, BECN1, BIN3, BTBD10, C11orf30, C12orf4, C1orf27, C2orf47, CACNB1, CACNB4, CADM2, CDH18, CENPI, CEP162, CEP170, CEP192, CHEK1, CHRM2, CMAHP, CNRIP1, CNTN1, CRYBG3, CUX1, DAAM1, DCAF17, DCUN1D4, DDX42, DENND1A, DENND4A, DENND5A, DET1, DGKI, DHFR, DIAPH3, DLG5, DYRK1A, DZIP1L, ELMO2, ENAH, ENOX1, ERC2, EVC, FAM162A, FAM174A, FAM195B, FAM208B, FAM69B, FBXL16, FGD4, FHOD3, GALC, GLCE, GOLGB1, GXYLT1, HDAC5, HDX, HTT, IFT57, INO80, INVS, KDM6A, KIDINS220, KIF21A, L3MBTL2, LINCR-0002, LINGO2, LOC400927, LPHN1, LRRC1, LRRC42, LYRM1, MACROD2, MAPK10, 44628, MDN1, MEAF6, MEMO1, MFN2, MLLT10, MRPL39, MRPL45, MRPS28, MTMR3, MYB, MYCBP2, MYLK, NLGN1, NSUN4, NUPL1, OSBPL3, PAPD4, PCDH10, PDE3A, PDE7A, PDXDC1, PDXDC2P, PELI1, PITPNB, PMS1, POMT2, PSMA4, RAB23, RAF1, RASIP1, RCOR3, RERE, RNF130 RNF144A RNF213, RPF2, RPS10, SCO1, SENP6, SF3B3, SGMS1, SGPL1, SLC25A16, SLC25A17, SNX24, SNX7, SORCS1, SPIDR, SPRYD7, SREK1, SSBP1, STRADB, STXBP4, SUPT20H, TAF2, TARBP1, TASP1, TBCA, TCF4, TEKT4P2, TET1, TIAM1, TJP2, TMEM214, TNRC6A, TRAF3, TRIM65, TSPAN7, UBN2, URGCP-MRPS24, UVRAG, WDR27, WDR90, WNK1, XRN2, ZFP82, ZMIZ2, ZNF138, ZNF208, ZNF212, ZNF280D, ZNF37BP, ZNF426, ZNF618, ZNF680, ZNF730, ZNF836, and ZSCAN25; or
(c) ABHD10, ADAM17, AGPAT4, AGPS, AKT1, ANKRD13C, ANXA11, APIP, APPL2, ARHGAP1, ARHGAP5, ARL15, ARL5B, ASAP1, ATF6, BECN1, BHMT2, BIN3, BNC2, BTBD10, C10orf76, C11orf30, C11orf73, C12orf4, C1orf27, C1QTNF9B-AS1, CCNL2, CDH18, CENPI, CEP57, CMSS1, CNOT7, COPS7B, CRISPLD2, CUX1, DCAF17, DDX42, DENND4A, DENND5A, DET1, DLG5, DMXL1, DNAJA4, DNMBP, ENAH, EP300, ERC1, EVC, EXOC3, EXOC6B, FAM162A, FAM174A, FAM208B, FAM49B, FBN2, GBP1, GNG12, GXYLT1, HDX, HMGXB4, HOXB3, HSD17B4, IFT57, IKBKAP, INO80, INPP4B, ITCH, IVD, KDM6A, KDSR, KIAA1524, KIAA1715, KIDINS220, L3MBTL2, LGALS3, LOC400927, LRRC42, LYRM1, MACROD2, MANEA, MARCH7, MARCH8, MEAF6, MEMO1, MFN2, MMS19, MORF4L1, MRPL39, MRPL45, MRPS28, MYCBP2, MYLK, MZT1, NEDD4, NFASC, NGF, NIPA1, NLN, NREP, NUPL1, OSBPL3, PAPD4, PBX3, PDE7A, PIGN, PITPNB, PNISR, POMT2, PPARG, PPFIBP1, PRPF31, PSMA4, PXK, RAB23, RAF1, RAPGEF1, RBBP8, RERE, RGL1, RPF2, SAMD4A, SCO1, SENP6, SF3B3, SGIP1, SH2B3, SKP1, SLC12A2, SLC25A17, SMOX, SNAP23, SNX24, SNX7, SOCS6, SOGA2, SPIDR, SSBP1, STRADB, STXBP6, SUPT20H, TAF2, TASP1, TBCA, TBL1XR1, TCF4, TJAP1, TJP2, TMEM214, TMX3, TNRC6A, TXNL4B, UBE2D3, UBE2L3, UNC13B, URGCP-MRPS24, VDAC2, WHSC2, WNK1, XRN2, ZFP82, ZNF138, ZNF350, ZNF37BP, ZNF618, ZNF680, ZNF777, ZNF804A, and ZSCAN25.
3. The method of claim 1 , wherein the iREMS comprises an RNA sequence GAguragu, and wherein r is adenine or guanine.
4. The method of claim 1 , wherein the iREMS comprises an RNA sequence NNGAgurngn (SEQ ID NO: 1), wherein r is adenine or guanine and n or N is any nucleotide, and wherein the RNA sequence NNGAgurngn (SEQ ID NO: 1) is selected from the group consisting of ANGAgurngn (SEQ ID NO: 4), CNGAgurngn (SEQ ID NO: 5), GNGAgurngn (SEQ ID NO: 6), UNGAgurngn (SEQ ID NO: 7), NAGAgurngn (SEQ ID NO: 8), NCGAgurngn (SEQ ID NO: 9), NGGAgurngn (SEQ ID NO: 10), NUGAgurngn (SEQ ID NO: 11), AAGAgurngn (SEQ ID NO: 12), ACGAgurngn (SEQ ID NO: 13), AGGAgurngn (SEQ ID NO: 14), AUGAgurngn (SEQ ID NO: 15), CAGAgurngn (SEQ ID NO: 16), CCGAgurngn (SEQ ID NO: 17), CGGAgurngn (SEQ ID NO: 18), CUGAgurngn (SEQ ID NO: 19), GAGAgurngn (SEQ ID NO: 20), GCGAgurngn (SEQ ID NO: 21), GGGAgurngn (SEQ ID NO: 22), GUGAgurngn (SEQ ID NO: 23), UAGAgurngn (SEQ ID NO: 24), UCGAgurngn (SEQ ID NO: 25), UGGAgurngn (SEQ ID NO: 52), and UUGAgurngn (SEQ ID NO: 53), wherein r is adenine or guanine and n or N is any nucleotide.
5. The method of claim 1 , wherein the iREMS comprises an RNA sequence NNGAguragu (SEQ ID NO: 2), wherein r is adenine or guanine and N is any nucleotide, and wherein the RNA sequence NNGAguragu (SEQ ID NO: 2) is selected from the group consisting of ANGAguragu (SEQ ID NO: 28), CNGAguragu (SEQ ID NO: 29), GNGAguragu (SEQ ID NO: 30), UNGAguragu (SEQ ID NO: 31), NAGAguragu (SEQ ID NO: 32), NCGAguragu (SEQ ID NO: 33), NGGAguragu (SEQ ID NO: 34), NUGAguragu (SEQ ID NO: 35), AAGAguragu (SEQ ID NO: 36), ACGAguragu (SEQ ID NO: 37), AGGAguragu (SEQ ID NO: 38), AUGAguragu (SEQ ID NO: 39), CAGAguragu (SEQ ID NO: 40), CCGAguragu (SEQ ID NO: 41), CGGAguragu (SEQ ID NO: 42), CUGAguragu (SEQ ID NO: 43), GAGAguragu (SEQ ID NO: 44), GCGAguragu (SEQ ID NO: 45), GGGAguragu (SEQ ID NO: 46), GUGAguragu (SEQ ID NO: 47), UAGAguragu (SEQ ID NO: 48), UCGAguragu (SEQ ID NO: 49), UGGAguragu (SEQ ID NO: 489) and UUGAguragu (SEQ ID NO: 508), wherein r is adenine or guanine, and N is any nucleotide.
6. The method of claim 2 , wherein the iREMS comprises an RNA sequence GAguragu, and wherein r is adenine or guanine.
7. The method of claim 2 , wherein the iREMS comprises an RNA sequence NNGAgurngn (SEQ ID NO: 1), wherein r is adenine or guanine and n or N is any nucleotide, and wherein the RNA sequence NNGAgurngn (SEQ ID NO: 1) is selected from the group consisting of ANGAgurngn (SEQ ID NO: 4), CNGAgurngn (SEQ ID NO: 5), GNGAgurngn (SEQ ID NO: 6), UNGAgurngn (SEQ ID NO: 7), NAGAgurngn (SEQ ID NO: 8), NCGAgurngn (SEQ ID NO: 9), NGGAgurngn (SEQ ID NO: 10), NUGAgurngn (SEQ ID NO: 11), AAGAgurngn (SEQ ID NO: 12), ACGAgurngn (SEQ ID NO: 13), AGGAgurngn (SEQ ID NO: 14), AUGAgurngn (SEQ ID NO: 15), CAGAgurngn (SEQ ID NO: 16), CCGAgurngn (SEQ ID NO: 17), CGGAgurngn (SEQ ID NO: 18), CUGAgurngn (SEQ ID NO: 19), GAGAgurngn (SEQ ID NO: 20), GCGAgurngn (SEQ ID NO: 21), GGGAgurngn (SEQ ID NO: 22), GUGAgurngn (SEQ ID NO: 23), UAGAgurngn (SEQ ID NO: 24), UCGAgurngn (SEQ ID NO: 25), UGGAgurngn (SEQ ID NO: 52), and UUGAgurngn (SEQ ID NO: 53), wherein r is adenine or guanine and n or N is any nucleotide.
8. The method of claim 2 , wherein the iREMS comprises an RNA sequence NNGAguragu (SEQ ID NO: 2), wherein r is adenine or guanine and N is any nucleotide, and wherein the RNA sequence NNGAguragu (SEQ ID NO: 2) is selected from the group consisting of ANGAguragu (SEQ ID NO: 28), CNGAguragu (SEQ ID NO: 29), GNGAguragu (SEQ ID NO: 30), UNGAguragu (SEQ ID NO: 31), NAGAguragu (SEQ ID NO: 32), NCGAguragu (SEQ ID NO: 33), NGGAguragu (SEQ ID NO: 34), NUGAguragu (SEQ ID NO: 35), AAGAguragu (SEQ ID NO: 36), ACGAguragu (SEQ ID NO: 37), AGGAguragu (SEQ ID NO: 38), AUGAguragu (SEQ ID NO: 39), CAGAguragu (SEQ ID NO: 40), CCGAguragu (SEQ ID NO: 41), CGGAguragu (SEQ ID NO: 42), CUGAguragu (SEQ ID NO: 43), GAGAguragu (SEQ ID NO: 44), GCGAguragu (SEQ ID NO: 45), GGGAguragu (SEQ ID NO: 46), GUGAguragu (SEQ ID NO: 47), UAGAguragu (SEQ ID NO: 48), UCGAguragu (SEQ ID NO: 49), UGGAguragu (SEQ ID NO: 489) and UUGAguragu (SEQ ID NO: 508), wherein r is adenine or guanine, and N is any nucleotide.
9. The method of claim 1 , wherein the pre-mRNA transcript is a pre-mRNA transcript of a gene selected from the group consisting of:
(a) C12orf4, CDH18, CHEK1, DHFR, HDX, LOC400927, LRRC42, MEAF6, MYCBP2, PAPD4, PDE7A, POMT2, TAF2, TRIM65, and WDR27;
(b) ADAMTS19, BECN1, CACNB4, CADM2, CHEK1, CHRM2, CMAHP, DENND4A, DHFR, EVC, GXYLT1, MEMO1, MYCBP2, NUPL1, PDXDC1, SENP6, SPIDR, TNRC6A, TRIM65, URGCP-MRPS24, WDR90, ZFP82, ZNF618, and ZNF680; or
(c) AGPS, AKT1, ANXA11, ARHGAP5, ARL15, ATF6, BIN3, C11orf30, C11orf73, CDH18, CENPI, DCAF17, DENND4A, EXOC6B, FAM162A, FAM174A, FAM208B, HOXB3, IFT57, IVD, KIAA1715, KIDINS220, MYCBP2, SLC25A17, SNX24, SNX7, SPIDR, STRADB, TASP1, TCF4, TMEM214, UBE2D3, XRN2, ZNF618, and ZNF777.
10. The method of claim 1 , wherein the pre-mRNA transcript is a pre-mRNA transcript of a gene selected from the group consisting of:
(a) ARL15, PDXDC2P, and ZNF37BP;
(b) ERC2, FHOD3, HDX, HTT, KDM6A, LOC400927, LRRC42, MACROD2, MEAF6, PAPD4, PDE7A, TAF2, TET1, TIAM1, and WDR27; or
(c) BECN1, BHMT2, C1orf27, ENAH, KIAA1524, LOC400927, LRRC42, LYRM1, MFN2, MORF4L1, NGF, NUPL1, PAPD4, PDE7A, RERE, SF3B3, STXBP6, TAF2, URGCP-MRPS24, WNK1, ZNF350, and ZNF680.
11. The method of claim 1 , wherein the pre-mRNA transcript is a pre-mRNA transcript of a gene selected from the group consisting of:
(a) ELMO2;
(b) ARL15, C12orf4, CDH18, ELMO2, PDXDC2P, POMT2, RASIP1, and ZNF37BP; or
(c) ARL15, ASAP1, C12orf4, EVC, GXYLT1, HDX, KDM6A, MACROD2, MEAF6, MEMO1, POMT2, SENP6, TBCA, TNRC6A, UBE2L3, VDAC2, ZFP82, ZNF138, and ZNF37BP.
12. The method of claim 1 , wherein:
(a) the pre-mRNA transcript is a pre-mRNA transcript of the HTT gene;
(b) the pre-mRNA transcript is a pre-mRNA transcript of a gene selected from the group consisting of: ARL15, C12orf4, CDH18, CHEK1, DHFR, ELMO2, HDX, LOC400927, LRRC42, MEAF6, MYCBP2, PAPD4, PDE7A, PDXDC2P, POMT2, TAF2, TRIM65, WDR27, ZNF37BP, ADAMTS19, BECN1, CACNB4, CADM2, CHRM2, CMAHP, DENND4A, ERC2, EVC, FHOD3, GXYLT1, HTT, KDM6A, MACROD2, MEMO1, NUPL1, PDXDC1, RASIP1, SENP6, SPIDR, TET1, TIAM1, TNRC6A, URGCP-MRPS24, WDR90, ZFP82, ZNF618, ZNF680, AGPS, AKT1, ANXA11, ARHGAP5, ATF6, ASAP1, BHMT2, BIN3, C11orf30, C11orf73, C1orf27, CENP1, DCAF17, ENAH, EXOC6B, FAM162A, FAM174A, FAM208B, HOXB3, IFT57, IVD, KIAA1524, KIAA1715, KIDINS220, LYRM1, MFN2, MORF4L1, NGF, RERE, SF3B3, SLC25A17, SNX24, SNX7, STRADB, STXBP6, TA5P1, TBCA, TCF4, TMEM214, UBE2D3, UBE2L3, VDAC2, WNK1, XRN2, ZNF138, ZNF350, and ZNF777; or
(c) the pre-mRNA transcript is a pre-mRNA transcript of a gene selected from the group consisting of DIAPH3, NIPA1, RAF1, DCAF17 2a, GNG12, HMGXB4, MRPL45, NSUN4, PITPNB, DCAF17 6a, DMXL1, GALC, GBP1, SREK1, SSBP1, DENND5A, DGK1, GTSF1, L3MBTL2, MMS19, PMS1, PRPF31, SKP1, and SUPT20H.
13. The method of claim 2 , wherein the intron further comprises in 5′ to 3′ order: a 5′ splice site, a branch point, and a 3′ splice site, wherein the 5′ splice site, the branch point, and the 3′ splice site are upstream of the iREMS.
14. The method of claim 2 , wherein the pre-mRNA transcript is a pre-mRNA transcript of a gene selected from the group consisting of:
(a) C12orf4, CDH18, CHEK1, DHFR, HDX, LOC400927, LRRC42, MEAF6, MYCBP2, PAPD4, PDE7A, POMT2, TAF2, TRIM65, and WDR27;
(b) ADAMTS19, BECN1, CACNB4, CADM2, CHEK1, CHRM2, CMAHP, DENND4A, DHFR, EVC, GXYLT1, MEMO1, MYCBP2, NUPL1, PDXDC1, SENP6, SPIDR, TNRC6A, TRIM65, URGCP-MRPS24, WDR90, ZFP82, ZNF618, and ZNF680; or
(c) AGPS, AKT1, ANXA11, ARHGAP5, ARL15, ATF6, BIN3, C11orf30, C11orf73, CDH18, CENPI, DCAF17, DENND4A, EXOC6B, FAM162A, FAM174A, FAM208B, HOXB3, IFT57, IVD, KIAA1715, KIDINS220, MYCBP2, SLC25A17, SNX24, SNX7, SPIDR, STRADB, TASP1, TCF4, TMEM214, UBE2D3, XRN2, ZNF618, and ZNF777.
15. The method of claim 2 , wherein the pre-mRNA transcript is a pre-mRNA transcript of a gene selected from the group consisting of:
(a) ARL15, PDXDC2P, and ZNF37BP;
(b) ERC2, FHOD3, HDX, HTT, KDM6A, LOC400927, LRRC42, MACROD2, MEAF6, PAPD4, PDE7A, TAF2, TET1, TIAM1, and WDR27; or
(c) BECN1, BHMT2, C1orf27, ENAH, KIAA1524, LOC400927, LRRC42, LYRM1, MFN2, MORF4L1, NGF, NUPL1, PAPD4, PDE7A, RERE, SF3B3, STXBP6, TAF2, URGCP-MRPS24, WNK1, ZNF350, and ZNF680.
16. The method of claim 2 , wherein the pre-mRNA transcript is a pre-mRNA transcript of a gene selected from the group consisting of:
(a) ELMO2;
(b) ARL15, C12orf4, CDH18, ELMO2, PDXDC2P, POMT2, RASIP1, and ZNF37BP; or
(c) ARL15, ASAP1, C12orf4, EVC, GXYLT1, HDX, KDM6A, MACROD2, MEAF6, MEMO1, POMT2, SENP6, TBCA, TNRC6A, UBE2L3, VDAC2, ZFP82, ZNF138, and ZNF37BP.
17. The method of claim 2 , wherein:
(a) the pre-mRNA transcript is a pre-mRNA transcript of the HTT gene;
(b) the pre-mRNA transcript is a pre-mRNA transcript of a gene selected from the group consisting of: ARL15, C12orf4, CDH18, CHEK1, DHFR, ELMO2, HDX, LOC400927, LRRC42, MEAF6, MYCBP2, PAPD4, PDE7A, PDXDC2P, POMT2, TAF2, TRIM65, WDR27, ZNF37BP, ADAMTS19, BECN1, CACNB4, CADM2, CHRM2, CMAHP, DENND4A, ERC2, EVC, FHOD3, GXYLT1, HTT, KDM6A, MACROD2, MEMO1, NUPL1, PDXDC1, RASIP1, SENP6, SPIDR, TET1, TIAM1, TNRC6A, URGCP-MRPS24, WDR90, ZFP82, ZNF618, ZNF680, AGPS, AKT1, ANXA11, ARHGAP5, ATF6, ASAP1, BHMT2, BIN3, C11orf30, C11orf73, C1orf27, CENP1, DCAF17, ENAH, EXOC6B, FAM162A, FAM174A, FAM208B, HOXB3, IFT57, IVD, KIAA1524, KIAA1715, KIDINS220, LYRM1, MFN2, MORF4L1, NGF, RERE, SF3B3, SLC25A17, SNX24, SNX7, STRADB, STXBP6, TASP1, TBCA, TCF4, TMEM214, UBE2D3, UBE2L3, VDAC2, WNK1, XRN2, ZNF138, ZNF350, and ZNF777; or
(c) the pre-mRNA transcript is a pre-mRNA transcript of a gene selected from the group consisting of DIAPH3, NIPA1, RAF1, DCAF17 2a, GNG12, HMGXB4, MRPL45, NSUN4, PITPNB, DCAF17 6a, DMXL1, GALC, GBP1, SREK1, SSBP1, DENND5A, DGK1, GTSF1, L3MBTL2, MMS19, PMS1, PRPF31, SKP1, and SUPT20H.