WO2017106382A1 - Compositions and methods for treatment of central nervous system diseases - Google Patents

Compositions and methods for treatment of central nervous system diseases Download PDF

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WO2017106382A1
WO2017106382A1 PCT/US2016/066721 US2016066721W WO2017106382A1 WO 2017106382 A1 WO2017106382 A1 WO 2017106382A1 US 2016066721 W US2016066721 W US 2016066721W WO 2017106382 A1 WO2017106382 A1 WO 2017106382A1
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Prior art keywords
mrna
nucleobases
ric pre
intron
retained intron
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French (fr)
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Isabel AZNAREZ
Huw M. Nash
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Cold Spring Harbor Laboratory
Stoke Therapeutics Inc
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Cold Spring Harbor Laboratory
Stoke Therapeutics Inc
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Priority to EP22166699.3A priority Critical patent/EP4104867A3/en
Priority to JP2018529257A priority patent/JP7049249B2/ja
Priority to EP16876621.0A priority patent/EP3389725B1/en
Priority to CA3005246A priority patent/CA3005246A1/en
Publication of WO2017106382A1 publication Critical patent/WO2017106382A1/en
Priority to US16/007,435 priority patent/US11096956B2/en
Anticipated expiration legal-status Critical
Priority to US17/379,793 priority patent/US20220118000A1/en
Priority to JP2022013867A priority patent/JP2022062141A/ja
Ceased legal-status Critical Current

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    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Definitions

  • Certain diseases affecting central nervous system function are associated with a deficiency in the expression of a gene, and in turn, a deficiency in the gene product.
  • gene products for which increased expression can provide benefit in central nervous system diseases or conditions include, ATP1A2, CACNAl A, SETD5, SHANK3, NF2, DNMTl, TCF4, RAI1, PEXl, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, MFSD8, STXBPl, PRICKLE2, PRRT2, IDUA and STX1B.
  • the invention provides compositions and methods for treating a central nervous system (CNS) disease or conditions, including antisense oligomers (ASOs) that promote constitutive splicing at intron splice sites of a retained-intron-containing pre-mRNA (RIC pre-mRNA) encoding a gene product that is deficient in the central nervous system disease or condition.
  • ASOs antisense oligomers
  • RIC pre-mRNA retained-intron-containing pre-mRNA
  • the invention further provides compositions and methods for increasing production of mature mRNA encoding a gene product, wherein either the gene product is deficient in a CNS disease or condition, or wherein increased expression of the gene product could provide benefit in a subject having a CNS disease or condition.
  • Increasing the production of the mature mRNA results in increased production of the encoded protein in cells of a subject in need thereof, for example, any subject that can benefit from increased production of the gene product.
  • the described methods may be used to treat subjects having a CNS disease or condition caused by a gene mutation(s), including missense, splicing, frameshift and nonsense mutations, as well as whole gene deletions, that result in deficient protein production.
  • ASO antisense oligomer
  • the CNS disease is Familial hemiplegic migraine-2, Familial Basilar migraine, Alternating hemiplegia of childhood, Episodic ataxia type 2, Familial hemiplegic migraine, Spinocerebellar ataxia type 6 , Mental retardation -23, 3p25 microdeletion syndrome, Phelan-McDermid syndrome,
  • a method of increasing expression of a target protein wherein the target protein is ATP1 A2, CACNAIA, SETD5, SHANK3, NF2, DNMTl, TCF4, RAIl, PEXl, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, STXBPl, PRICKLE2, PRRT2, MFSD8, IDUA, or STXIB expression by improving splicing efficiency of ATP1A2, CACNAIA, SETD5, SHANK3, NF2, DNMTl, TCF4, RAIl, PEXl, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, STXBPl, PRICKLE2, PRRT2, MFSD8, IDUA, or STXIB, by cells having a retained-intron-containing pre-mRNA (RIC pre-mRNA), the RIC pre-mRNA comprising a retained intron, an exon flanking the 5' s
  • RIC pre-mRNA a
  • the target protein is ATP1 A2, CACNAIA, SETD5, SHANK3, NF2, DNMTl, TCF4, RAIl, PEXl, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, STXBP1, PRICKLE2, PRRT2, or STX1B.
  • the target protein is ATP1A2, CACNAIA, SETD5, SHANK3, NF2, DNMTl, TCF4, RAIl, PEXl, ARSA, EIF2B5, EIF2B2, NPCl, ADAR, STXBP1, PRICKLE2, PRRT2, or STX1B.
  • the target protein or the functional RNA is a compensating protein or a compensating functional RNA that functionally augments or replaces a target protein or functional RNA that is deficient in amount or activity in the subject.
  • the cells are in or from a subject having a condition caused by a deficient amount or activity of ATP1 A2, CACNAIA, SETD5, SHANK3, NF2, DNMTl, TCF4, RAIl, PEXl, ARSA, EIF2B5, , EIF2B2, NPCl, ADAR, STXBP1, PRICKLE2, PRRT2, or STX1B protein.
  • the cells are in or from a subject having a condition caused by a deficient amount or activity of ATP1 A2,
  • the deficient amount of the target protein is caused by haploinsufficiency of the target protein, wherein the subject has a first allele encoding a functional target protein, and a second allele from which the target protein is not produced, or a second allele encoding a nonfunctional target protein, and wherein the antisense oligomer binds to a targeted portion of a RIC pre-mRNA transcribed from the first allele.
  • the subject has a condition caused by a disorder resulting from a deficiency in the amount or function of the target protein, wherein the subject has (a) a first mutant allele from which (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 having reduced function compared to an equivalent wild-type protein, or (iii) the target protein is not produced, and (b) a second mutant allele from which (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 having reduced function compared to an equivalent wild-type protein, or (iii) the target protein is not produced, and wherein when the subject has a first mutant allele a(iii), the second mutant allele is b(i) or b(ii), and wherein when the subject has a second mutant allele b(iii), the first mutant allele
  • the target protein is produced in a form having reduced function compared to the equivalent wild-type protein. In some embodiments, the target protein is produced in a form that is fully-functional compared to the equivalent wild-type protein. In some embodiments, the targeted portion of the RIC pre-mRNA is in the retained intron within the region +6 relative to the 5' splice site of the retained intron to -16 relative to the 3' splice site of the retained intron.
  • the targeted portion of the RIC pre-mRNA is in the retained intron within: (a) the region +6 to +4000, +6 to + 3000, +6 to +2000 or +6 to +100 relative to the 5' splice site of the retained intron; or (b) the region -16 to -4000, -16 to -2000, -16 to -1000, -16 to -500 or -16 to -100 relative to the 3' splice site of the retained intron.
  • the targeted portion of the RIC pre-mRNA is within: (a) the region +2e to -4e in the exon flanking the 5' splice site of the retained intron; or (b) the region +2e to -4e in the exon flanking the 3 ' splice site of the retained intron.
  • the RIC pre-mRNA is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NOs: 1-19.
  • the RIC pre-mRNA comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to any one of SEQ ID NOs: 20-80.
  • the antisense oligomer does not increase the amount of the target protein or the functional RNA by modulating alternative splicing of pre-mRNA transcribed from a gene encoding the functional RNA or target protein. In some embodiments, the antisense oligomer does not increase the amount of the target protein or the functional RNA by modulating aberrant splicing resulting from mutation of the gene encoding the target protein or the functional RNA.
  • the RIC pre-mRNA was produced by partial splicing of a full-length pre-mRNA or partial splicing of a wild-type pre-mRNA.
  • the mRNA encoding the target protein or functional RNA is a full-length mature mRNA, or a wild-type mature mRNA.
  • the target protein produced is full-length protein, or wild-type protein.
  • the total amount of the mRNA encoding the target protein or functional RNA produced in the cell contacted with the antisense oligomer is increased about 1.1 to about 10-fold, about 1.5 to about 10-fold, about 2 to about 10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1 to about 5-fold, about 1.1 to about 6-fold, about 1.1 to about 7-fold, about 1.1 to about 8-fold, about 1.1 to about 9-fold, about 2 to about 5-fold, about 2 to about 6-fold, about 2 to about 7- fold, about 2 to about 8-fold, about 2 to about 9-fold, about 3 to about 6-fold, about 3 to about 7- fold, about 3 to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold, about 4 to about 8- fold, about 4 to about 9-fold, at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at
  • the total amount of target protein produced by the cell contacted with the antisense oligomer is increased about 1.1 to about 10-fold, about 1.5 to about 10-fold, about 2 to about 10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1 to about 5-fold, about 1.1 to about 6-fold, about 1.1 to about 7-fold, about 1.1 to about 8-fold, about 1.1 to about 9-fold, about 2 to about 5-fold, about 2 to about 6-fold, about 2 to about 7-fold, about 2 to about 8-fold, about 2 to about 9-fold, about 3 to about 6-fold, about 3 to about 7-fold, about 3 to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold, about 4 to about 8-fold, about 4 to about 9-fold, at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 5-fold, or
  • the antisense oligomer comprises a backbone modification comprising a phosphorothioate linkage or a phosphorodiamidate linkage. In some embodiments, the antisense oligomer comprises a phosphorodiamidate morpholino, a locked nucleic acid, a peptide nucleic acid, a 2'-0-methyl, a 2'-Fluoro, or a 2'-0-methoxyethyl moiety. In some embodiments, the antisense oligomer comprises at least one modified sugar moiety. In some embodiments, each sugar moiety is a modified sugar moiety.
  • the antisense oligomer consists of from 8 to 50 nucleobases, 8 to 40 nucleobases, 8 to 35 nucleobases, 8 to 30 nucleobases, 8 to 25 nucleobases, 8 to 20 nucleobases, 8 to 15 nucleobases, 9 to 50 nucleobases, 9 to 40 nucleobases, 9 to 35 nucleobases, 9 to 30 nucleobases, 9 to 25 nucleobases, 9 to 20 nucleobases, 9 to 15 nucleobases, 10 to 50 nucleobases, 10 to 40 nucleobases, 10 to 35 nucleobases, 10 to 30 nucleobases, 10 to 25 nucleobases, 10 to 20 nucleobases, 10 to 15 nucleobases, 11 to 50 nucleobases, 11 to 40 nucleobases, 11 to 35 nucleobases, 11 to 30 nucleobases, 11 to 25 nucleobases, 11 to 20 nucleobases
  • the antisense oligomer is at least 80%, at least 85%, at least 90%), at least 95%, at least 98%>, at least 99%, or 100%>, complementary to the targeted portion of the RIC pre-mRNA encoding the protein.
  • the targeted portion of the RIC pre-mRNA is within a sequence selected from SEQ ID NOs: 24351-24354, 24356-24378, 24380-24386, or 28515-28516.
  • the antisense oligomer comprises a nucleotide sequence that is at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of SEQ ID NOs: 81-2675, 2676-3302, 3303- 3552, 3553-3794, 3795-4032, 4033-6411, 6412-7753, 7754-7964, 7965-8053, 8054-9332, 9333- 9600, 9601-9803, 24387-28514, 13692-13760, 13761-15914, 15915-16930, 16931-23347, 23348-23535, or 23536-24350.
  • the antisense oligomer comprises a nucleotide sequence selected from SEQ ID NOs: 81-2675, 2676-3302, 3303-3552, 3553-3794, 3795-4032, 4033-6411, 6412-7753, 7754-7964, 7965-8053, 8054-9332, 9333-9600, 9601-9803, 24387-28514, 13692-13760, 13761-15914, 15915-16930, 16931-23347, 23348-23535, or 23536-24350.
  • the cell comprises a population of RIC pre-mRNAs transcribed from the gene encoding the target protein or functional RNA, wherein the population of RIC pre-mRNAs comprises two or more retained introns, and wherein the antisense oligomer binds to the most abundant retained intron in the population of RIC pre-mRNAs.
  • the binding of the antisense oligomer to the most abundant retained intron induces splicing out of the two or more retained introns from the population of RIC pre-mRNAs to produce mRNA encoding the target protein or functional RNA.
  • the cell comprises a population of RIC pre-mRNAs transcribed from the gene encoding the target protein or functional RNA, wherein the population of RIC pre-mRNAs comprises two or more retained introns, and wherein the antisense oligomer binds to the second most abundant retained intron in the population of RIC pre-mRNAs.
  • the binding of the antisense oligomer to the second most abundant retained intron induces splicing out of the two or more retained introns from the population of RIC pre-mRNAs to produce mRNA encoding the target protein or functional RNA.
  • the condition is a disease or disorder.
  • the disease or disorder is Familial hemiplegic migraine-2, Familial Basilar migraine, Alternating hemiplegia of childhood, Episodic ataxia type 2, Familial hemiplegic migraine, Spinocerebellar ataxia type 6 , Mental retardation-23, 3p25 microdeletion syndrome, Phelan-McDermid syndrome, Schizophrenia- 15, Neurofibromatosis, type 2, Meningioma, NF2- related, Schwannomatosis 1, Hereditary sensory neuropathy type IE, Autosomal dominant cerebellar ataxia, deafness, and narcolepsy, Pitt-hopkins syndrome, Smith-magenis syndrome, peroxisome biogenesis disorder la, Heimler syndrome-1, Metachromatic Leukodystrophy, Leukoencephalopathy with vanishing white matter, Niemann-Pick disease type CI and
  • the target protein and the RIC pre-mRNA are encoded by the ATP1 A2, CACNA1 A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEX1, ARSA, EIF2B5, , EIF2B2, NPC1, ADAR, STXBP1, PRICKLE2, PRRT2, or STX1B gene.
  • the method further comprises assessing protein expression.
  • the antisense oligomer binds to a targeted portion of a ATP1A2, CACNA1A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEX1, ARSA, EIF2B5, , EIF2B2, NPC1, ADAR, STXBP1, PRICKLE2, PRRT2, or STX1B RIC pre-mRNA.
  • the subject is a human.
  • the subject is a non-human animal.
  • the subject is a fetus, an embryo, or a child.
  • the cells are ex vivo.
  • the antisense oligomer is administered by intrathecal injection, intracerebroventricular injection, intraperitoneal injection, intramuscular injection, subcutaneous injection, or intravenous injection of the subject.
  • the 9 nucleotides at -3e to - le of the ex on flanking the 5' splice site and +1 to +6 of the retained intron are identical to the corresponding wild-type sequence.
  • the 16 nucleotides at -15 to -1 of the retained intron and +le of the exon flanking the 3' splice site are identical to the corresponding wild-type sequence.
  • Described herein, in certain embodiments, is an antisense oligomer as used in a method described above.
  • an antisense oligomer comprising a sequence with at least about 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to any one of SEQ ID NOs: 81-2675, 2676-3302, 3303-3552, 3553-3794, 3795-4032, 4033-6411, 6412- 7753, 7754-7964, 7965-8053, 8054-9332, 9333-9600, 9601-9803, 24387-28514, 13692-13760, 13761-15914, 15915-16930, 16931-23347, 23348-23535, or 23536-24350.
  • a pharmaceutical composition comprising the antisense oligomer described above, and an excipient.
  • a method of treating a subject in need thereof by administering the pharmaceutical composition by intrathecal injection, intracerebroventricular injection, intraperitoneal injection, intramuscular injection, subcutaneous injection, or intravenous injection.
  • compositions comprising an antisense oligomer for use in a method of increasing expression of a target protein or a functional RNA by cells to treat Familial hemiplegic migraine-2, Familial Basilar migraine, Alternating hemiplegia of childhood, Episodic ataxia type 2, Familial hemiplegic migraine, Spinocerebellar ataxia type 6 , Mental retardation-23, 3p25 microdeletion syndrome, Phelan-McDermid syndrome,
  • compositions comprising an antisense oligomer for use in a method of treating a condition associated with ATP1 A2, CACNA1 A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEXl, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, MFSD8, STXBPl, PRICKLE2, PRRT2, IDUA, or STX1B protein in a subject in need thereof, the method comprising the step of increasing expression of ATP1A2, CACNA1A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEXl, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, MFSD8, STXBPl, PRICKLE2, PRRT2, IDUA, or STX1B protein by cells of the subject, wherein the cells have a retained- intron-containing pre-mRNA (RIC pre-mRNA) comprising the step of increasing expression of ATP1
  • the target protein is ATP1 A2, CACNA1 A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEX1, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, STXBPl, PRICKLE2, PRRT2, or STXIB.
  • the target protein is ATP1A2, CACNA1A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEX1, ARSA, EIF2B5, EIF2B2, NPCl, ADAR, STXBPl, PRICKLE2, PRRT2, or STXIB.
  • the condition is a disease or disorder.
  • the disease or disorder is Familial hemiplegic migraine-2, Familial Basilar migraine, Alternating hemiplegia of childhood, Episodic ataxia type 2, Familial hemiplegic migraine, Spinocerebellar ataxia type 6 , Mental retardation -23, 3p25 microdeletion syndrome, Phelan-McDermid syndrome, Schizophrenia- 15, Neurofibromatosis, type 2, Meningioma, NF2-related, Schwannomatosis 1, Hereditary sensory neuropathy type IE, Autosomal dominant cerebellar ataxia, deafness, and narcolepsy, Pitt- hopkins syndrome, Smith-magenis syndrome, peroxisome biogenesis disorder la, Heimler syndrome- 1, Metachromatic Leukodystrophy, Leukoencephalopathy with vanishing white matter, Niemann-Pick disease type CI and Niemann-Pick disease type D, Aicardi-Goutieres syndrome-6, early infantile epileptic
  • the target protein and RIC pre-mRNA are encoded by the ATP1 A2, CACNA1A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEX1, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, STXBPl, PRICKLE2, PRRT2, or STXIB gene.
  • the target protein and RIC pre-mRNA are encoded by the ATP1 A2, CACNA1 A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEX1, ARSA, EIF2B5, EIF2B2, NPCl, ADAR, STXBPl, PRICKLE2, PRRT2, or STXIB gene.
  • the antisense oligomer targets a portion of the RIC pre-mRNA that is in the retained intron within the region +6 relative to the 5' splice site of the retained intron to -16 relative to the 3' splice site of the retained intron. In some embodiments, the antisense oligomer targets a portion of the RIC pre-mRNA that is in the retained intron within: (a) the region +6 to +100 relative to the 5' splice site of the retained intron; or (b) the region -16 to -100 relative to the 3' splice site of the retained intron.
  • the antisense oligomer targets a portion of the RIC pre-mRNA that is within the region about 100 nucleotides downstream of the 5' splice site of the at least one retained intron, to about 100 nucleotides upstream of the 3' splice site of the at least one retained intron.
  • the targeted portion of the RIC pre-mRNA is within: (a) the region +2e to -4e in the exon flanking the 5' splice site of the retained intron; or (b) the region +2e to -4e in the exon flanking the 3 ' splice site of the retained intron.
  • the RIC pre-mRNA is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to SEQ ID NOs: 1-19.
  • the RIC pre-mRNA comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to any one of SEQ ID NOs: 20-80.
  • the antisense oligomer does not increase the amount of target protein or functional RNA by modulating alternative splicing of the pre-mRNA transcribed from a gene encoding the target protein or functional RNA.
  • the antisense oligomer does not increase the amount of the functional RNA or functional protein by modulating aberrant splicing resulting from mutation of the gene encoding the target protein or faunctional RNA.
  • the RIC pre-mRNA was produced by partial splicing from a full-length pre-mRNA or a wild-type pre-mRNA.
  • the mRNA encoding the target protein or functional RNA is a full-length mature mRNA, or a wild-type mature mRNA.
  • the target protein produced is full-length protein, or wild-type protein.
  • the retained intron is a rate-limiting intron.
  • said retained intron is the most abundant retained intron in said RIC pre-mRNA. In some embodiments, the retained intron is the second most abundant retained intron in said RIC pre-mRNA.
  • the antisense oligomer comprises a backbone modification comprising a phosphorothioate linkage or a phosphorodiamidate linkage. In some embodiments, said antisense oligomer is an antisense oligonucleotide.
  • the antisense oligomer comprises a phosphorodiamidate morpholino, a locked nucleic acid, a peptide nucleic acid, a 2'-0-methyl, a 2'-Fluoro, or a 2'-0- methoxyethyl moiety.
  • the antisense oligomer comprises at least one modified sugar moiety. In some embodiments, each sugar moiety is a modified sugar moiety.
  • the antisense oligomer consists of from 8 to 50 nucleobases, 8 to 40 nucleobases, 8 to 35 nucleobases, 8 to 30 nucleobases, 8 to 25 nucleobases, 8 to 20 nucleobases, 8 to 15 nucleobases, 9 to 50 nucleobases, 9 to 40 nucleobases, 9 to 35 nucleobases, 9 to 30 nucleobases, 9 to 25 nucleobases, 9 to 20 nucleobases, 9 to 15 nucleobases, 10 to 50 nucleobases, 10 to 40 nucleobases, 10 to 35 nucleobases, 10 to 30 nucleobases, 10 to 25 nucleobases, 10 to 20 nucleobases, 10 to 15 nucleobases, 11 to 50 nucleobases, 11 to 40 nucleobases, 11 to 35 nucleobases, 11 to 30 nucleobases, 11 to 25 nucleobases, 11 to 20 nucleobases
  • the antisense oligomer is at least 80%, at least 85%>, at least 90%), at least 95%, at least 98%>, at least 99%, or is 100%> complementary to the targeted portion of the RIC pre-mRNA encoding the protein.
  • the antisense oligomer binds to a targeted portion of a tuberin RIC pre-mRNA, wherein the targeted portion of the RIC pre- mRNA is within a sequence selected from SEQ ID NOs: 24351-24354, 24356-24378, 24380- 24386, or 28515-28516.
  • the antisense oligomer comprises a nucleotide sequence that is at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of SEQ ID NOs: 81-2675, 2676-3302, 3303-3552, 3553- 3794, 3795-4032, 4033-6411, 6412-7753, 7754-7964, 7965-8053, 8054-9332, 9333-9600, 9601- 9803, 24387-28514, 13692-13760, 13761-15914, 15915-16930, 16931-23347, 23348-23535, or 23536-24350.
  • the antisense oligomer comprises a nucleotide sequence selected from SEQ ID NOs: 81-2675, 2676-3302, 3303-3552, 3553-3794, 3795-4032, 4033- 6411, 6412-7753, 7754-7964, 7965-8053, 8054-9332, 9333-9600, 9601-9803, 24387-28514, 13692-13760, 13761-15914, 15915-16930, 16931-23347, 23348-23535, or 23536-24350.
  • the antisense oligomer binds to a targeted portion of a ATP1 A2,
  • CACNA1A SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEX1, ARSA, EIF2B5, EIF2B1, EIF2B2, NPC1, ADAR, STXBP1, PRICKLE2, PRRT2, or STX1B RIC pre-mRNA.
  • the antisense oligomer binds to a targeted portion of a ATP1 A2, CACNA1 A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEX1, ARSA, EIF2B5, EIF2B2, NPCl, ADAR, STXBP1, PRICKLE2, PRRT2, or STX1B RIC pre-mRNA.
  • a pharmaceutical composition comprising the antisense oligomer of any of the compositions described above, and an excipient.
  • a method of treating a subject in need thereof by administering the pharmaceutical composition by intrathecal injection, intracerebroventricular injection, intraperitoneal injection, intramuscular injection, subcutaneous injection, or intravenous injection.
  • a pharmaceutical composition comprising: an antisense oligomer that hybridizes to a target sequence of a deficient ATP1A2, CACNA1A, SETD5, SHANK3, NF2, DNMTL TCF4, RAIL PEXL ARSA, EIF2B5, EIF2BL EIF2B2, NPCL ADAR, STXBP1, PRICKLE2, PRRT2, MFSD8, IDUA, or STX1B mRNA transcript, wherein the deficient ATP1A2, CACNA1A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAIl, PEX1, ARSA, EIF2B5, EIF2B1, EIF2B2, NPC1, ADAR, STXBP1, PRICKLE2, PRRT2, MFSD8, IDUA, or STX1B mRNA transcript comprises a retained intron, wherein the antisense oligomer induces splicing out of the retained intron from the deficient ATP1
  • the antisense oligomer hybridizes to a target sequence of a deficient ATP1A2, CACNA1A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAIl, PEX1, ARSA, EIF2B5, EIF2B1, EIF2B2, NPC1, ADAR, STXBP1, PRICKLE2, PRRT2, or STX1B mRNA transcript.
  • the deficient ATP1A2, CACNA1A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAIl, PEX1, ARSA, EIF2B5, EIF2B1, EIF2B2, NPC1, ADAR, STXBP1, PRICKLE 2, PRRT2, or STX1B mRNA transcript is aATP!A2, CACNA1A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAIl, PEX1, ARSA, EIF2B5, EIF2B1, EIF2B2, NPC1, ADAR, STXBP1, PRICKLE2, PRRT2, or STX1B RIC pre-mRNA transcript.
  • the antisense oligomer hybridizes to a target sequence of a deficient ATP1A2, CACNA1A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAIl, PEX1, ARSA, EIF2B5, EIF2B2, NPC1, ADAR, STXBP1, PRICKLE2, PRRT2, or STX1B mRNA transcript.
  • the deficient ATP1A2, CACNA1A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAIl, PEX1, ARSA, EIF2B5, EIF2B2, NPC1, ADAR, STXBP1, PRICKLE2, PRRT2, or STX1B mRNA transcript is aATP!A2,
  • the targeted portion of the RIC pre-mRNA transcript is in the retained intron within the region +4000 relative to the 5' splice site of the retained intron to -2000 relative to the 3' spliced site of the retained intron.
  • the RIC pre-mRNA transcript is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to SEQ ID NOs: 1-19. In some embodiments, the RIC pre-mRNA transcript comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to any one of SEQ ID NOs: 20-80. In some embodiments, the antisense oligomer comprises a backbone modification comprising a phosphorothioate linkage or a phosphorodiamidate linkage.
  • the antisense oligomer is an antisense oligonucleotide.
  • the antisense oligomer comprises a phosphorodiamidate morpholino, a locked nucleic acid, a peptide nucleic acid, a 2'-0-methyl, a 2'-Fluoro, or a 2'-0- methoxyethyl moiety.
  • the antisense oligomer comprises at least one modified sugar moiety.
  • the antisense oligomer comprises from 8 to 50 nucleobases, 8 to 40 nucleobases, 8 to 35 nucleobases, 8 to 30 nucleobases, 8 to 25 nucleobases, 8 to 20 nucleobases, 8 to 15 nucleobases, 9 to 50 nucleobases, 9 to 40 nucleobases, 9 to 35 nucleobases, 9 to 30 nucleobases, 9 to 25 nucleobases, 9 to 20 nucleobases, 9 to 15 nucleobases, 10 to 50 nucleobases, 10 to 40 nucleobases, 10 to 35 nucleobases, 10 to 30 nucleobases, 10 to 25 nucleobases, 10 to 20 nucleobases, 10 to 15 nucleobases, 11 to 50 nucleobases, 11 to 40 nucleobases, 11 to 35 nucleobases, 11 to 30 nucleobases, 11 to 25 nucleobases, 11 to 20 nucleobases, 11
  • the antisense oligomer is at least 80%, at least 85%>, at least 90%), at least 95%, at least 98%>, at least 99%, or is 100%> complementary to a targeted portion of the RIC pre-mRNA transcript.
  • the targeted portion of the RIC pre-mRNA transcript is within a sequence selected from SEQ ID NOs: 24351-24354, 24356-24378, 24380- 24386, or 28515-28516.
  • the antisense oligomer comprises a nucleotide sequence that is at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of SEQ ID NOs: 81-2675, 2676-3302, 3303-3552, 3553- 3794, 3795-4032, 4033-6411, 6412-7753, 7754-7964, 7965-8053, 8054-9332, 9333-9600, 9601- 9803, 24387-28514, 13692-13760, 13761-15914, 15915-16930, 16931-23347, 23348-23535, or 23536-24350.
  • the antisense oligomer comprises a nucleotide sequence selected from SEQ ID NOs: 81-2675, 2676-3302, 3303-3552, 3553-3794, 3795-4032, 4033- 6411, 6412-7753, 7754-7964, 7965-8053, 8054-9332, 9333-9600, 9601-9803, 24387-28514, 13692-13760, 13761-15914, 15915-16930, 16931-23347, 23348-23535, or 23536-24350.
  • the pharmaceutical composition is formulated for intrathecal injection, intracerebroventricular injection, intraperitoneal injection, intramuscular injection, subcutaneous injection, or intravenous injection.
  • a method of inducing processing of a mRNA transcript to facilitate removal of a retained intron to produce a fully processed mRNA transcript that encodes a functional form of a target protein comprising: (a) contacting an antisense oligomer to a target cell of a subject; (b) hybridizing the antisense oligomer to the mRNA transcript, wherein the mRNA transcript is capable of encoding the functional form of the target protein and comprises at least one retained intron; (c) removing the at least one retained intron from the mRNA transcript to produce the fully processed mRNA transcript that encodes the functional form of the target protein; and (d) translating the functional form of the target protein from the fully processed mRNA transcript; wherein the mRNA transcript is selected from ATP1A2, CACNAIA, SETD5, SHANK3, NF2, DNMTl, TCF4, RAI1, PEX1, ARSA, EIF2B5, EIF2B
  • the retained intron is an entire retained intron.
  • the mRNA transcript is a RIC pre-mRNA transcript.
  • the mRNA transcript is selected from ATP 1A2, CACNAIA, SETD5, SHANK3, NF2, DNMTI, TCF4, RAI1, PEXl, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, STXBP1, PRICKLE2, PRRT2, or STX1B mRNA transcript.
  • the mRNA transcript is selected from ATP1A2, CACNAIA, SETD5, SHANK3, NF2, DNMTI, TCF4, RAI1, PEXl, ARSA, EIF2B5, EIF2B2, NPCl, ADAR, STXBP1, PRICKLE2, PRRT2, or STX1B mRNA transcript.
  • a method of treating a subject having a condition caused by a deficient amount or activity of a target protein comprising: administering to the subject an antisense oligomer comprising a nucleotide sequence with at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of SEQ ID NOs: 81-2675, 2676-3302, 3303-3552, 3553-3794, 3795-4032, 4033-6411, 6412- 7753, 7754-7964, 7965-8053, 8054-9332, 9333-9600, 9601-9803, 24387-28514, 13692-13760, 13761-15914, 15915-16930, 16931-23347, 23348-23535, or 23536-24350.
  • FIG. 1 illustrates a schematic representation of an exemplary retained-intron-containing (RIC) pre-mRNA transcript.
  • the 5' splice site consensus sequence is indicated with underlined letters (letters are nucleotides; upper case: exonic portion and lower case: intronic portion) from -3e to -le and +1 to +6 (numbers labeled "e” are exonic and unlabeled numbers are intronic).
  • the 3' splice site consensus sequence is indicated with underlined letters (letters are nucleotides; upper case: exonic portion and lower case: intronic portion) from -15 to -1 and +le (numbers labeled "e” are exonic and unlabeled numbers are intronic).
  • Intronic target regions for ASO screening comprise nucleotides +6 relative to the 5' splice site of the retained intron (arrow at left) to -16 relative to the 3' splice site of the retained intron (arrow at right).
  • intronic target regions for ASO screening comprise nucleotides +6 to +100 relative to the 5' splice site of the retained intron and -16 to -100 relative to the 3' splice site of the retained intron.
  • Exonic target regions comprise nucleotides +2e to -4e in the ex on flanking the 5' splice site of the retained intron and +2e to -4e in the ex on flanking the 3' splice site of the retained intron.
  • n or N denote any nucleotide
  • y denotes pyrimidine.
  • the sequences shown represent consensus sequences for mammalian splice sites and individual introns and exons need not match the consensus sequences at every position.
  • FIG. 2A-FIG. 2B show schematic representations of the Targeted Augmentation of Nuclear Gene Output (TANGO) approach.
  • FIG. 2A shows a cell divided into nuclear and cytoplasmic compartments.
  • a pre-mRNA transcript of a target gene consisting of exons (rectangles) and introns (connecting lines) undergoes splicing to generate an mRNA, and this mRNA is exported to the cytoplasm and translated into target protein.
  • the splicing of intron 1 is inefficient and a retained intron-containing (RIC) pre-mRNA accumulates primarily in the nucleus, and if exported to the cytoplasm, is degraded, leading to no target protein production.
  • FIG. 2B shows an example of the same cell divided into nuclear and cytoplasmic compartments.
  • Treatment with an antisense oligomer (ASO) promotes the splicing of intron 1 and results in an increase in mRNA, which is in turn translated into higher levels of target protein.
  • ASO antisense oligomer
  • FIG. 3 depicts a schematic of the ReSeq Genes for ADAR intron 2 corresponding to
  • FIG. 4 depicts a schematic of the ReSeq Genes for ARSA intron 3 corresponding to
  • FIG. 5 depicts a schematic of the ReSeq Genes for ARSA intron 4 corresponding to
  • FIG. 6 depicts a schematic of the ReSeq Genes for DNMTl intron 30 corresponding to
  • FIG. 8 depicts a schematic of the ReSeq Genes for EIF2B2 intron 1 corresponding to
  • FIG. 10 depicts a schematic of the ReSeq Genes for EIF2B5 intron 12 corresponding to NM 003907. The Percent Intron Retention (PIR) of the circled intron is shown.
  • FIG. 12 depicts a schematic of the ReSeq Genes for EIF2B5 intron 13 corresponding to NM 003907.
  • the Percent Intron Retention (PIR) of the circled intron is shown.
  • FIG. 14 depicts a schematic of the ReSeq Genes for PEXl intron 10 corresponding to NM 000466.
  • the Percent Intron Retention (PIR) of the circled intron is shown.
  • FIG. 16 depicts a schematic of the ReSeq Genes for PEXl intron 14 corresponding to NM 000466.
  • the Percent Intron Retention (PIR) of the circled intron is shown.
  • FIG. 18 depicts a schematic of the ReSeq Genes for PRICKLE2 intron 4 corresponding to NM l 98859.
  • the Percent Intron Retention (PIR) of the circled intron is shown.
  • FIG. 20 depicts a schematic of the ReSeq Genes for PRRT2 intron 1 corresponding to NM 145239.
  • the Percent Intron Retention (PIR) of the circled intron is shown.
  • FIG. 21 depicts a schematic of the ReSeq Genes for RAI1 intron 4 corresponding to NM 030665.
  • the Percent Intron Retention (PIR) of the circled intron is shown.
  • FIG. 23 depicts a schematic of the ReSeq Genes for SHANK3 intron 16 corresponding to NM 033517.
  • the Percent Intron Retention (PIR) of the circled intron is shown.
  • FIG. 25 depicts a schematic of the ReSeq Genes for STXBPl intron 18 corresponding to NM_001032221.
  • the Percent Intron Retention (PIR) of the circled intron is shown.
  • FIG. 27 depicts a schematic of the ReSeq Genes for SETD5 intron 4 corresponding to NM 001080517.
  • the Percent Intron Retention (PIR) of the circled intron is shown.
  • FIG. 28 depicts a schematic of the ReSeq Genes for ATP 1A2 intron 22 corresponding to NM 000702.
  • the Percent Intron Retention (PIR) of the circled intron is shown.
  • FIG. 29 depicts a schematic of the ReSeq Genes for CACNA1A intron 36
  • FIG. 30 depicts a schematic of the ReSeq Genes for CACNA1A intron 37
  • FIG. 31 depicts a schematic of the ReSeq Genes for NF2 intron 16 corresponding to
  • FIG. 32 depicts a schematic of the ReSeq Genes for PEX1 intron 19 corresponding to
  • FIG. 33 depicts a schematic of the ReSeq Genes for PEX1 intron 21 corresponding to
  • FIG. 34 depicts a schematic of the ReSeq Genes for STX1B intron 6 corresponding to
  • FIG. 35 depicts a schematic of the ReSeq Genes for STX1B intron 7 corresponding to
  • FIG. 36 depicts a schematic of the ReSeq Genes for NF2 intron 16 corresponding to
  • FIG. 38 depicts a schematic of the ReSeq Genes ior NPCl intron 15 corresponding to NM 000271. The Percent Intron Retention (PIR) of the circled intron is shown.
  • PIR Percent Intron Retention
  • FIG. 40 depicts a schematic of the ReSeq Genes for ATP1A2 intron 22 corresponding to NM 000702.
  • the Percent Intron Retention (PIR) of the circled intron is shown.
  • FIG. 42 depicts a schematic of the ReSeq Genes for TCF4 intron 18 corresponding to NM 001243226.
  • the Percent Intron Retention (PIR) of the circled intron is shown.
  • introns in primary transcripts of protein-coding genes having more than one intron are spliced from the primary transcript with different efficiencies. In most cases only the fully spliced mRNA is exported through nuclear pores for subsequent translation in the cytoplasm. Unspliced and partially spliced transcripts are detectable in the nucleus. It is generally thought that nuclear accumulation of transcripts that are not fully spliced is a mechanism to prevent the accumulation of potentially deleterious mRNAs in the cytoplasm that may be translated to protein. For some genes, splicing of the least efficient intron is a rate- limiting post-transcriptional step in gene expression, prior to translation in the cytoplasm.
  • EIF2B5 protein/EIF2B 1 protein/EIF2B2 deficient in Leukoencephalopathy with vanishing white matter (VWM); NPCl protein, deficient in Niemann-Pick disease type CI and Niemann-Pick disease type D; ADAR protein, deficient in Aicardi-Goutieres syndrome-6 (AGS6); MFSD8 protein, deficient in Neuronal ceroid lipofuscinosis-7; STXBPl protein, deficient in early infantile epileptic encephalopathy-4; PRICKLE2 protein, deficient in progressive myoclonic epilepsy 5; PRRT2 protein, deficient in familial infantile convulsion with paroxysmal choreoathetosis, episodic kinesigenic dyskinesia 1, or benign familial infantile seizuers-2; IDUA protein, deficient in attenuated MPS-1 (Hurler-scheie syndrome); and STXIB protein, deficient in generalized Epilepsy with febrile seizure plus type 9
  • ATP1A2, CACNA1A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEX1, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, MFSD8, STXBPl, PRICKLE2, PRRT2, and STXIB pre-mRNA species comprise at least one retained intron.
  • the present invention provides compositions and methods for upregulating splicing of one or more retained ATP1A2, CACNA1A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEX1, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, MFSD8, STXBPl, PRICKLE2, PRRT2, IDUA, or STXIB introns that are rate-limiting for the nuclear stages of gene expression to increase steady- state production of fully-spliced, mature mRNA, and thus, translated ATP1 A2, CACNA1 A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEX1, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, MFSD8, STXBPl, PRICKLE2, PRRT2, IDUA, or STXIB protein levels.
  • compositions and methods can utilize antisense oligomers (ASOs) that promote constitutive splicing at intron splice sites of a retained-intron-containing ATP1 A2, CACNA1 A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEX1, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, MFSD8, STXBPl, PRICKLE2, PRRT2, IDUA, or STXIB pre-mRNA (RIC pre- mRNA) that accumulates in the nucleus.
  • ASOs antisense oligomers
  • ATP1 A2, CACNA1 A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEX1, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, MFSD8, STXBPl, PRICKLE2, PRRT2, IDUA, or STXIB protein can be increased using the methods of the invention to treat a condition caused by ATP1 A2, CACNA1 A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEX1, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, MFSD8, STXBPl, PRICKLE2, PRRT2, IDUA, or STXIB deficiency.
  • compositions and methods can utilize antisense oligomers (ASOs) that promote constitutive splicing at intron splice sites of a retained-intron-containing ATP1 A2, CACNA1 A, SETD5, SHANK3, NF2, DNMTl, TCF4, RAIl, PEXl, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, STXBPl, PRICKLE2, PRRT2, or STXIB pre-mRNA (RIC pre-mRNA) that accumulates in the nucleus.
  • ASOs antisense oligomers
  • ATP1 A2, CACNA1 A, SETD5, SHANK3, NF2, DNMTl, TCF4, RAIl, PEXl, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, STXBPl, PRICKLE2, PRRT2, or STXIB protein can be increased using the methods of the invention to treat a condition caused by ATP1 A2, CACNA1 A, SETD5, SHANK3, NF2, DNMTl, TCF4, RAIl, PEXl, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, STXBPl, PRICKLE2, PRRT2, or STXIB deficiency.
  • CACNA1A SETD5, SHANK3, NF2, DNMTl, TCF4, RAIl, PEXl, ARSA, EIF2B5, EIF2B2, NPCl, ADAR, STXBPl, PRICKLE2, PRRT2, or STXIB protein levels.
  • compositions and methods can utilize antisense oligomers (ASOs) that promote constitutive splicing at intron splice sites of a retained-intron-containing ATP1A2, CACNA1A, SETD5, SHANK3, NF2, DNMTl, TCF4, RAIl, PEXl, ARSA, EIF2B5, EIF2B2, NPCl, ADAR, STXBPl, PRICKLE2, PRRT2, or STXIB pre-mRNA (RIC pre-mRNA) that accumulates in the nucleus.
  • ASOs antisense oligomers
  • ATP1A2, CACNA1A, SETD5, SHANK3, NF2, DNMTl, TCF4, RAIl, PEXl, ARSA, EIF2B5, EIF2B2, NPCl, ADAR, STXBPl, PRICKLE2, PRRT2, or STXIB protein can be increased using the methods of the invention to treat a condition caused by ATP1 A2, CACNA1A, SETD5, SHANK3, NF2, DNMTl, TCF4, RAIl, PEXl, ARSA, EIF2B5, EIF2B2, NPCl, ADAR, STXBPl, PRICKLE2, PRRT2, or STXIB deficiency.
  • the methods of the invention can be used to increase ATP1 A2, CACNA1A, SETD5, SHANK3, NF2, DNMTl, TCF4, RAIl, PEXl, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, MFSD8, STXBPl, PRICKLE2, PRRT2, IDUA, or STXIB production to treat a condition in a subject in need thereof.
  • the subject has a condition in which ATP1A2, CACNA1A, SETD5, SHANK3, NF2, DNMTl, TCF4, RAIl, PEXl, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, MFSD8, STXBPl, PRICKLE2, PRRT2, IDUA, or STXIB is not necessarily deficient relative to wild-type, but where an increase in ATP1 A2, CACNA1A, SETD5, SHANK3, NF2, DNMTl, TCF4, RAIl, PEXl, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, MFSD8, STXBPl, PRICKLE2, PRRT2, IDUA, or STXIB mitigates the condition nonetheless.
  • the condition can be caused by a ATP1 A2,
  • CACNAIA SETD5, SHANK3, NF2, DNMTl, TCF4, RAIl, PEXl, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, MFSD8, STXBPl, PRICKLE2, PRRT2, IDUA, or STX1B
  • the methods of the invention can be used to increase ATP1 A2, CACNAIA, SETD5, SHANK3, NF2, DNMTl, TCF4, RAIl, PEXl, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, STXBPl, PRICKLE2, PRRT2, or STX1B production to treat a condition in a subject in need thereof.
  • the subject has a condition in which ATP1A2, CACNAIA, SETD5, SHANK3, NF2, DNMTl, TCF4, RAIl, PEXl, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, STXBPl, PRICKLE2, PRRT2, or STX1B is not necessarily deficient relative to wild-type, but where an increase in ATP1 A2, CACNAIA, SETD5,
  • the condition can be caused by a ATP1 A2, CACNAIA, SETD5, SHANK3, NF2, DNMTl, TCF4, RAIl, PEXl, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, STXBPl, PRICKLE2, PRRT2, or STX1B mitigates the condition nonetheless.
  • the condition can be caused by a ATP1 A2, CACNAIA, SETD5, SHANK3, NF2, DNMTl, TCF4, RAIl, PEXl, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, STXBPl, PRICKLE2, PRRT2, or STX1B haploinsufficiency.
  • the methods of the invention can be used to increase
  • the subject has a condition in which ATP1A2, CACNAIA, SETD5, SHANK3, NF2, DNMTl, TCF4, RAIl, PEXl, ARSA, EIF2B5, EIF2B2, NPCl, ADAR, STXBPl, PRICKLE2, PRRT2, or STX1B is not necessarily deficient relative to wild-type, but where an increase in ATP1 A2, CACNAIA, SETD5, SHANK3, NF2, DNMTl, TCF4, RAIl, PEXl, ARSA, EIF2B5, , EIF2B2, NPCl, ADAR, STXBPl, PRICKLE2, PRRT2, or STX1B mitigates the condition nonetheless.
  • the condition can be caused by a ATP1A2, CACNAIA, SETD5, SHANK3, NF2, DNMTl, TCF4, RAIl, PEXl, ARSA, EIF2B5, EIF2B2, NPCl, ADAR, STXBPl, PRICKLE2, PRRT2, or STX1B
  • the described compositions and methods are used to treat a subject or patient having a CNS disease or condition that is caused by a deficiency in the target protein. In embodiments the described compositions and methods are used to treat a subject or patient having a CNS disease or condition that is not caused by a deficiency in the target protein. In embodiments, the subject or patient having a CNS disease or condition can benefit from increased production of the target protein by supplementing normal production of the target protein. In embodiments, the target protein acts on a secondary target to ameliorate or treat the CNS disease or condition in the subject. In embodiments, the secondary target protein is deficient in the subject. In embodiments, the secondary target protein is not deficient in the subject.
  • ATP1A2 encodes the a2 isoform of Na+K+-ATPase (sodium potassium ATPase).
  • the a2 isoform belongs to the family of P-type cation transport ATPases, and to the subfamily of Na+/K+ -ATPases.
  • Na+/K+ -ATPase is an integral membrane protein responsible for establishing and maintaining the electrochemical gradients of Na and K ions across the plasma membrane. These gradients are essential for osmoregulation, for sodium-coupled transport of a variety of organic and inorganic molecules, and for electrical excitability of nerve and muscle.
  • Na+/K+ -ATPase transfers Na+ out and K+ into the cell, using ATP as energy source.
  • Na+/K+ ATPases are present in all human cells; however, the a2 isoform is mainly restricted to the brain and muscle.
  • Na+/K+ -ATPases that include the a -2 subunit are primarily found in glia cells, particularly in astrocytes, where they contribute to the glial clearance of high extracellular K+ to prevent further depolarization. Through its action in glia, the Na+/K+ -ATPase plays a critical role in the normal function of neurons. Communication between neurons depend neurotransmitters. Briefly, neurons release neurotransmitters, which bind to receptor proteins on neighboring neurons.
  • ATP1 A2 is associated with genetic diseases, for example familial hemiplegic migraine-2 (FHM2), familial basilar migraine and alternating hemiplegia of childhood.
  • FHM2 familial hemiplegic migraine-2
  • Familial hemiplegic migraine-2 (FHM2) and familial basilar migraine are caused by heterozygous mutation in ATP1A2.
  • FHM2 is a monogenic variant of migraine with aura.
  • Migraines can cause intense, throbbing pain in one area of the head, often accompanied by nausea, vomiting, and extreme sensitivity to light and sound. These recurrent headaches can begin in childhood or adolescence and can be triggered by certain foods, emotional stress, and minor head trauma. Each headache may last from a few hours to a few days. In some types of migraine, including familial hemiplegic migraine, a pattern of neurological symptoms called an aura precedes the headache. The most common symptoms associated with an aura are temporary visual changes such as blind spots (scotomas), flashing lights, zig-zagging lines, and double vision.
  • auras are also characterized by temporary numbness or weakness, often affecting one side of the body (hemiparesis). Additional features of an aura can include difficulty with speech, confusion, and drowsiness. An aura can develops gradually over a few minutes and lasts about an hour. Familial hemiplegic migraine episodes includes fever, seizures, prolonged weakness, coma, and, rarely, death. Although most people with familial hemiplegic migraine recover completely between episodes, neurological symptoms such as memory loss and problems with attention can last for weeks or months. About 20 percent of people with this condition develop mild but permanent difficulty coordinating movements (ataxia), which may worsen with time, and rapid, involuntary eye movements called nystagmus.
  • FFDVI 2 is caused by mutations present in ATPl A2.
  • the mutations and deficiencies in ATP1A2 that cause FFDVI2 are responsible for approximately 20% of FHM in families.
  • Almost all FFDVI2 mutations are non-synonymous S Ps, but there are also small deletions and a mutation affecting the stop codon, causing an extension of the ATPl A2 protein by 27 amino acid residues.
  • Most of the mutations are associated with pure FFDVI without additional clinical symptoms.
  • ATPl A2 is expressed primarily in astrocytes in the adult, where it appears functionally coupled to various transporters (glutamate transporter and Na + /Ca 2+ exchanger), and is essential in the clearance of released glutamate and potassium from the extracellular space during neuronal activity.
  • FFDVI2 mutations that cause loss of function of ATP1A2 may lead to decreased glutamate clearance and an increase of potassium in the synaptic cleft during neuronal activity, which could lead to prolonged recovery time after neuronal excitation, and may render the brain to be more susceptible to cortical spreading depression.
  • Cortical spreading depression is a wave of continual strong neuronal depolarization that slowly progresses across the cortex, generating a brief intense spike of activity that is followed by long-lasting neural suppression. Cortical spreading depression has been shown to activate the trigeminovascular system which is responsible for the headache associated with migraines.
  • ATPl A2 mutations were reported to be associated with FHM and cerebellar problems, specifically motor problems, childhood convulsions, epilepsy, and mental retardation. Some ATPl A2 mutations have been shown to be associated with non-hemiplegic migraine phenotypes, such as basilar migraine and the common migraine.
  • Basilar migraine is a subtype of migraine with aura in which the aura symptoms originate from the brainstem or reflect the simultaneous involvement of both hemispheres.
  • Alternating hemiplegia of childhood is an autosomal dominant condition. Alternating hemiplegia of childhood can result from new mutations in the gene and occur in people with no history of the disorder in their family.
  • the primary feature of this condition is recurrent episodes of temporary paralysis, often affecting one side of the body (hemiplegia). During some episodes, the paralysis alternates from one side to the other or affects both sides of the body at the same time.
  • the known ATPl A2 gene mutation associated with this condition replaces a single amino acid in Na+/K+ ATPase: the amino acid threonine is replaced with the amino acid asparagine at protein position 378. This genetic change can impair the protein's ability to transport ions.
  • affected individuals can have sudden attacks of uncontrollable muscle activity; these can cause involuntary limb movements (choreoathetosis), muscle tensing
  • Alternating hemiplegia of childhood also causes mild to severe cognitive problems. Almost all affected individuals have some level of developmental delay and intellectual disability. Their cognitive functioning typically declines over time.
  • CACNA1A gene encodes the alpha-1 subunit of the calcium channel CaV2.1.
  • Voltage-dependent Ca(2+) channels not only mediate the entry of Ca(2+) ions into excitable cells but are also involved in a variety of Ca(2+)-dependent processes, including muscle contraction, hormone or neurotransmitter release, and gene expression.
  • Ca(2+)-dependent processes including muscle contraction, hormone or neurotransmitter release, and gene expression.
  • Diriong et al. (1995) noted that calcium channels are multisubunit complexes and that the channel activity is directed by a pore-forming alpha- 1 subunit, which is often sufficient to generate voltage-sensitive Ca(2+) channel activity. This subunit forms the pore through which calcium ions can flow.
  • CaV2.1 channels play an essential role in neuronal communication. These channels help control the release of neurotransmitters, and are involved in neuronal plasticity.
  • FHM familial hemiplegic migraine
  • EA2 episodic ataxia type 2
  • SCA6 spinocerebellar ataxia type 6
  • SCA6 spinocerebellar ataxia type 6
  • Episodic ataxia is a group of related conditions that affect the nervous system and cause problems with movement. People with episodic ataxia have recurrent episodes of poor coordination and balance (ataxia). During these episodes, many affected individuals also experience dizziness (vertigo), nausea and vomiting, migraine headaches, blurred or double vision, slurred speech, and ringing in the ears (tinnitus). Seizures, muscle weakness, and paralysis affecting one side of the body (hemiplegia) may also occur during attacks.
  • myokymia muscle abnormality
  • This abnormality can cause muscle cramping, stiffness, and continuous, fine muscle twitching that appears as rippling under the skin.
  • Episodes of ataxia and other symptoms can begin anytime from early childhood to adulthood. They can be triggered by environmental factors such as emotional stress, caffeine, alcohol, certain medications, physical activity, and illness. The frequency of attacks ranges from several per day to one or two per year. Between episodes, some affected individuals continue to experience ataxia, which may worsen over time, as well as involuntary eye movements called nystagmus.
  • type 1 through type 7 The types are distinguished by their pattern of signs and symptoms, age of onset, length of attacks, and, when known, genetic cause.
  • EA2 episodic ataxia type 2
  • ataxia the most common form of episodic ataxia.
  • EA2 is associated with involuntary eye movements called nystagmus.
  • the CACNAl A mutations responsible for EA2 reduce the production of functional CaV2.1 channels or prevent these channels from reaching the cell membrane, where they are needed to transport calcium ions.
  • a decrease in the number of these channels reduces the total flow of calcium ions into neurons, which disrupts the release of neurotransmitters in the brain.
  • FHM1 familial hemiplegic migraine type 1
  • FHM familial hemiplegic migraine type 1
  • FHM is characterized by an aura of hemiplegia that is always associated with at least one other aura symptom (e.g., hemianopsia, hemisensory deficit, aphasia). The aura is followed by a moderate to severe headache.
  • the aura includes temporary numbness or weakness on one side of the body (hemiparesis).
  • FHM1 is commonly associated with ataxia and nystagmus.
  • Most of the mutations that cause FFDVI1 change single amino acids in the CaV2.1 channel. The most common mutation, which has been found in more than a dozen affected families, replaces the amino acid threonine with the amino acid methionine at protein position 666.
  • CACNAl A mutations responsible for familial hemiplegic migraine change the structure of the CaV2.1 channel.
  • the altered channels open more easily than usual, which increases the inward flow of calcium ions.
  • a greater influx of calcium ions through CaV2.1 channels increases the cell's release of neurotransmitters.
  • the resulting changes in signaling between neurons lead to development of these severe headaches in people with familial hemiplegic migraine.
  • Spinocerebellar ataxia type 6 is a late-onset, autosomal dominant disorder.
  • SCA6 Spinocerebellar ataxia type 6
  • the major features of this condition include progressive ataxia, nystagmus, and impaired speech (dysarthria), most often beginning in a person's forties or fifties.
  • SCA6 results from an increased number of copies (expansion) of the CAG trinucleotide repeat in the CACNAl A gene. Most cases of SCA6 are a result of CAG repeat expansion beyond the normal range, i.e., more than 19 repeats. In people with this condition, the CAG segment is repeated from 20 to more than 30 times.
  • An increase in the length of the CAG segment leads to the production of an abnormally long version of the alpha- 1 subunit.
  • the abnormal subunit is found in the cell membrane as well as in the cytoplasm, where it clusters together and forms aggregates. The effect these aggregates have on cell functioning is unknown.
  • the lack of normal calcium channels impairs the cells' ability to transport calcium ions.
  • These changes alter the release of neurotransmitters in the brain and eventually lead to the death of neurons.
  • Certain neurons called Purkinje cells seem to be particularly sensitive to a disruption in calcium transport. Purkinje cells are located in the part of the brain that coordinates movement (cerebellum). Over time, the loss of Purkinje cells and other cells of the cerebellum causes the movement problems characteristic of SCA6.
  • the SETD5 gene encodes a 1,442-residue protein that is a putative methyltransferase. Mutations in this gene have been associated with autosomal dominant mental retardation-23.
  • MRD23 Autosomal dominant mental retardation-23
  • MRD23 is a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period.
  • MRD23 patients manifest moderate to severe intellectual disability with additional variable features of brachycephaly, a low hairline, depressed nasal bridge, prominent high nasal root, tubular nose, upslanting palpebral fissures, long and smooth philtrum, micrognathia, thin upper lip, and crowded teeth.
  • Behavioral problems including obsessive- compulsive disorder, hand flapping with ritualized behavior, and autism, are prominent features. The disease is caused by mutations affecting the gene represented in this entry.
  • Characteristic features of the distal 3p- syndrome include low birth weight, microcephaly, trigonocephaly, hypotonia, psychomotor and growth retardation, ptosis, telecanthus, downslanting palpebral fissures, and micrognathia.
  • Postaxial Polydactyly, renal anomalies, cleft palate, congenital heart defects (especially atrioventricular septal defects), preauricular pits, sacral dimple, and gastrointestinal anomalies are variable features.
  • SHANK3 encodes SH3 and multiple ankyrin repeat domains 3 (SHANK3), also known as proline-rich synapse-associated protein 2 (ProSAP2).
  • SHANK3 gene spans 60 kb and contains 22 exons.
  • PSAP2 is expressed preferentially in cerebral cortex and cerebellum.
  • This gene is a member of the Shank gene family.
  • Shank proteins are multidomain scaffold proteins of the postsynaptic density that connect neurotransmitter receptors, ion channels, and other membrane proteins to the actin cytoskeleton and G-protein-coupled signaling pathways. Shank proteins also play a role in synapse formation and dendritic spine maturation.
  • SHANK3 is one of the genes disrupted in patients with the 22ql3.3 deletion syndrome, also known as Phelan-McDermid syndrome.
  • Phelan-McDermid syndrome Phelan-McDermid syndrome
  • Phelan-McDermid syndrome can be caused by a heterozygous contiguous gene deletion at chromosome 22ql3 or by mutation in the SHANK3 gene.
  • Phelan-McDermid syndrome is a developmental disorder with variable features. Common features include neonatal hypotonia, global developmental delay, normal to accelerated growth, absent to severely delayed speech, autistic behavior, and minor dysmorphic features. Other less common features associated with this syndrome included increased tolerance to pain, dysplastic toenails, chewing behavior, fleshy hands, dysplastic ears, pointed chin, dolichocephaly, ptosis, tendency to overheat, and epicanthic folds.
  • Phelan-McDermid syndrome neurons have reduced SHANK3 expression and major defects in excitatory, but not inhibitory, synaptic transmission.
  • Excitatory synaptic transmission in Phelan-McDermid syndrome neurons could be corrected by restoring SHANK3 expression or by treating neurons with insulin-like growth factor-1.
  • IGF1 treatment promoted formation of mature excitatory synapses that lack SHANK3 but contained PSD95 and NMDA receptors with fast deactivation kinetics.
  • Schizophrenia- 15 is a complex, multifactorial psychotic disorder or group of disorders characterized by disturbances in the form and content of thought (e.g. delusions, hallucinations), in mood (e.g. inappropriate affect), in sense of self and relationship to the external world (e.g. loss of ego boundaries, withdrawal), and in behavior (e.g playful or apparently purposeless behavior). Although it affects emotions, it is distinguished from mood disorders in which such disturbances are primary. Similarly, there may be mild impairment of cognitive function, and it is distinguished from the dementias in which disturbed cognitive function is considered primary. Some patients manifest schizophrenic as well as bipolar disorder symptoms and are often given the diagnosis of schizoaffective disorder.
  • the NF2 gene encodes the protein merlin, also known as schwannomin.
  • Merlin is a membrane-cytoskeleton scaffolding protein, i.e. linking actin filaments to cell membrane or membrane glycoproteins.
  • Human merlin is predominantly found in nervous tissue, but also in several other fetal tissues, and is mainly located in adherens junctions.
  • NF2 belongs to the tumor suppressor group of genes.
  • the phosphorylation of serine 518 is known to alter the functional state of merlin.
  • the signaling pathway of merlin is proposed to include several salient cell growth controlling molecules, including eIF3c, CD44, protein kinase A, and p21 activated kinases.
  • Mutations of the NF2 gene cause a human autosomal dominant disease called neurofibromatosis type 2. It is characterized by the development of tumors of the nervous system, most commonly of bilateral vestibular schwannomas (also called acoustic neuromas).
  • Neurofibromatosis type 2
  • Neurofibromatosis type II is caused by mutation in the gene encoding neurofibromin-2, which is also called merlin, on chromosome 22ql2.2. Neurofibromatosis type II is an inheritable disorder with an autosomal dominant mode of transmission. Incidence of the disease is about 1 in 60,000. Through statistics, it is suspected that one-half of cases are inherited, and one-half are the result of new, de novo mutations.
  • NF2 neurofibromatosis type 2
  • NF2 mutations have been identified in people with neurofibromatosis type 2.
  • About 90 percent of NF2 mutations result in an abnormally shortened version of the merlin protein.
  • This short protein cannot perform its normal tumor suppressor function in cells.
  • the most common tumors in neurofibromatosis type 2 are vestibular schwannomas, which develop along the nerve that carries information from the inner ear to the brain. Other tumors affecting the nervous system also occur in people with this condition.
  • Somatic mutations in the NF2 gene are involved in the development of several types of tumors, both noncancerous (benign) and cancerous (malignant).
  • merlin's deficiency can result in unmediated progression through the cell cycle due to the lack of contact-mediated tumor suppression, sufficient to result in the tumors characteristic of Neurofibromatosis type II. Mutations of NF II is presumed to result in either a failure to synthesize merlin or the production of a defective peptide that lacks the normal tumor- suppressive effect. Meningioma, NF2-related
  • Meningioma is a relatively common neoplasm of the central nervous system that arises from arachnoidal cells. The majority are well differentiated vascular tumors which grow slowly and have a low potential to be invasive, although malignant subtypes occur. Meningiomas have a predilection to arise from the parasagittal region, cerebral convexity, sphenoidal ridge, olfactory groove, and spinal canal.
  • Meningiomas tend to present in the fourth to sixth decades of life with signs indicative of a slowly progressive mass lesion. Specific clinical manifestations depend on the location of the tumor, but may include intracranial hypertension, cranial neuropathies, ataxia, and other focal neurologic signs. Most meningiomas are benign; only a very small percentage of meningiomas become malignant. Many
  • meningiomas are asymptomatic, producing no symptoms throughout a person's life, and if discovered, require no treatment other than periodic observation. Typically, symptomatic meningiomas are treated with either radiosurgery or conventional surgery. Historical evidence of meningiomas has been found going back hundreds of years, with some successful surgeries for their removal beginning in the 1800s.
  • schwannoma tumors from patients with schwannomatosis have been found to harbor somatic mutations in the neurofibromin-2 gene (NF2).
  • NF2 neurofibromin-2 gene
  • schwannomas in the same individual suggest an underlying tumor predisposition syndrome.
  • the most common such syndrome is neurofibromatosis II.
  • the hallmark of F2 is the development of bilateral vestibular nerve schwannomas, but two-thirds or more of all NF2- affected individuals develop schwannomas in other locations, and dermal schwannomas (or neurilemmomas) may precede vestibular tumors in F2-affected children.
  • the D MT1 gene encodes the enzyme DNA (cytosine-5)-methyltransferase 1.
  • This enzyme is involved in DNA methylation. In particular, the enzyme helps add methyl groups to cytosines. DNA methylation is important in many cellular functions. These functions include gene silencing, regulating reactions involving proteins and lipids, and controlling the processing of neurotransmitters.
  • DNA (cytosine-5)-methyltransferase 1 is active in the adult nervous system. Although its specific function is not well understood, the enzyme may help regulate neuron maturation and differentiation, the ability of neurons to migrate where needed and connect with each other, and neuron survival. In vitro functional expression studies in E.
  • coli and HeLa cells showed that the mutations affected proper folding of DNMT1 and resulted in premature degradation, reduced methyltransferase activity, and impaired heterochromatin binding during the G2 cell cycle phase, leading to global hypomethylation and site-specific hypermethylation. These changes indicated epigenetic dysregulation.
  • HSN1E Hereditary sensory neuropathy type IE
  • Hereditary sensory neuropathy type IE (HSN1E) is caused by heterozygous mutation in the D MT1 gene on chromosome 19p 13.
  • Hereditary sensory neuropathy type IE is an autosomal dominant neurodegenerative disorder characterized by adult onset of progressive peripheral sensory loss associated with progressive hearing impairment and early-onset dementia. At least three D MT1 gene mutations have been identified in people with hereditary sensory and autonomic neuropathy (HSAN IE), a disorder characterized by a gradual dementia, deafness, and sensory problems in the feet.
  • HSAN IE is further characterized by impaired function of sensory neurons, which transmit information about sensations such as pain, temperature, and touch. Sensations in the feet and legs are particularly affected in people with HSAN IE. Gradual loss of sensation in the feet (peripheral neuropathy), which usually begins in adolescence or early adulthood, can lead to difficulty walking. Affected individuals may not be aware of injuries to their feet, which can lead to open sores and infections. If these
  • HSAN IE is also characterized by a loss of the ability to sweat (sudomotor function), especially on the hands and feet. Sweating is a function of the autonomic nervous system, which also controls involuntary body functions such as heart rate, digestion, and breathing. These other autonomic functions are unaffected in people with HSAN IE.
  • the severity of the signs and symptoms of HSAN IE and their age of onset are variable, even within the same family.
  • the mutations in exon 20 reduce or eliminate the DNA (cytosine-5)-methyltransferase 1 enzyme's methylation function. As a result, maintenance of the neurons that make up the nervous system is impaired. However, it is not known how the mutations cause the specific signs and symptoms of HSAN IE.
  • ADCADN Autosomal dominant cerebellar ataxia, deafness, and narcolepsy
  • ADCADN Autosomal dominant cerebellar ataxia, deafness, and narcolepsy
  • ADCADN is caused by heterozygous mutation in the DNMTl gene on chromosome 19p 13.
  • ADCADN is an autosomal dominant neurologic disorder characterized by adult onset of progressive cerebellar ataxia, narcolepsy/cataplexy, sensorineural deafness, and dementia. More variable features include optic atrophy, sensory neuropathy, psychosis, and depression.
  • DNMTl gene mutations have been identified in people with autosomal dominant cerebellar ataxia, deafness, and narcolepsy.
  • the mutations associated with this disorder are in exon 2 the D MT1 gene. Mutations in different locations within the gene may affect the DNA (cytosine-5)-methyltransferase 1 enzyme differently, which can lead to particular combinations of signs and symptoms.
  • TCF4 encodes transcription factor 4, a basic helix-loop-helix transcription factor.
  • the encoded protein recognizes an Ephrussi-box ('E-box') binding site ('CANNTG') - a motif first identified in immunoglobulin enhancers.
  • This gene is broadly expressed, and may play an important role in nervous system development.
  • the TCF4 protein is found in the brain, muscles, lungs, and heart. This protein also appears to be active in various tissues before birth.
  • the TCF4 protein plays a role cell differentiation and apoptosis.
  • Pitt-Hopkins syndrome is characterized by mental retardation, wide mouth and distinctive facial features, and intermittent hyperventilation followed by apnea.
  • Pitt-Hopkins syndrome is linked to haploinsufficiency of the TCF4 transcription factor gene.
  • At least 50 mutations in the TCF4 gene have been found to cause Pitt-Hopkins syndrome.
  • Some mutations delete a nucleotide within the TCF4 gene, while other mutations delete the TCF4 gene as well as a number of genes that surround it.
  • Still other TCF4 gene mutations replace single nucleotides. The size of the mutation does not appear to affect the severity of the condition; individuals with large deletions and those with single nucleotide changes seem to have similar signs and symptoms.
  • TCF4 gene mutations disrupt the protein's ability to bind to DNA and control the activity of certain genes. These gene mutations typically do not affect the TCF4 protein's ability to bind to other proteins.
  • the RAI1 gene encodes Retinoic acid-induced protein 1.
  • Retinoic acid-induced protein 1 is an important transcriptional regulator of the circadian clock components: CLOCK,
  • Retinoic acid-induced protein 1 positively regulates the transcriptional activity of CLOCK a core component of the circadian clock. Retinoic acid-induced protein 1 regulates transcription through chromatin remodeling by interacting with other proteins in chromatin as well as proteins in the basic transcriptional machinery. Retinoic acid-induced protein 1 may be important for embryonic and postnatal development. Retinoic acid-induced protein 1 may be involved in neuronal differentiation. Mutations in one copy of this gene lead to the production of a nonfunctional version of the RAI1 protein or reduce the amount of this protein that is produced.
  • Smith-Magenis syndrome is caused in most cases (90%) by a 3.7-Mb interstitial deletion in chromosome 17pl 1.2.
  • the disorder can also be caused by mutations in the RAI1 gene, which is within the Smith-Magenis chromosome region.
  • Smith-Magenis syndrome is a developmental disorder that affects many parts of the body. The major features of this condition include mild to moderate intellectual disability, delayed speech and language skills, distinctive facial features, sleep disturbances, and behavioral problems. Most people with Smith-Magenis syndrome have a broad, square-shaped face with deep-set eyes, full cheeks, and a prominent lower jaw. The middle of the face and the bridge of the nose often appear flattened.
  • Affected individuals may be very sleepy during the day, but they have trouble falling asleep and awaken several times each night.
  • Individuals with Smith-Magenis syndrome have affectionate, engaging personalities, but most also have behavioral problems. These include frequent temper tantrums and outbursts, aggression, anxiety, impulsiveness, and difficulty paying attention.
  • Self- injury including biting, hitting, head banging, and skin picking, is very common.
  • Repetitive self-hugging is a behavioral trait that may be unique to Smith-Magenis syndrome. Individuals with this condition also compulsively lick their fingers and flip pages of books and magazines (a behavior known as "lick and flip").
  • Smith-Magenis syndrome Other signs and symptoms of Smith-Magenis syndrome include short stature, abnormal curvature of the spine (scoliosis), reduced sensitivity to pain and temperature, and a hoarse voice. Some people with this disorder have ear abnormalities that lead to hearing loss. Affected individuals may have eye abnormalities that cause nearsightedness (myopia) and other vision problems. Although less common, heart and kidney defects also have been reported in people with Smith-Magenis syndrome. A small percentage of individuals with Smith-Magenis syndrome have a mutation in the RAIl gene instead of a chromosomal deletion. Although these individuals have many of the major features of the condition, they are less likely than people with a chromosomal deletion to have short stature, hearing loss, and heart or kidney abnormalities. PEX1
  • the PEX1 gene encodes peroxisomal biogenesis factor 1 (Pexlp), which is part of a group of proteins called peroxins.
  • Peroxins are essential for the formation and normal functioning of cell structures called peroxisomes. Peroxisomes are sac-like compartments that contain enzymes needed to break down many different substances, including fatty acids and certain toxic compounds. They are also important for the production of lipids used in digestion and in the nervous system. Peroxins assist in the biogenesis of peroxisomes by producing the membrane that separates the peroxisome from the rest of the cell and by importing enzymes into the peroxisome. Pexlp enables other peroxins to bring enzymes into the peroxisome.
  • Zellweger syndrome (PBD1A) is caused by homozygous or compound heterozygous mutation in the PEX1 gene on chromosome 7q21-q22.
  • Zellweger syndrome is an autosomal recessive systemic disorder characterized clinically by severe neurologic dysfunction, craniofacial abnormalities, and liver dysfunction, and biochemically by the absence of peroxisomes. Most severely affected individuals with classic Zellweger syndrome phenotype die within the first year of life.
  • At least 114 mutations in the PEX1 gene have been identified in people with Zellweger spectrum disorder.
  • the conditions' features, which vary in severity, can include weak muscle tone (hypotonia), developmental delay, and vision and hearing problems.
  • Mutations in the PEX1 gene are the most common cause of Zellweger spectrum disorder and are found in nearly 70 percent of affected individuals.
  • One mutation replaces the amino acid glycine with the amino acid aspartic acid at position 843 in Pexlp (written as Gly843 Asp or G843D). This mutation leads to reduced levels of the protein. Individuals who have the G843D mutation tend to have signs and symptoms that are at the less-severe end of the condition spectrum.
  • the other common mutation which is known as the 1700fs mutation, leads to the production of an abnormally short, nonfunctional Pexlp. Individuals who have the 1700fs mutation often have signs and symptoms that are at the severe end of the condition spectrum. Mutations in the PEX1 gene that cause Zellweger spectrum disorder reduce or eliminate the activity of the Pexlp protein.
  • HMLR1 Heimler syndrome-1
  • HMLR1 is caused by homozygous or compound heterozygous mutations in the PEX1 gene on chromosome 7q21.
  • HMLR1 represents the mildest end of the peroxisomal biogenesis disorder spectrum.
  • Heimler syndrome-1 is a rare autosomal recessive disorder characterized by sensorineural hearing loss, enamel hyoplasia of the secondary dentition, and nail abnormalities.
  • the ARSA encodes enzyme arylsulfatase A. This enzyme is localized in lysosomes. Arylsulfatase A aids the processing of sulfatides. For example, Arylsulfatase A hydrolyzes cerebroside sulfate to cerebroside and sulfate. Sulfatides are a subgroup of sphingolipids, a category of fats that are important components of cell membranes. Sulfatides are abundant in the nervous system's white matter, consisting of nerve fibers covered by myelin.
  • Metachromatic leukodystrophy is caused by mutation in the arylsulfatase A gene (ARSA) on chromosome 22ql3. Metachromatic leukodystrophy is an inherited disorder characterized by the accumulation of sulfatides in cells. This accumulation especially affects cells in the nervous system that produce myelin. Sulfatide accumulation in myelin-producing cells causes progressive destruction of white matter (leukodystrophy) throughout the nervous system, including in the central nervous system and the nerves connecting the brain and spinal cord to muscles and sensory cells that detect sensations such as touch, pain, heat, and sound (the peripheral nervous system).
  • Sulfatide accumulation in myelin-producing cells causes progressive destruction of white matter (leukodystrophy) throughout the nervous system, including in the central nervous system and the nerves connecting the brain and spinal cord to muscles and sensory cells that detect sensations such as touch, pain, heat, and sound (the peripheral nervous system).
  • metachromatic leukodystrophy typically do not survive past childhood. In 20 to 30 percent of individuals with metachromatic leukodystrophy, onset occurs between the age of 4 and adolescence. In this juvenile form, the first signs of the disorder may be behavioral problems and increasing difficulty with schoolwork. Progression of the disorder is slower than in the late infantile form, and affected individuals may survive for about 20 years after diagnosis.
  • the adult form of metachromatic leukodystrophy affects approximately 15 to 20 percent of individuals with the disorder. In this form, the first symptoms appear during the teenage years or later. Often behavioral problems such as alcoholism, drug abuse, or difficulties at school or work are the first symptoms to appear. The affected individual may experience psychiatric symptoms such as delusions or hallucinations. People with the adult form of metachromatic leukodystrophy may survive for 20 to 30 years after diagnosis. During this time there may be some periods of relative stability and other periods of more rapid decline.
  • EIF2B5 encodes a subunit of eukaryotic translation initiation factor 2B (eIF2B), a heteropentameric guanine nucleotide exchange factor necessary for the proper function of the translation initiation factor eIF2, and an essential regulator for protein synthesis.
  • eIF2B catalyzes the exchange of GDP for GTP.
  • eIF2B increases protein synthesis under other conditions, eLF2B slows protein synthesis.
  • Proper regulation of protein synthesis is vital for ensuring that the correct levels of protein are available for the cell to cope with changing conditions. Mutations in eIF2B can cause partial loss of eIF2B function. Impairment of eIF2B function makes it more difficult for cells to regulate protein synthesis and deal with changing conditions and stress.
  • VWM vanishing white matter
  • VWM vanishing white matter
  • EIF2B translation initiation factor
  • EIF2B1 on chromosome 12q24
  • EIF2B2 on chromosome 14q24
  • EIF2B3 on chromosome lp34
  • EIF2B4 on chromosome 2p23
  • EIF2B5 on the translation initiation factor
  • Vanishing white matter leukodystrophy is an autosomal recessive neurologic disorder characterized by variable neurologic features, including progressive cerebellar ataxia, spasticity, and cognitive impairment associated with white matter lesions on brain imaging.
  • the age at onset can range from early infancy to adulthood. Rapid neurologic deterioration can occur following minor head trauma.
  • Female mutation carriers may develop ovarian failure, manifest as primary amenorrhea or as secondary amenorrhea lasting more than 6 months, associated with elevated gonadotropin levels at age less than 40 years.
  • Neurologic deterioration usually begins in late infancy or early childhood, but juvenile- and adult-onset cases have been described. Mild and severe cases have been observed, even within families.
  • the neurologic signs include progressive cerebellar ataxia, spasticity, inconstant optic atrophy, and relatively preserved mental abilities.
  • Disease is chronic-progressive with, in most individuals, additional episodes of rapid deterioration following febrile infections or minor head trauma. Head trauma leads only to motor deterioration, whereas infections with fever may end in coma. Death occurs after a variable period of several years to a few decades, usually following an episode of fever and coma.
  • MRI is diagnostic and shows a diffuse abnormality of the cerebral white matter beginning in the presymptomatic stage. Both MRI and magnetic resonance spectroscopy indicate that, with time, an increasing amount of the abnormal white matter vanishes and is replaced by cerebrospinal fluid.
  • the mode of inheritance is autosomal recessive.
  • NPCl encodes Niemann-Pick disease, type CI (NPCl), a large protein that resides in the limiting membrane of endosomes and lysosomes and mediates intracellular cholesterol trafficking via binding of cholesterol to its N-terminal domain. It is predicted to have a cytoplasmic C-terminus, 13 transmembrane domains, and 3 large loops in the lumen of the endosome - the last loop being at the N-terminus. This protein transports low-density
  • lipoproteins to late endosomal/lysosomal compartments where they are hydrolized and released as free cholesterol.
  • NPCl Mutations in NPCl leads to a shortage of NPCl, which prevents movement of cholesterol and other lipids, leading to their accumulation in cells. Because these lipids are not in their proper location in cells, many normal cell functions that require lipids (such as cell membrane formation) are impaired. The accumulation of lipids as well as the cell dysfunction eventually leads to cell death, causing the tissue and organ damage seen in Niemann-Pick disease types CI .
  • Niemann-Pick disease type CI and Niemann-Pick disease type D are caused by mutation in the NPCl gene.
  • Niemann-Pick type C (NPC) disease is an autosomal recessive lipid storage disorder characterized by progressive
  • type CI Approximately 95% of cases are caused by mutations in the NPCl gene, referred to as type CI; 5% are caused by mutations in the NPC2 gene , referred to as type C2.
  • the clinical manifestations of types CI and C2 are similar because the respective genes are both involved in egress of lipids, particularly cholesterol, from late endosomes or lysosomes.
  • Niemann-Pick disease types CI and C2 usually become apparent in childhood, although signs and symptoms can develop at any time. People with these types usually develop difficulty coordinating movements (ataxia), an inability to move the eyes vertically (vertical supranuclear gaze palsy), poor muscle tone (dystonia), severe liver disease, and interstitial lung disease.
  • ADAR ( adenosine deaminase acting on RNA) encodes Double-stranded RNA-specific adenosine deaminase. ADAR catalyzes the deamination of adenosine to inosine in dsRNA substrates, induces translation within the nucleus, possibly at the surface of the nucleolus.
  • ADAR catalyzes the hydrolytic deamination of adenosine to inosine in double-stranded RNA (dsRNA) referred to as A-to-I RNA editing.
  • dsRNA double-stranded RNA
  • This may affect gene expression and function in a number of ways that include mRNA translation by changing codons and hence the amino acid sequence of proteins; pre-mRNA splicing by altering splice site recognition sequences; RNA stability by changing sequences involved in nuclease recognition; genetic stability in the case of RNA virus genomes by changing sequences during viral RNA replication; and RNA structure- dependent activities such as microRNA production or targeting or protein-RNA interactions.
  • ADAR can edit both viral and cellular RNAs and can edit RNAs at multiple sites (hyper-editing) or at specific sites (site-specific editing).
  • ADAR cellular RNA substrates include: bladder cancer-associated protein (BLCAP), neurotransmitter receptors for glutamate (GRIA2) and serotonin (HTR2C) and GABA receptor (GABRA3).
  • BLCAP bladder cancer-associated protein
  • GRIA2 neurotransmitter receptors for glutamate
  • HTR2C serotonin
  • GABA receptor GABA receptor
  • Site-specific RNA editing of transcripts encoding these proteins results in amino acid substitutions which consequently alters their functional activities. Exhibits low-level editing at the GRIA2 Q/R site, but edits efficiently at the R/G site and HOTSPOT1.
  • Its viral RNA substrates include: hepatitis C virus (HCV), vesicular stomatitis virus (VSV), measles virus (MV), hepatitis delta virus (
  • ADAR immunodeficiency virus type 1
  • ADAR exhibits either a proviral (HDV, MV, VSV and HIV-1) or an antiviral effect (HCV) and this can be editing-dependent (HDV and HCV), editing- independent (VSV and MV) or both (HIV-1).
  • ADAR impairs HCV replication via RNA editing at multiple sites.
  • ADAR enhances the replication of MV, VSV and HIV-1 through an editing- independent mechanism via suppression of EIF2AK2/PKR activation and function.
  • ADAR stimulates both the release and infectivity of HIV-1 viral particles by an editing-dependent mechanism where it associates with viral RNAs and edits adenosines in the 5'UTR and the Rev and Tat coding sequence.
  • ADAR can enhance viral replication of HDV via A-to-I editing at a site designated as amber/W, thereby changing an UAG amber stop codon to an UIG tryptophan (W) codon that permits synthesis of the large delta antigen (L-HDAg) which has a key role in the assembly of viral particles.
  • high levels of ADAR1 inhibit HDV replication.
  • Aicardi-Goutieres syndrome-6 (AGS 6)
  • Aicardi-Goutieres syndrome-6 can be caused by homozygous, compound heterozygous, or heterozygous mutation in the ADAR gene on chromosome lq21.3.
  • Aicardi- Goutieres syndrome (AGS) manifests as an early-onset encephalopathy that usually, but not always, results in severe intellectual and physical handicap.
  • a subgroup of infants with AGS present at birth with abnormal neurologic findings, hepatosplenomegaly, elevated liver enzymes, and thrombocytopenia, a picture highly suggestive of congenital infection. Otherwise, most affected infants present at variable times after the first few weeks of life, frequently after a period of apparently normal development.
  • MFSD8 gene encodes a putative lysosomal transporter, on chromosome 4q28.
  • the MFSD8 protein is found in lysosomes.
  • the MFSD8 protein belongs to a large group of related proteins called the major facilitator superfamily of secondary active transporter proteins.
  • Proteins in this family move certain molecules between structures in cells or in and out of cells. While it is likely that the MFSD8 protein transports molecules, the specific molecules it moves are unknown. The MFSD8 protein probably transports substances across the membranes of lysosomes.
  • Neuronal ceroid lipofuscinosis-7 (CLN7) is caused by homozygous or compound heterozygous mutation in the MFSD8 gene, which encodes a putative lysosomal transporter, on chromosome 4q28.
  • the neuronal ceroid-lipofuscinoses (NCLs) are a group of inherited, neurodegenerative, lysosomal storage disorders characterized by progressive intellectual and motor deterioration, seizures, and early death. Visual gvhmloss is a feature of most forms.
  • STXBPl gene encodes a syntaxin-binding protein.
  • the encoded protein can play a role in release of neurotransmitters via regulation of syntaxin, a transmembrane attachment protein receptor. Mutations in STXBPl gene is associated with infantile epileptic encephalopathy -4.
  • STXBPl can participate in the regulation of synaptic vesicle docking and fusion, through interaction with GTP -binding proteins.
  • STXBPl can interact with syntaxins 1, 2, and 3 but not syntaxin 4.
  • STXBPl can play a role in determining the specificity of intracellular fusion reactions.
  • STXBPl is expressed as a 4-kb transcript in various tissues. The highest levels of expression can be observed in the retina and cerebellum.
  • Epileptic encephalopathy, early infantile, 4 (EIEE4) is a severe form of epilepsy characterized by frequent tonic seizures or spasms beginning in infancy with a specific EEG finding of suppression-burst patterns, characterized by high-voltage bursts alternating with almost flat suppression phases. Affected individuals can have neonatal or infantile onset of seizures, profound mental retardation, and MRI evidence of brain hypomyelination.
  • encephalopathy-4 can develop seizures by age 10 days with a suppression-burst pattern on EEG. In some cases, a patient with early infantile epileptic encephalopathy-4 can have profound mental retardation and spastic paraplegia at about age 37 years.
  • encephalopathy-4 can have infantile onset of tonic and myoclonic seizures with suppression- burst pattern and hypsarrhythmia, delayed brain myelination, and spastic quadriplegia.
  • mutations in the STXBPl gene can impair structural stability, lower
  • thermostability and decrease binding to several functional synaptic proteins.
  • encephalopathy-4 can develop tonic seizures at age 6 weeks and can later have profoundly delayed development. In some cases, a patient with early infantile epileptic encephalopathy-4 can have delayed brain myelination. [0126] In some cases, in a patient with early infantile epileptic encephalopathy-4, a heterozygous 251T-A transversion in the STXBP1 gene, resulting in a val84-to-asp (V84D) substitution can be identified. In some cases, a patient with early infantile epileptic
  • encephalopathy-4 can develop tonic seizures at age 2 months with suppression-burst pattern and hypsarrhythmia, and can later show profound mental retardation.
  • a de novo heterozygous 1162C-T transition in exon 14 of the STXBP1 gene, resulting in an arg388-to-ter (R388X) substitution, predicted to truncate the domain-3 region, which together with domain-1 provides a binding surface for syntaxin-1 can be identified.
  • a patient with early infantile epileptic encephalopathy-4 can have severe mental retardation, with hypotonia, abnormal gait, tremor, and/or seizures.
  • a de novo heterozygous G-to-A transition in intron 3 of the STXBP1 gene, resulting in the creation of a stop codon downstream of exon 3 can be identified.
  • a patient with early infantile epileptic encephalopathy-4 can have severe mental retardation, with hypotonia, abnormal gait, tremor, and/or seizures.
  • the PRICKLE2 gene encodes a postsynaptic protein involved in neuronal architecture and function, prickle planar cell polarity protein 2. Mutations in this gene are associated with progressive myoclonic epilepsy type 5.
  • Epilepsy progressive myoclonic 5 (EPM5) is a neurodegenerative disorder characterized by myoclonic seizures and variable neurologic symptoms including cognitive decline and persistent movement abnormalities.
  • a heterozygosity for a complex mutation in the PRICKLE2 gene, a 443G- A transition, resulting in an argl48-to-his (R148H) substitution, and a 457G-A transition, resulting in a vall53-to-ile (VI 531) substitution can be identified in a progressive myoclonic epilepsy patient.
  • a heterozygous 1813G-T transversion in the PRICKLE2 gene, resulting in a val605-to-phe (V605F) substitution can be identified in a progressive myoclonic epilepsy patient.
  • the PRRT2 gene provides instructions for making the proline-rich transmembrane protein 2 (PRRT2).
  • PRRT2 protein The function of this protein is thought to be involved in signaling in the brain.
  • ICCA Infantile Convulsions and paroxysmal Choreo Athetosis (ICCA) syndrome is a neurological condition characterized by the occurrence of seizures during the first year of life (Benign familial infantile epilepsy) and choreoathetotic dyskinetic attacks during childhood or adolescence. Benign familial infantile epilepsy can begin at 3 to 12 months of age with a family history of the same type of seizures. Seizures are afebrile, partial or sometimes generalized, and normally disappear after the first year of life. During childhood or adolescence, affected individuals present with paroxysmal kinesigenic dyskinesia with frequent and recurrent episodic choreathetotic or dystonic movements that last less than 1 minute.
  • the attacks can be triggered by the initiation of voluntary movements or startle.
  • the association with other paroxysmal disorders such as migraine, with or without aura, hemiplegic migraine, episodic ataxia and tics has also been described.
  • the genetic loci of ICCA syndrome have been described on chromosomes 16pl 1.2-ql2.1, 16ql3-q22.1 and 3 q29-29.
  • Mutations in the Proline-rich transmembrane protein 2 (PRRT2) gene, located on 16pl 1.2, have recently been found in families affected by ICCA syndrome. This gene encodes a membrane protein that interacts with the presynaptic protein SNAP -25 but the mechanism leading to the disease remains unknown.
  • PRRT2 Proline-rich transmembrane protein 2
  • the diagnosis is mainly clinical, based on the appearance of infantile convulsions with benign evolution followed by kinesigenic dyskinesia attacks later on. Genetic testing can confirm the diagnosis.
  • Differential diagnosis can include other paroxysmal dystonias such as paroxysmal exertion-induced dyskinesia and paroxysmal non-kinesigenic dyskinesia triggered by drugs or food intake (such as caffeine and alcohol).
  • ICCA syndrome can present as sporadic or familial; in the latter case, it is transmitted as an autosomal dominant trait that can be variably expressed within the same family.
  • Antiepileptic drugs mainly phenytoin or carbamazepine, can be effective in controlling seizures and dyskinesia during the active phase of the disorder.
  • Epidsodic kinesigenic dyskinesia 1 can be referred to as familial paroxysmal kinesiginc dyskinesia.
  • Familial paroxysmal kinesigenic dyskinesia is a disorder characterized by episodes of abnormal movement that range from mild to severe. In the condition name, paroxysmal indicates that the abnormal movements come and go over time, kinesigenic indicates that episodes are triggered by movement, and dyskinesia refers to involuntary movement of the body.
  • the disorder begins in infancy with recurring seizures called benign infantile convulsions. These seizures usually develop in the first year of life and stop by age 3.
  • benign infantile convulsions are associated with familial paroxysmal kinesigenic dyskinesia, the condition is known as infantile convulsions and choreoathetosis (ICCA).
  • ICCA choreoathetosis
  • a heterozygous 487C-T transition in exon 2 of the PRRT2 gene can be identified.
  • a heterozygous 796C-T transition in exon 2 of the PRRT2 gene, resulting in an arg266-to-trp (R266W) substitution in a highly conserved residue can be identified.
  • a heterozygous 1-bp deletion (649delC) in the PRRT2 gene resulting in a frameshift and premature termination (Arg217GlufsTerl2) can be identified.
  • a heterozygous 748C-T transition in the PRRT2 gene resulting in a gln250-to-ter (Q250X) substitution in the N- terminal extracellular domain can be identified.
  • Benign familial infantile epilepsy is a genetic epileptic syndrome characterized by the occurrence of afebrile repeated seizures in healthy infants, between the third and eighth month of life. Although BFIE cases have been reported worldwide, prevalence and incidence remain unknown. In an Argentinian case series, BFIE have been listed as the third most common type of epilepsy in the first two years of life. Seizures usually occur between 3 to 8 months of life, with clusters (8-10 a day) of repeated and brief episodes (2-5 minutes) over a few days. They are usually focal but can sometimes become generalized.
  • BFIE has been associated with familial or sporadic hemiplegic migraine.
  • PRRT2 proline-rich transmembrane protein 2
  • EEG electroencephalography
  • video recordings can show that partial seizures originate from the parietal- occipital region and that the side of the hemisphere involved can vary between episodes.
  • Seizures can sometimes spread and involve the entire brain.
  • postictal EEG shows lateralized occipito-parietal delta waves and spikes.
  • waking and sleeping interictal EEG is normal.
  • Interictal neurological examination and brain imaging are normal. Genetic testing can confirm the diagnosis.
  • Differential diagnosis can include benign familial neonatal-infantile seizures, an epileptic syndrome with an intermediate onset between the neonatal and infantile age that shares overlapping clinical characteristics with BFIE and that is mainly due to mutations in the SCN2A gene.
  • Other differential diagnoses are benign non-familial infantile seizures, benign infantile seizures associated with mild gastroenteritis and benign infantile focal epilepsy with midline spikes and waves during sleep (BEVISE)
  • BFIE is transmitted as an autosomal dominant trait with incomplete penetrance.
  • anti-epileptic treatment e.g. carbamazepine, valproate, phenobarbital
  • symptoms quickly disappear and no other type of epilepsy has been reported to reappear.
  • a heterozygous 1-bp deletion (629delC) in the PRRT2 gene, resulting in a frameshift and premature termination (Pro210GlnfsTerl9) can be identified.
  • a heterozygous 1-bp deletion (291delC) in the PRRT2 gene, resulting in a frameshift and premature termination (Asn98ThrfsTerl7) can be identified.
  • a heterozygous 1-bp deletion (c.650delG) in the PRRT2 gene, resulting in a frameshift and premature termination (Arg217GlnfsTerl2) can be identified.
  • the protein encoded by this gene belongs to a family of proteins thought to play a role in the exocytosis of synaptic vesicles. Vesicle exocytosis releases vesicular contents and is important to various cellular functions. For instance, the secretion of transmitters from neurons plays an important role in synaptic transmission. After exocytosis, the membrane and proteins from the vesicle are retrieved from the plasma membrane through the process of endocytosis. Mutations in this gene have been identified as one cause of fever-associated epilepsy syndromes. A possible link between this gene and Parkinson's disease has also been suggested.
  • Syntaxins are cellular receptors for transport vesicles.
  • One of these proteins designated syntaxin IB (STX1B)
  • STX1B syntaxin IB
  • STX1B syntaxin IB
  • STX1B syntaxin IB
  • the expression of this protein is transiently induced by long-term potentiation of synaptic responses in the rat hippocampus.
  • the protein may play an important role in the excitatory pathway of synaptic transmission, which is known to be implicated in several neurologic diseases.
  • Generalized epilepsy with febrile seizures plus-9 is an autosomal dominant neurologic disorder characterized by onset of febrile and/or afebrile seizures in early childhood, usually before age 3 years. Seizure types are variable and include generalized tonic-clonic, atonic, myoclonic, complex partial, and absence. Most patients have remission of seizures later in childhood with no residual neurologic deficits, but rare patients may show mild developmental delay or mild intellectual disabilities.
  • the IDUA gene provides instructions for producing the enzyme alpha-L-iduronidase, which is essential for the breakdown of large sugar molecules, for example glycosaminoglycans (GAGs).
  • alpha-L-iduronidase uses water molecules to break down unsulfated alpha-L-iduronic acid, which is present in heparan sulfate and dermatan sulfate.
  • Alpha-L-iduronidase can be located in lysosomes. More than 100 mutations in the IDUA gene have been found to cause mucopolysaccharidosis type I (MPS I). Many mutations that cause MPS I reduce or completely eliminate the function of alpha-L-iduronidase. It usually cannot be determined whether a certain mutation will cause severe or attenuated MPS I; however, people who do not produce alpha-L-iduronidase have the severe form of this disorder.
  • MPS I mucopolysaccharidosis type I
  • Hurler-Scheie syndrome is the intermediate form of mucopolysaccharidosis type 1 (MPSl) between the two extremes Hurler syndrome and Scheie syndrome, it is a rare lysosomal storage disease, characterized by skeletal deformities and a delay in motor development.
  • MPS I mucopolysaccharidosis type 1
  • the prevalence of MPS I has been estimated at 1/100,000, with Hurler-Scheie syndrome accounting for 23% of cases or a prevalence of approximately 1/435,000.
  • Patients with Hurler-Scheie syndrome have normal or almost normal intelligence but exhibit various degrees of physical impairment.
  • Hydrocephaly can occur after the age of two. Corneal opacity is seen between two and four years of age and requires keratoplasty to restore sight. Other manifestations may include organomegaly, hernias and hirsutism.
  • Hurler-Scheie syndrome is caused by mutations in the IDUA gene (4pl6.3) leading to partial deficiency in the alpha-L-iduronidase enzyme and lysosomal accumulation of dermatan sulfate and heparan sulfate. Early diagnosis is difficult because the first clinical signs are not specific. Diagnosis can be based on detection of increased urinary secretion of heparan and dermatan sulfate through 1,9-dimethylmethylene blue (DMB) test and glycosaminoglycan (GAG) electrophoresis, and demonstration of enzymatic deficiency in leukocytes or fibroblasts. Genetic testing is available.
  • DMB 1,9-dimethylmethylene blue
  • GAG glycosaminoglycan
  • Differential diagnoses can include the milder and more severe forms of mucopolysaccharidosis type 1 (Scheie syndrome and Hurler syndrome respectively), mucopolysaccharidosis typeVI and mucopolysaccharidosis type II.
  • Antenatal diagnosis is possible by measurement of enzymatic activity in cultivated chorionic villus or amniocytes and by genetic testing if the disease-causing mutation is known. Transmission is autosomal recessive. Bone marrow or umbilical cord blood transplant has been successful and can preserve neurocognition, improve some aspects of the somatic disease and increase survival. However, it is associated with many risks and most of the positive effects occur only if the procedure is performed in the first two years of life.
  • the enzyme substitute obtained EU marketing authorization as an orphan drug in 2003. Given through weekly infusions it leads to improvement of lung function and joint mobility.
  • Enzyme replacement therapy (ERT) can be started at diagnosis and may be beneficial in patients awaiting hematopoietic stem cell transplantation (HSCT). Early treatment can slow the progression of the disease. In individual patients with MPS1 of intermediate severity, HSCT may be considered if there is a suitable donor. There are however no data on the efficacy of HSCT in patients with this form of the disease.
  • homozygosity for an arg619-to- gly (R619G) mutation due to a C-to-G transversion at nucleotide 1943 can be identified.
  • homozygosity for a thr364-to-met (T364M) mutation in the IDUA gene can be identified.
  • RIC Pre-mRNA Retained Intron Containing Pre-mRNA
  • the methods of the present invention can exploit the presence of retained-intron-containing pre-mRNA (RIC pre-mRNA) transcribed from the ATP1 A2,
  • CACNAl A SETD5, SHANK3, NF2, DNMTl, TCF4, RAI1, PEXl, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, MFSD8, STXBPl, PRICKLE2, PRRT2, IDUA, or STX1B gene and encoding ATP1A2, CACNAl A, SETD5, SHANK3, NF2, DNMTl, TCF4, RAI1, PEXl, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, MFSD8, STXBPl, PRICKLE2, PRRT2, IDUA, or STX1B protein, in the cell nucleus.
  • the resulting mature ATP1A2, CACNAl A, SETD5, SHANK3, NF2, DNMTl, TCF4, RAI1, PEXl, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, MFSD8, STXBPl, PRICKLE2, PRRT2, IDUA, or STX1B mRNA can be exported to the cytoplasm and translated, thereby increasing the amount of ATP1A2, CACNAl A, SETD5, SHANK3, NF2, DNMTl, TCF4, RAI1, PEXl, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, MFSD8, STXBPl, PRICKLE2, PRRT2, IDUA, or STX1B protein in the patient's cells and alleviating symptoms of the CNS disease or conditions caused by deficiency in ATP1 A2, CACNAIA, SETD5, SHANK3, NF2, DNMTl, TCF4, RAIl, PEXl
  • the methods of the present invention can exploit the presence of retained- intron-containing pre-mRNA (RIC pre-mRNA) transcribed from the ATP1A2, CACNAIA, SETD5, SHANK3, NF2, DNMTl, TCF4, RAIl, PEXl, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, STXBP1, PRICKLE2, PRRT2, or STX1B gene and encoding ATP1A2, CACNAIA, SETD5, SHANK3, NF2, DNMTl, TCF4, RAIl, PEXl, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, STXBP1, PRICKLE2, PRRT2, or STX1B protein, in the cell nucleus.
  • RIC pre-mRNA retained- intron-containing pre-mRNA
  • the resulting mature ATP1 A2, CACNAIA, SETD5, SHANK3, NF2, DNMTl, TCF4, RAIl, PEXl, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, STXBP1, PRICKLE2, PRRT2, or STX1B mRNA can be exported to the cytoplasm and translated, thereby increasing the amount of ATP1 A2, CACNAIA, SETD5, SHANK3, NF2, DNMTl, TCF4, RAIl, PEXl, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, STXBP1, PRICKLE2, PRRT2, or STX1B protein in the patient's cells and alleviating symptoms of the CNS disease or conditions caused by deficiency in ATP1A2, CACNAIA, SETD5, SHANK3, NF2, DNMTl, TCF4, RAIl, PEXl, ARSA, EIF2B5, EIF2B1, EIF
  • the methods of the present invention can exploit the presence of retained-intron-containing pre-mRNA (RIC pre-mRNA) transcribed from the ATP1 A2, CACNAIA, SETD5, SHANK3, NF2, DNMTl, TCF4, RAIl, PEXl, ARSA, EIF2B5, EIF2B2, NPCl, ADAR, STXBP1, PRICKLE2, PRRT2, or STX1B gene and encoding ATP1A2, CACNAIA, SETD5, SHANK3, NF2, DNMTl, TCF4, RAIl, PEXl, ARSA, EIF2B5, EIF2B2, NPCl, ADAR, STXBP1, PRICKLE2, PRRT2, or STX1B protein, in the cell nucleus.
  • RIC pre-mRNA retained-intron-containing pre-mRNA
  • D MT1, TCF4, RAI1, PEX1, ARSA, EIF2B5, EIF2B2, PC1, ADAR, STXBP1, PRICKLE2, PRRT2, or STXIB mRNA can be exported to the cytoplasm and translated, thereby increasing the amount of ATP1A2, CACNA1A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEX1, ARSA, EIF2B5, EIF2B2, NPC1, ADAR, STXBP1, PRICKLE2, PRRT2, or STXIB protein in the patient's cells and alleviating symptoms of the CNS disease or conditions caused by deficiency in ATP1A2, CACNA1A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEX1, ARSA, EIF2B5, EIF2B2, NPC1, ADAR, STXBP1, PRICKLE2, PRRT2, or STXIB.
  • This method is known as Targeted Augmentation of Nuclear Gene Output (TANGO)
  • ATP1A2, CACNA1A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEX1, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, MFSD8, STXBP1, PRICKLE2, PRRT2, IDUA, or STXIB gene can be analyzed for intron-retention events.
  • ATP1 A2, CACNA1 A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEX1, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, STXBP1, PRICKLE2, PRRT2, or STXIB gene can be analyzed for intron- retention events.
  • ATP1A2, CACNA1A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEX1, ARSA, EIF2B5, EIF2B2, NPCl, ADAR, STXBP1, PRICKLE2, PRRT2, or STXIB gene can be analyzed for intron-retention events.
  • RNA sequencing can be visualized in the UCSC genome browser, and can show ATP1 A2, CACNA1 A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEX1, ARSA, MFSD8, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, STXBP1, PRICKLE2, PRRT2, or STXIB transcripts expressed in human cortical neurons (HCN) or (AST) and localized in either the cytoplasmic or nuclear fraction.
  • HCN cortical neurons
  • AST AST
  • a retained intron is an intron that is identified as a retained intron based on a determination of at least about 5%, at least about 10%, at least about 15%, at least about 20%), at least about 25%, at least about 30%>, at least about 35%, at least about 40%, at least about 45%), or at least about 50%, retention.
  • a retained intron is an intron that is identified as a retained intron based on a determination of about 5% to about 100%, about 5% to about 95%), about 5% to about 90%, about 5% to about 85%, about 5% to about 80%, about 5% to about 75%, about 5% to about 70%, about 5% to about 65%, about 5% to about 60%, about 5% to about 65%, about 5% to about 60%, about 5% to about 55%, about 5% to about 50%, about 5% to about 45%, about 5% to about 40%, about 5% to about 35%, about 5% to about 30%, about 5% to about 25%, about 5% to about 20%, about 5% to about 15%, about 10% to about 100%, about 10% to about 95%, about 10% to about 90%, about 10% to about 85%, about 10% to about 80%, about 10% to about 75%, about 10% to about 70%, about 10% to about 65%, about 10% to about 60%, about 10% to about 65%, about 10% to about 60%, about 10% to about 5
  • Table 1 provides a non-limiting list of target sequences of RIC pre-mRNA transcript of
  • other ASOs useful for these purposes are identified, using, e.g., methods described herein. Table 1. List of targets and ASOs that targeting a gene disclosed herein
  • EIF2B1 NM_001414 SEQ ID NOs: 7754- SEQID 6 24353
  • EIF2B2 NM_014239 SEQ ID NOs: 7965- SEQID 1 24358
  • PRRT2 PRRT2 NM_001256443 SEQ ID NOs: 8054-
  • PRRT2 NM_001256442 SEQ ID NOs: 9022-
  • SEQ ID NO: 40 SEQ ID NOs: 9380- NO: 11 7 24375
  • TCF4 NM_001243236 SEQ ID NOs: 24387-
  • TCF4 NM_001243235 SEQ ID NOs: 24644-
  • TCF4 NM_001243234 SEQ ID NOs: 24901-
  • TCF4 NM_001243233 SEQ ID NOs: 25160-
  • TCF4 NM_001243232 SEQ ID NOs: 25417-
  • TCF4 NM_001243231 SEQ ID NOs: 25676-
  • TCF4 NM_001306207 SEQ ID NOs: 26190-
  • TCF4 NM_001306208 SEQ ID NOs: 26447-
  • TCF4 NM_001243227 SEQ ID NOs: 26704-
  • TCF4 NM_001243228 SEQ ID NOs: 26963-
  • TCF4 NM_001243230 SEQ ID NOs: 27222-
  • TCF4 NM_001083962 SEQ ID NOs: 27738-
  • TCF4 NM_001330605 SEQ ID NOs: 27997-
  • TCF4 NM_001330604 SEQ ID NOs: 28256-
  • DNMT1 SEQ ID NOs: 15915-
  • the ASOs disclosed herein target a RIC pre-mRNA transcribed from a ADAR genomic sequence. In some embodiments, the ASO targets a RIC pre-mRNA transcript from a ADAR genomic sequence comprising a retained intron. In some embodiments, the ASO targets a RIC pre-mRNA transcript of SEQ ID NO: 1. In some embodiments, the ASO targets a RIC pre-mRNA transcript of SEQ ID NO: 1 comprising a retained intron. In some embodiments, the ASOs disclosed herein target a ADAR RIC pre-mRNA sequence.
  • the ASO targets a ADAR RIC pre-mRNA transcriptcomprising a retained intron at 2, wherein the intron numbering correspond to the mRNA sequence at NM_001193495. In some embodiments, the ASO targets a ADAR RIC pre-mRNA transcriptcomprising a retained intron at 2, wherein the intron numbering correspond to the mRNA sequence at NM_015841. In some embodiments, the ASO targets a ADAR RIC pre-mRNA transcriptcomprising a retained intron at 2, wherein the intron numbering correspond to the mRNA sequence at NM_015840.
  • the ASO targets a ADAR RIC pre-mRNA transcriptcomprising a retained intron at 2, wherein the intron numbering correspond to the mRNA sequence at NM 001111. In some embodiments, the ASO targets a ADAR RIC pre-mRNA transcriptcomprising a retained intron at 2, wherein the intron numbering correspond to the mRNA sequence at NM_001025107.
  • the ASO targets a ADAR RIC pre-mRNA sequence according to SEQ ID NO: 20. In some embodiments, the ASO targets a ADAR RIC pre-mRNA sequence according to SEQ ID NO: 20 comprising a retained intron 2. In some embodiments, the ASO targets a ADAR RIC pre-mRNA sequence according to SEQ ID NO: 21. In some embodiments, the ASO targets a ADAR RIC pre-mRNA sequence according to SEQ ID NO: 21 comprising a retained intron 2. In some embodiments, the ASO targets a ADAR RIC pre-mRNA sequence according to SEQ ID NO: 22.
  • the ASO targets a ADAR RIC pre-mRNA sequence according to SEQ ID NO: 22 comprising a retained intron 2. In some embodiments, the ASO targets a ADAR RIC pre-mRNA sequence according to SEQ ID NO: 23. In some embodiments, the ASO targets a ADAR RIC pre-mRNA sequence according to SEQ ID NO: 23 comprising a retained intron 2. In some embodiments, the ASO targets a ADAR RIC pre-mRNA sequence according to SEQ ID NO: 24. In some embodiments, the ASO targets a ADAR RIC pre-mRNA sequence according to SEQ ID NO: 24 comprising a retained intron 2. In some embodiments, the ASOs disclosed herein target SEQ ID NO: 24383. In some embodiments, the ASO has a sequence according to any one of SEQ ID NOs: 81-2675.
  • the ASO targets exon 2 or ex on 3 of aADAR RIC pre-mRNA comprising a retained intron 2, wherein the intron numbering correspond to the mRNA sequence at NM 001193495.
  • the ASO targets an exon 2 sequence upstream (or 5') from the 5' splice site of a ADAR RIC pre-mRNA comprising the retained intron 2.
  • the ASO targets an exon 2 sequence about 4 to about 1566 or about 14 to about 1566 nucleotides upstream (or 5') from the 5' splice site of a ADAR RIC pre-mRNA comprising the retained intron 2.
  • the ASO targets an exon 3 sequence downstream (or 3') from the 3' splice site of a ADAR RIC pre-mRNA comprising the retained intron 2. In some embodiments, the ASO targets an exon 3 sequence about 2 to about 165 nucleotides downstream (or 3 ') from the 3' splice site of aADAR RIC pre-mRNA comprising the retained intron 2.
  • the ASO targets intron 2 in a ADAR RIC pre-mRNA comprising a retained intron 2, wherein the intron numbering correspond to the mRNA sequence at
  • the ASO targets an intron 2 sequence downstream (or 3') from the 5' splice site of aADAR RIC pre-mRNA comprising the retained intron 2. In some embodiments, the ASO targets an intron 2 sequence about 6 to about 500 nucleotides downstream (or 3 ') from the 5' splice site of aADAR RIC pre-mRNA comprising the retained intron 2. In some embodiments, the ASO targets an intron 2 sequence upstream (or 5') from the 3' splice site of a ADAR RIC pre-mRNA comprising the retained intron 2. In some
  • the ASO targets an intron 2 sequence about 16 to about 499 nucleotides upstream (or 5') from the 3' splice site of a ADAR RIC pre-mRNA comprising the retained intron 2.
  • the ASO targets exon 2 or exon 3 of aADAR RIC pre-mRNA comprising a retained intron 2, wherein the intron numbering correspond to the mRNA sequence at NM_015841.
  • the ASO targets an exon 2 sequence upstream (or 5') from the 5' splice site of a ADAR RIC pre-mRNA comprising the retained intron 2.
  • the ASO targets an exon 2 sequence about 4 to about 1566 or about 14 to about 1566 nucleotides upstream (or 5') from the 5' splice site of a ADAR RIC pre-mRNA comprising the retained intron 2. In some embodiments, the ASO targets an exon 3 sequence downstream (or 3') from the 3' splice site of a ADAR RIC pre-mRNA comprising the retained intron 2. In some embodiments, the ASO targets an exon 3 sequence about 2 to about 165 nucleotides downstream (or 3 ') from the 3' splice site of aADAR RIC pre-mRNA comprising the retained intron 2.
  • the ASO targets intron 2 in a ADAR RIC pre-mRNA comprising a retained intron 2, wherein the intron numbering correspond to the mRNA sequence at
  • the ASO targets an intron 2 sequence downstream (or 3 ') from the 5' splice site of a ADAR RIC pre-mRNA comprising the retained intron 2. In some embodiments, the ASO targets an intron 2 sequence about 6 to about 500 nucleotides downstream (or 3 ') from the 5' splice site of aADAR RIC pre-mRNA comprising the retained intron 2. In some embodiments, the ASO targets an intron 2 sequence upstream (or 5') from the 3' splice site of a ADAR RIC pre-mRNA comprising the retained intron 2. In some embodiments,
  • the ASO targets an intron 2 sequence about 16 to about 499 nucleotides upstream (or 5') from the 3' splice site of a ADAR RIC pre-mRNA comprising the retained intron 2.
  • the ASO targets exon 2 or exon 3 of a ADAR RIC pre-mRNA comprising a retained intron 2, wherein the intron numbering correspond to the mRNA sequence at NM_015840.
  • the ASO targets an exon 2 sequence upstream (or 5') from the 5' splice site of a ADAR RIC pre-mRNA comprising the retained intron 2.
  • the ASO targets an exon 2 sequence about 4 to about 1566 or about 14 to about 1566 nucleotides upstream (or 5') from the 5' splice site of a ADAR RIC pre-mRNA comprising the retained intron 2.
  • the ASO targets an exon 3 sequence downstream (or 3') from the 3' splice site of a ADAR RIC pre-mRNA comprising the retained intron 2. In some embodiments, the ASO targets an exon 3 sequence about 2 to about 165 nucleotides downstream (or 3 ') from the 3' splice site of aADAR RIC pre-mRNA comprising the retained intron 2.
  • the ASO targets intron 2 in a ADAR RIC pre-mRNA comprising a retained intron 2, wherein the intron numbering correspond to the mRNA sequence at
  • the ASO targets an intron 2 sequence downstream (or 3 ') from the 5' splice site of a ADAR RIC pre-mRNA comprising the retained intron 2. In some embodiments, the ASO targets an intron 2 sequence about 6 to about 500 nucleotides downstream (or 3 ') from the 5' splice site of aADAR RIC pre-mRNA comprising the retained intron 2. In some embodiments, the ASO targets an intron 2 sequence upstream (or 5') from the 3' splice site of a ADAR RIC pre-mRNA comprising the retained intron 2. In some embodiments,
  • the ASO targets an intron 2 sequence about 16 to about 499 nucleotides upstream (or 5') from the 3' splice site of a ADAR RIC pre-mRNA comprising the retained intron 2.
  • the ASO targets exon 2 or exon 3 of a ADAR RIC pre-mRNA comprising a retained intron 2, wherein the intron numbering correspond to the mRNA sequence at NM 001111.
  • the ASO targets an exon 2 sequence upstream (or 5') from the 5' splice site of a ADAR RIC pre-mRNA comprising the retained intron 2.
  • the ASO targets an exon 2 sequence about 4 to about 1566 or about 14 to about 1566 nucleotides upstream (or 5') from the 5' splice site of a ADAR RIC pre-mRNA comprising the retained intron 2.
  • the ASO targets an exon 3 sequence downstream (or 3') from the 3' splice site of a ADAR RIC pre-mRNA comprising the retained intron 2. In some embodiments, the ASO targets an exon 3 sequence about 2 to about 165 nucleotides downstream (or 3 ') from the 3' splice site of aADAR RIC pre-mRNA comprising the retained intron 2.
  • the ASO targets intron 2 in a ADAR RIC pre-mRNA comprising a retained intron 2, wherein the intron numbering correspond to the mRNA sequence at
  • the ASO targets an intron 2 sequence downstream (or 3') from the 5' splice site of a ADAR RIC pre-mRNA comprising the retained intron 2. In some embodiments, the ASO targets an intron 2 sequence about 6 to about 500 nucleotides downstream (or 3 ') from the 5' splice site of aADAR RIC pre-mRNA comprising the retained intron 2. In some embodiments, the ASO targets an intron 2 sequence upstream (or 5') from the 3' splice site of a ADAR RIC pre-mRNA comprising the retained intron 2. In some embodiments,
  • the ASO targets an intron 2 sequence about 16 to about 499 nucleotides upstream (or 5') from the 3' splice site of a ADAR RIC pre-mRNA comprising the retained intron 2.
  • the ASO targets exon 2 or exon 3 of a ADAR RIC pre-mRNA comprising a retained intron 2, wherein the intron numbering correspond to the mRNA sequence at NM_001025107.
  • the ASO targets an exon 2 sequence upstream (or 5') from the 5' splice site of a ADAR RIC pre-mRNA comprising the retained intron 2.
  • the ASO targets an exon 2 sequence about 4 to about 1566 or about 14 to about 1566 nucleotides upstream (or 5') from the 5' splice site of a ADAR RIC pre-mRNA comprising the retained intron 2.
  • the ASO targets an exon 3 sequence downstream (or 3') from the 3' splice site of a ADAR RIC pre-mRNA comprising the retained intron 2. In some embodiments, the ASO targets an exon 3 sequence about 2 to about 165 nucleotides downstream (or 3 ') from the 3' splice site of aADAR RIC pre-mRNA comprising the retained intron 2.
  • the ASO targets intron 2 in a ADAR RIC pre-mRNA comprising a retained intron 2, wherein the intron numbering correspond to the mRNA sequence at
  • the ASO targets an intron 2 sequence downstream (or 3') from the 5' splice site of aADAR RIC pre-mRNA comprising the retained intron 2. In some embodiments, the ASO targets an intron 2 sequence about 6 to about 500 nucleotides downstream (or 3 ') from the 5' splice site of aADAR RIC pre-mRNA comprising the retained intron 2. In some embodiments, the ASO targets an intron 2 sequence upstream (or 5') from the 3' splice site of a ADAR RIC pre-mRNA comprising the retained intron 2. In some
  • the ASO targets an intron 2 sequence about 16 to about 499 nucleotides upstream (or 5') from the 3' splice site of a ADAR RIC pre-mRNA comprising the retained intron 2.
  • the ASOs disclosed herein target a RIC pre-mRNA transcribed from a ATPlA2 genomic sequence. In some embodiments, the ASO targets a RIC pre-mRNA transcript from a ATPlA2 genomic sequence comprising a retained intron. In some
  • the ASO targets a RIC pre-mRNA transcript of SEQ ID NO: 2. In some embodiments, the ASO targets a RIC pre-mRNA transcript of SEQ ID NO: 2 comprising a retained intron. In some embodiments, the ASOs disclosed herein target a ATP1A2 RIC pre- mRNA sequence. In some embodiments, the ASO targets a ATPlA2 RIC pre-mRNA transcript comprising a retained intron at 22, wherein the intron numbering correspond to the mRNA sequence at NM_000702.
  • the ASO targets a ATPlA2 RIC pre-mRNA sequence according to SEQ ID NO: 25. In some embodiments, the ASO targets a ATPlA2 RIC pre-mRNA sequence according to SEQ ID NO: 25 comprising a retained intron 22. In some embodiments, the ASOs disclosed herein target SEQ ID NO: 24359. In some embodiments, the ASO has a sequence according to any one of SEQ ID NOs: 2676-3302.
  • the ASO targets exon 22 or exon 23 of aATPlA2 RIC pre-mRNA comprising a retained intron 22, wherein the intron numbering correspond to the mRNA sequence at NM_000702.
  • the ASO targets an exon 22 sequence upstream (or 5') from the 5' splice site of a ATPlA2 RIC pre-mRNA comprising the retained intron 22.
  • the ASO targets an exon 22 sequence about 4 to about 71 nucleotides upstream (or 5') from the 5' splice site of aATPlA2 RIC pre-mRNA comprising the retained intron 22.
  • the ASO targets an exon 23 sequence downstream (or 3') from the 3' splice site of a ATP!A2 RIC pre-mRNA comprising the retained intron 22. In some embodiments, the ASO targets an exon 23 sequence about 2 to about 2271 nucleotides downstream (or 3 ') from the 3' splice site of aATP!A2 RIC pre-mRNA comprising the retained intron 22.
  • the ASO targets intron 22 in a ATP!A2 RIC pre-mRNA comprising a retained intron 22, wherein the intron numbering correspond to the mRNA sequence at NM_000702.
  • the ASO targets an intron 22 sequence downstream (or 3 ') from the 5' splice site of aATP!A2 RIC pre-mRNA comprising the retained intron 22.
  • the ASO targets an intron 22 sequence about 6 to about 498 or about 21 to about 498 nucleotides downstream (or 3') from the 5' splice site of aATPlA2 RIC pre-mRNA comprising the retained intron 22.
  • the ASO targets an intron 22 sequence upstream (or 5') from the 3' splice site of a ATPlA2 RIC pre-mRNA comprising the retained intron 22. In some embodiments, the ASO targets an intron 22 sequence about 16 to about 500 nucleotides upstream (or 5') from the 3' splice site of a ATPlA2 RIC pre-mRNA comprising the retained intron 22.
  • the ASOs disclosed herein target a RIC pre-mRNA transcribed from a PRICKLE2 genomic sequence. In some embodiments, the ASO targets a RIC pre- mRNA transcript from a PRICKLE2 genomic sequence comprising a retained intron. In some embodiments, the ASO targets a RIC pre-mRNA transcript of SEQ ID NO: 3. In some embodiments, the ASO targets a RIC pre-mRNA transcript of SEQ ID NO: 3 comprising a retained intron. In some embodiments, the ASOs disclosed herein target a PRICKLE2 RIC pre- mRNA sequence. In some embodiments, the ASO targets a PRICKLE2 RIC pre-mRNA transcript comprising a retained intron at 4, wherein the intron numbering correspond to the mRNA sequence at NM_198859.
  • the ASO targets a PRICKLE2 RIC pre-mRNA sequence according to SEQ ID NO: 26. In some embodiments, the ASO targets a PRICKLE2 RIC pre- mRNA sequence according to SEQ ID NO: 26 comprising a retained intron 4. In some embodiments, the ASOs disclosed herein target SEQ ID NO: 24372. In some embodiments, the ASO has a sequence according to any one of SEQ ID NOs: 3303-3552.
  • the ASO targets exon 4 or exon 5 of a PRICKLE2 RIC pre- mRNA comprising a retained intron 4, wherein the intron numbering correspond to the mRNA sequence at NM_198859.
  • the ASO targets an exon 4 sequence upstream (or 5') from the 5' splice site of a PRICKLE2 RIC pre-mRNA comprising the retained intron 4.
  • the ASO targets an exon 4 sequence about 4 to about 119 nucleotides upstream (or 5') from the 5' splice site of a PRICKLE2 RIC pre-mRNA comprising the retained intron 4.
  • the ASO targets an exon 5 sequence downstream (or 3') from the 3' splice site of a PRICKLE2 RIC pre-mRNA comprising the retained intron 4. In some embodiments, the ASO targets an exon 5 sequence about 2 to about 187 nucleotides downstream (or 3') from the 3' splice site of a PRICKLE2 RIC pre-mRNA comprising the retained intron 4.
  • the ASO targets intron 4 in a PRICKLE2 RIC pre-mRNA comprising a retained intron 4, wherein the intron numbering correspond to the mRNA sequence at NM l 98859.
  • the ASO targets an intron 4 sequence downstream (or 3') from the 5' splice site of a PRICKLE2 RIC pre-mRNA comprising the retained intron 4.
  • the ASO targets an intron 4 sequence about 6 to about 496 nucleotides downstream (or 3 ') from the 5' splice site of a PRICKLE2 RIC pre-mRNA comprising the retained intron 4.
  • the ASO targets an intron 4 sequence upstream (or 5') from the 3' splice site of a PRICKLE2 RIC pre-mRNA comprising the retained intron 4. In some embodiments, the ASO targets an intron 4 sequence about 16 to about 499 nucleotides upstream (or 5') from the 3' splice site of a PRICKLE2 RIC pre-mRNA comprising the retained intron 4.
  • the ASOs disclosed herein target a RIC pre-mRNA transcribed from a SETD5 genomic sequence. In some embodiments, the ASO targets a RIC pre-mRNA transcript from a SETD5 genomic sequence comprising a retained intron. In some embodiments, the ASO targets a RIC pre-mRNA transcript of SEQ ID NO: 4. In some embodiments, the ASO targets a RIC pre-mRNA transcript of SEQ ID NO: 4 comprising a retained intron. In some embodiments, the ASOs disclosed herein target a SETD5 RIC pre-mRNA sequence.
  • the ASO targets a SETD5 RIC pre-mRNA transcript comprising a retained intron at 4, wherein the intron numbering correspond to the mRNA sequence at NM_001080517. In some embodiments, the ASO targets a SETD5 RIC pre-mRNA transcript comprising a retained intron at 5, wherein the intron numbering correspond to the mRNA sequence at
  • the ASO targets a SETD5 RIC pre-mRNA sequence according to SEQ ID NO: 27. In some embodiments, the ASO targets a SETD5 RIC pre-mRNA sequence according to SEQ ID NO: 27 comprising a retained intron 4. In some embodiments, the ASO targets a SETD5 RIC pre-mRNA sequence according to SEQ ID NO: 28. In some embodiments, the ASO targets a SETD5 RIC pre-mRNA sequence according to SEQ ID NO: 28 comprising a retained intron 5. In some embodiments, the ASOs disclosed herein target SEQ ID NO: 24386. In some embodiments, the ASO has a sequence according to any one of SEQ ID NOs: 3553- 3794.
  • the ASO targets exon 4 or exon 5 of a SETD5 RIC pre-mRNA comprising a retained intron 4, wherein the intron numbering correspond to the mRNA sequence at NM_001080517.
  • the ASO targets an exon 4 sequence upstream (or 5') from the 5' splice site of a SETD5 RIC pre-mRNA comprising the retained intron 4.
  • the ASO targets an exon 4 sequence about 4 to about 89 nucleotides upstream (or 5') from the 5' splice site of a SETD5 RIC pre-mRNA comprising the retained intron 4.
  • the ASO targets an exon 5 sequence downstream (or 3') from the 3' splice site of a SETD5 RIC pre-mRNA comprising the retained intron 4. In some embodiments, the ASO targets an exon 5 sequence about 2 to about 132 nucleotides downstream (or 3') from the 3' splice site of a SETD5 RIC pre-mRNA comprising the retained intron 4.
  • the ASO targets intron 4 in a SETD5 RIC pre-mRNA comprising a retained intron 4, wherein the intron numbering correspond to the mRNA sequence at
  • the ASO targets an intron 4 sequence downstream (or 3') from the 5' splice site of a SETD5 RIC pre-mRNA comprising the retained intron 4. In some embodiments, the ASO targets an intron 4 sequence about 6 to about 204 nucleotides downstream (or 3 ') from the 5' splice site of a SETD5 RIC pre-mRNA comprising the retained intron 4. In some embodiments, the ASO targets an intron 4 sequence upstream (or 5') from the 3' splice site of a SETD5 RIC pre-mRNA comprising the retained intron 4. In some
  • the ASO targets an intron 4 sequence about 16 to about 204 nucleotides upstream (or 5') from the 3' splice site of a SETD5 RIC pre-mRNA comprising the retained intron 4.
  • the ASO targets exon 5 or exon 6 of a SETD5 RIC pre-mRNA comprising a retained intron 5, wherein the intron numbering correspond to the mRNA sequence at NM_001292043.
  • the ASO targets an exon 5 sequence upstream (or 5') from the 5' splice site of a SETD5 RIC pre-mRNA comprising the retained intron 5.
  • the ASO targets an exon 5 sequence about 4 to about 89 nucleotides upstream (or 5') from the 5' splice site of a SETD5 RIC pre-mRNA comprising the retained intron 5.
  • the ASO targets an exon 6 sequence downstream (or 3') from the 3' splice site of a SETD5 RIC pre-mRNA comprising the retained intron 5. In some embodiments, the ASO targets an exon 6 sequence about 2 to about 132 nucleotides downstream (or 3') from the 3' splice site of a SETD5 RIC pre-mRNA comprising the retained intron 5.
  • the ASO targets intron 5 in a SETD5 RIC pre-mRNA comprising a retained intron 5, wherein the intron numbering correspond to the mRNA sequence at
  • the ASO targets an intron 5 sequence downstream (or 3') from the 5' splice site of a SETD5 RIC pre-mRNA comprising the retained intron 5. In some embodiments, the ASO targets an intron 5 sequence about 6 to about 204 nucleotides downstream (or 3 ') from the 5' splice site of a SETD5 RIC pre-mRNA comprising the retained intron 5. In some embodiments, the ASO targets an intron 5 sequence upstream (or 5') from the 3' splice site of a SETD5 RIC pre-mRNA comprising the retained intron 5. In some
  • the ASO targets an intron 5 sequence about 16 to about 204 nucleotides upstream (or 5') from the 3' splice site of a SETD5 RIC pre-mRNA comprising the retained intron 5.
  • the ASOs disclosed herein target a RIC pre-mRNA transcribed from a EIF2B5 genomic sequence. In some embodiments, the ASO targets a RIC pre-mRNA transcript from a EIF2B5 genomic sequence comprising a retained intron. In some
  • the ASO targets a RIC pre-mRNA transcript of SEQ ID NO: 5. In some embodiments, the ASO targets a RIC pre-mRNA transcript of SEQ ID NO: 5 comprising a retained intron. In some embodiments, the ASOs disclosed herein target a EIF2B5 RIC pre- mRNA sequence. In some embodiments, the ASO targets a EIF2B5 RIC pre-mRNA transcript comprising a retained intron at 12, 13 or a combination thereof, wherein the intron numbering correspond to the mRNA sequence at NM_003907.
  • the ASO targets a EIF2B5 RIC pre-mRNA sequence according to SEQ ID NO: 29. In some embodiments, the ASO targets a EIF2B5 RIC pre-mRNA sequence according to SEQ ID NO: 29 comprising a retained intron 12, a retained intron 13, or a combination thereof. In some embodiments, the ASOs disclosed herein target SEQ ID NO: 29.
  • the ASO has a sequence according to any one of SEQ ID NOs: 3795-4032.
  • the ASO targets exon 12 or exon 13 of a EIF2B5 RIC pre-mRNA comprising a retained intron 12, wherein the intron numbering correspond to the mRNA sequence at NM_003907.
  • the ASO targets an exon 12 sequence upstream (or 5') from the 5' splice site of a EIF2B5 RIC pre-mRNA comprising the retained intron 12.
  • the ASO targets an exon 12 sequence about 4 to about 74 nucleotides upstream (or 5') from the 5' splice site of a EIF2B5 RIC pre-mRNA comprising the retained intron 12.
  • the ASO targets an exon 13 sequence downstream (or 3') from the 3' splice site of a EIF2B5 RIC pre-mRNA comprising the retained intron 12. In some embodiments, the ASO targets an exon 13 sequence about 2 to about 105 nucleotides downstream (or 3 ') from the 3' splice site of a EIF2B5 RIC pre-mRNA comprising the retained intron 12.
  • the ASO targets intron 12 in a EIF2B5 RIC pre-mRNA comprising a retained intron 12, wherein the intron numbering correspond to the mRNA sequence at NM_003907.
  • the ASO targets an intron 12 sequence downstream (or 3 ') from the 5' splice site of a EIF2B5 RIC pre-mRNA comprising the retained intron 12.
  • the ASO targets an intron 12 sequence about 6 to about 161 nucleotides downstream (or 3') from the 5' splice site of a EIF2B5 RIC pre-mRNA comprising the retained intron 12.
  • the ASO targets an intron 12 sequence upstream (or 5') from the 3' splice site of a EIF2B5 RIC pre-mRNA comprising the retained intron 12. In some embodiments, the ASO targets an intron 12 sequence about 16 to about 164 nucleotides upstream (or 5') from the 3' splice site of a EIF2B5 RIC pre-mRNA comprising the retained intron 12.
  • the ASO targets exon 13 or exon 14 of a EIF2B5 RIC pre-mRNA comprising a retained intron 13, wherein the intron numbering correspond to the mRNA sequence at NM_003907.
  • the ASO targets an exon 13 sequence upstream (or 5') from the 5' splice site of a EIF2B5 RIC pre-mRNA comprising the retained intron 13.
  • the ASO targets an exon 13 sequence about 4 to about 104 nucleotides upstream (or 5') from the 5' splice site of a EIF2B5 RIC pre-mRNA comprising the retained intron 13.
  • the ASO targets an exon 14 sequence downstream (or 3') from the 3' splice site of a EIF2B5 RIC pre-mRNA comprising the retained intron 13. In some embodiments, the ASO targets an exon 14 sequence about 2 to about 107 nucleotides downstream (or 3 ') from the 3' splice site of a EIF2B5 RIC pre-mRNA comprising the retained intron 13.
  • the ASO targets intron 13 in a EIF2B5 RIC pre-mRNA comprising a retained intron 13, wherein the intron numbering correspond to the mRNA sequence at NM_003907.
  • the ASO targets an intron 13 sequence downstream (or 3 ') from the 5' splice site of a EIF2B5 RIC pre-mRNA comprising the retained intron 13.
  • the ASO targets an intron 13 sequence about 6 to about 276 nucleotides downstream (or 3') from the 5' splice site of a EIF2B5 RIC pre-mRNA comprising the retained intron 13.
  • the ASO targets an intron 13 sequence upstream (or 5') from the 3' splice site of a EIF2B5 RIC pre-mRNA comprising the retained intron 13. In some embodiments, the ASO targets an intron 13 sequence about 16 to about 281 nucleotides upstream (or 5') from the 3' splice site of a EIF2B5 RIC pre-mRNA comprising the retained intron 13.
  • the ASOs disclosed herein target a RIC pre-mRNA transcribed from a PEXl genomic sequence. In some embodiments, the ASO targets a RIC pre-mRNA transcript from a PEXl genomic sequence comprising a retained intron. In some embodiments, the ASO targets a RIC pre-mRNA transcript of SEQ ID NO: 6. In some embodiments, the ASO targets a RIC pre-mRNA transcript of SEQ ID NO: 6 comprising a retained intron. In some embodiments, the ASOs disclosed herein target a PEXl RIC pre-mRNA sequence.
  • the ASO targets a PEXl RIC pre-mRNA transcript comprising a retained intron at 10, 19, 21, 14 or a combination thereof, wherein the intron numbering correspond to the mRNA sequence at NM_000466. In some embodiments, the ASO targets a PEXl RIC pre-mRNA transcript comprising a retained intron at 10, 18, 20, 13 or a combination thereof, wherein the intron numbering correspond to the mRNA sequence at NM 001282677. In some embodiments, the ASO targets a, PEXl RIC pre-mRNA transcript comprising a retained intron at 10, 19, 21, 14 or a combination thereof, wherein the intron numbering correspond to the mRNA sequence at NM_001282678.
  • the ASO targets a, PEXl RIC pre-mRNA sequence according to SEQ ID NO: 30. In some embodiments, the ASO targets a PEXl RIC pre-mRNA sequence according to SEQ ID NO: 30 comprising a retained intron 10, a retained intron 19, a retained intron 21, a retained intron 14, or a combination thereof. In some embodiments, the ASO targets a PEXl RIC pre-mRNA sequence according to SEQ ID NO: 31. In some embodiments, the ASO targets a PEXl RIC pre-mRNA sequence according to SEQ ID NO: 31 comprising a retained intron 10, a retained intron 18, a retained intron 20, a retained intron 13, or a
  • the ASO targets a PEXl RIC pre-mRNA sequence according to SEQ ID NO: 32. In some embodiments, the ASO targets a PEXl RIC pre-mRNA sequence according to SEQ ID NO: 32 comprising a retained intron 10, a retained intron 19, a retained intron 21, a retained intron 14, or a combination thereof. In some embodiments, the ASOs disclosed herein target SEQ ID NOs: 24356, 24380, 24370, or 24361. In some embodiments, the ASO has a sequence according to any one of SEQ ID NOs: 4033-6411.
  • the ASO targets exon 10 or exon 11 of a PEXl RIC pre-mRNA comprising a retained intron 10, wherein the intron numbering correspond to the mRNA sequence at NM_000466.
  • the ASO targets an exon 10 sequence upstream (or 5') from the 5' splice site of a PEXl RIC pre-mRNA comprising the retained intron 10.
  • the ASO targets an exon 10 sequence about 4 to about 114 nucleotides upstream (or 5') from the 5' splice site of a PEXl RIC pre-mRNA comprising the retained intron 10.
  • the ASO targets an exon 11 sequence downstream (or 3') from the 3' splice site of a PEXl RIC pre-mRNA comprising the retained intron 10. In some embodiments, the ASO targets an exon 11 sequence about 2 to about 77 nucleotides downstream (or 3') from the 3' splice site of a PEXl RIC pre-mRNA comprising the retained intron 10.
  • the ASO targets intron 10 in a PEXl RIC pre-mRNA comprising a retained intron 10, wherein the intron numbering correspond to the mRNA sequence at NM 000466.
  • the ASO targets an intron 10 sequence downstream (or 3') from the 5' splice site of a PEXl RIC pre-mRNA comprising the retained intron 10.
  • the ASO targets an intron 10 sequence about 6 to about 336 nucleotides downstream (or 3 ') from the 5' splice site of a PEXI RIC pre-mRNA comprising the retained intron 10.
  • the ASO targets an intron 10 sequence upstream (or 5') from the 3' splice site of a PEXI RIC pre-mRNA comprising the retained intron 10. In some embodiments, the ASO targets an intron 10 sequence about 16 to about 336 nucleotides upstream (or 5') from the 3' splice site of a PEXI RIC pre-mRNA comprising the retained intron 10.
  • the ASO targets exon 19 or exon 20 of a PEXl RIC pre-mRNA comprising a retained intron 19, wherein the intron numbering correspond to the mRNA sequence at NM_000466.
  • the ASO targets an exon 19 sequence upstream (or 5') from the 5' splice site of a PEX1 RIC pre-mRNA comprising the retained intron 19.
  • the ASO targets an exon 19 sequence about 4 to about 84 nucleotides upstream (or 5') from the 5' splice site of a PEXl RIC pre-mRNA comprising the retained intron 19.
  • the ASO targets an exon 20 sequence downstream (or 3') from the 3' splice site of a PEX1 RIC pre-mRNA comprising the retained intron 19. In some embodiments, the ASO targets an exon 20 sequence about 2 to about 157 nucleotides downstream (or 3 ') from the 3' splice site of a PEXl RIC pre-mRNA comprising the retained intron 19.
  • the ASO targets intron 19 in a PEXI RIC pre-mRNA comprising a retained intron 19, wherein the intron numbering correspond to the mRNA sequence at NM 000466.
  • the ASO targets an intron 19 sequence downstream (or 3') from the 5' splice site of a PEXl RIC pre-mRNA comprising the retained intron 19.
  • the ASO targets an intron 19 sequence about 6 to about 496 nucleotides downstream (or 3 ') from the 5' splice site of a PEXl RIC pre-mRNA comprising the retained intron 19.
  • the ASO targets an intron 19 sequence upstream (or 5') from the 3' splice site of a PEXl RIC pre-mRNA comprising the retained intron 19. In some embodiments, the ASO targets an intron 19 sequence about 16 to about 496 nucleotides upstream (or 5') from the 3' splice site of a PEXI RIC pre-mRNA comprising the retained intron 19.
  • the ASO targets exon 21 or exon 22 of a PEXl RIC pre-mRNA comprising a retained intron 21, wherein the intron numbering correspond to the mRNA sequence at NM_000466.
  • the ASO targets an exon 21 sequence upstream (or 5') from the 5' splice site of a PEXl RIC pre-mRNA comprising the retained intron 21.
  • the ASO targets an exon 21 sequence about 4 to about 214 nucleotides upstream (or 5') from the 5' splice site of a PEXl RIC pre-mRNA comprising the retained intron 21.
  • the ASO targets an exon 22 sequence downstream (or 3') from the 3' splice site of a PEXI RIC pre-mRNA comprising the retained intron 21. In some embodiments, the ASO targets an exon 22 sequence about 2 to about 177 nucleotides downstream (or 3 ') from the 3' splice site of a PEXl RIC pre-mRNA comprising the retained intron 21.
  • the ASO targets intron 21 in a PEXl RIC pre-mRNA comprising a retained intron 21, wherein the intron numbering correspond to the mRNA sequence at NM 000466.
  • the ASO targets an intron 21 sequence downstream (or 3') from the 5' splice site of a PEX1 RIC pre-mRNA comprising the retained intron 21.
  • the ASO targets an intron 21 sequence about 6 to about 496 nucleotides downstream (or 3 ') from the 5' splice site of a PEXl RIC pre-mRNA comprising the retained intron 21.
  • the ASO targets an intron 21 sequence upstream (or 5') from the 3' splice site of a PEXl RIC pre-mRNA comprising the retained intron 21. In some embodiments, the ASO targets an intron 21 sequence about 16 to about 497 nucleotides upstream (or 5') from the 3' splice site of a PEXI RIC pre-mRNA comprising the retained intron 21.
  • the ASO targets exon 14 or exon 15 of a PEXI RIC pre-mRNA comprising a retained intron 14, wherein the intron numbering correspond to the mRNA sequence at NM_000466.
  • the ASO targets an exon 14 sequence upstream (or 5') from the 5' splice site of a PEX1 RIC pre-mRNA comprising the retained intron 14.
  • the ASO targets an exon 14 sequence about 4 to about 169 nucleotides upstream (or 5') from the 5' splice site of a PEXI RIC pre-mRNA comprising the retained intron 14.
  • the ASO targets an exon 15 sequence downstream (or 3') from the 3' splice site of a PEXl RIC pre-mRNA comprising the retained intron 14. In some embodiments, the ASO targets an exon 15 sequence about 2 to about 147 nucleotides downstream (or 3 ') from the 3' splice site of a PEXl RIC pre-mRNA comprising the retained intron 14.
  • the ASO targets intron 14 in a PEXl RIC pre-mRNA comprising a retained intron 14, wherein the intron numbering correspond to the mRNA sequence at NM 000466.
  • the ASO targets an intron 14 sequence downstream (or 3') from the 5' splice site of a PEXl RIC pre-mRNA comprising the retained intron 14.
  • the ASO targets an intron 14 sequence about 6 to about 121 nucleotides downstream (or 3 ') from the 5' splice site of a PEXl RIC pre-mRNA comprising the retained intron 14.
  • the ASO targets an intron 14 sequence upstream (or 5') from the 3' splice site of a PEXl RIC pre-mRNA comprising the retained intron 14. In some embodiments, the ASO targets an intron 14 sequence about 16 to about 121 nucleotides upstream (or 5') from the 3' splice site of a PEXI RIC pre-mRNA comprising the retained intron 14.
  • the ASO targets exon 10 or exon 11 of a PEX1 RIC pre-mRNA comprising a retained intron 10, wherein the intron numbering correspond to the mRNA sequence at NM_001282677.
  • the ASO targets an exon 10 sequence upstream (or 5') from the 5' splice site of a PEXI RIC pre-mRNA comprising the retained intron 10.
  • the ASO targets an exon 10 sequence about 4 to about 114 nucleotides upstream (or 5') from the 5' splice site of a PEXI RIC pre-mRNA comprising the retained intron 10.
  • the ASO targets an exon 11 sequence downstream (or 3') from the 3' splice site of a PEXI RIC pre-mRNA comprising the retained intron 10. In some embodiments, the ASO targets an exon 11 sequence about 2 to about 77 nucleotides downstream (or 3') from the 3' splice site of a PEX1 RIC pre-mRNA comprising the retained intron 10.
  • the ASO targets intron 10 in a PEXI RIC pre-mRNA comprising a retained intron 10, wherein the intron numbering correspond to the mRNA sequence at NM 001282677.
  • the ASO targets an intron 10 sequence downstream (or 3') from the 5' splice site of a PEXI RIC pre-mRNA comprising the retained intron 10.
  • the ASO targets an intron 10 sequence about 6 to about 336 nucleotides downstream (or 3 ') from the 5' splice site of a PEXI RIC pre-mRNA comprising the retained intron 10.
  • the ASO targets an intron 10 sequence upstream (or 5') from the 3' splice site of a PEXI RIC pre-mRNA comprising the retained intron 10. In some embodiments, the ASO targets an intron 10 sequence about 16 to about 336 nucleotides upstream (or 5') from the 3' splice site of a PEXI RIC pre-mRNA comprising the retained intron 10.
  • the ASO targets exon 18 or exon 19 of a PEXI RIC pre-mRNA comprising a retained intron 18, wherein the intron numbering correspond to the mRNA sequence at NM_001282677.
  • the ASO targets an exon 18 sequence upstream (or 5') from the 5' splice site of a PEXI RIC pre-mRNA comprising the retained intron 18.
  • the ASO targets an exon 18 sequence about 4 to about 84 nucleotides upstream (or 5') from the 5' splice site of a PEXI RIC pre-mRNA comprising the retained intron 18.
  • the ASO targets an exon 19 sequence downstream (or 3') from the 3' splice site of a PEXI RIC pre-mRNA comprising the retained intron 18. In some embodiments, the ASO targets an exon 19 sequence about 2 to about 157 nucleotides downstream (or 3 ') from the 3' splice site of a PEXI RIC pre-mRNA comprising the retained intron 18. [0210] In some embodiments, the ASO targets intron 18 in a PEXI RIC pre-mRNA comprising a retained intron 18, wherein the intron numbering correspond to the mRNA sequence at NM 001282677.
  • the ASO targets an intron 18 sequence downstream (or 3') from the 5' splice site of a PEXI RIC pre-mRNA comprising the retained intron 18. In some embodiments, the ASO targets an intron 18 sequence about 6 to about 496 nucleotides downstream (or 3 ') from the 5' splice site of a PEXI RIC pre-mRNA comprising the retained intron 18. In some embodiments, the ASO targets an intron 18 sequence upstream (or 5') from the 3' splice site of a PEXI RIC pre-mRNA comprising the retained intron 18. In some embodiments, the ASO targets an intron 18 sequence about 16 to about 496 nucleotides upstream (or 5') from the 3' splice site of a PEXI RIC pre-mRNA comprising the retained intron 18.
  • the ASO targets ex on 20 or ex on 21 of a PEXI RIC pre-mRNA comprising a retained intron 20, wherein the intron numbering correspond to the mRNA sequence at NM_001282677.
  • the ASO targets an exon 20 sequence upstream (or 5') from the 5' splice site of a PEXI RIC pre-mRNA comprising the retained intron 20.
  • the ASO targets an exon 20 sequence about 4 to about 214 nucleotides upstream (or 5') from the 5' splice site of a PEXI RIC pre-mRNA comprising the retained intron 20.
  • the ASO targets an exon 21 sequence downstream (or 3') from the 3' splice site of a PEXI RIC pre-mRNA comprising the retained intron 20. In some embodiments, the ASO targets an exon 21 sequence about 2 to about 177 nucleotides downstream (or 3 ') from the 3' splice site of a PEXI RIC pre-mRNA comprising the retained intron 20.
  • the ASO targets intron 20 in a PEXI RIC pre-mRNA comprising a retained intron 20, wherein the intron numbering correspond to the mRNA sequence at NM_001282677.
  • the ASO targets an intron 20 sequence downstream (or 3') from the 5' splice site of a PEXI RIC pre-mRNA comprising the retained intron 20.
  • the ASO targets an intron 20 sequence about 6 to about 496 nucleotides downstream (or 3 ') from the 5' splice site of a PEXI RIC pre-mRNA comprising the retained intron 20.
  • the ASO targets an intron 20 sequence upstream (or 5') from the 3' splice site of a PEXI RIC pre-mRNA comprising the retained intron 20. In some embodiments, the ASO targets an intron 20 sequence about 16 to about 497 nucleotides upstream (or 5') from the 3' splice site of a PEXI RIC pre-mRNA comprising the retained intron 20.
  • the ASO targets exon 13 or exon 14 of a PEXI RIC pre-mRNA comprising a retained intron 13, wherein the intron numbering correspond to the mRNA sequence at M_001282677.
  • the ASO targets an exon 13 sequence upstream (or 5') from the 5' splice site of a PEXI RIC pre-mRNA comprising the retained intron 13.
  • the ASO targets an exon 13 sequence about 4 to about 169 nucleotides upstream (or 5') from the 5' splice site of a PEXI RIC pre-mRNA comprising the retained intron 13.
  • the ASO targets an exon 14 sequence downstream (or 3 ') from the 3 ' splice site of a PEXI RIC pre-mRNA comprising the retained intron 13. In some embodiments, the ASO targets an exon 14 sequence about 2 to about 147 nucleotides downstream (or 3 ') from the 3 ' splice site of a PEXI RIC pre-mRNA comprising the retained intron 13.
  • the ASO targets intron 13 in a PEXI RIC pre-mRNA comprising a retained intron 13, wherein the intron numbering correspond to the mRNA sequence at NM 001282677.
  • the ASO targets an intron 13 sequence downstream (or 3 ') from the 5' splice site of a PEXI RIC pre-mRNA comprising the retained intron 13.
  • the ASO targets an intron 13 sequence about 6 to about 121 nucleotides downstream (or 3 ') from the 5' splice site of a PEXI RIC pre-mRNA comprising the retained intron 13.
  • the ASO targets an intron 13 sequence upstream (or 5') from the 3 ' splice site of a PEXI RIC pre-mRNA comprising the retained intron 13. In some embodiments, the ASO targets an intron 13 sequence about 16 to about 121 nucleotides upstream (or 5') from the 3 ' splice site of a PEXI RIC pre-mRNA comprising the retained intron 13.
  • the ASO targets exon 10 or exon 1 1 of a PEX1 RIC pre-mRNA comprising a retained intron 10, wherein the intron numbering correspond to the mRNA sequence at NM OO 1282678.
  • the ASO targets an exon 10 sequence upstream (or 5') from the 5' splice site of a PEXI RIC pre-mRNA comprising the retained intron 10.
  • the ASO targets an exon 10 sequence about 4 to about 1 14 nucleotides upstream (or 5') from the 5' splice site of a PEXI RIC pre-mRNA comprising the retained intron 10.
  • the ASO targets an exon 1 1 sequence downstream (or 3 ') from the 3 ' splice site of a PEXI RIC pre-mRNA comprising the retained intron 10. In some embodiments, the ASO targets an exon 1 1 sequence about 2 to about 77 nucleotides downstream (or 3 ') from the 3 ' splice site of a PEX1 RIC pre-mRNA comprising the retained intron 10.
  • the ASO targets intron 10 in a PEXI RIC pre-mRNA comprising a retained intron 10, wherein the intron numbering correspond to the mRNA sequence at NM OO 1282678.
  • the ASO targets an intron 10 sequence downstream (or 3 ') from the 5' splice site of a PEXI RIC pre-mRNA comprising the retained intron 10.
  • the ASO targets an intron 10 sequence about 6 to about 336 nucleotides downstream (or 3 ') from the 5' splice site of a PEXI RIC pre-mRNA comprising the retained intron 10.
  • the ASO targets an intron 10 sequence upstream (or 5') from the 3 ' splice site of a PEXI RIC pre-mRNA comprising the retained intron 10. In some embodiments, the ASO targets an intron 10 sequence about 16 to about 336 nucleotides upstream (or 5') from the 3 ' splice site of a PEXI RIC pre-mRNA comprising the retained intron 10.
  • the ASO targets exon 19 or exon 20 of a PEXI RIC pre-mRNA comprising a retained intron 19, wherein the intron numbering correspond to the mRNA sequence at NM OO 1282678.
  • the ASO targets an exon 19 sequence upstream (or 5') from the 5' splice site of a PEXI RIC pre-mRNA comprising the retained intron 19.
  • the ASO targets an exon 19 sequence about 4 to about 84 nucleotides upstream (or 5') from the 5' splice site of a PEXI RIC pre-mRNA comprising the retained intron 19.
  • the ASO targets an exon 20 sequence downstream (or 3 ') from the 3 ' splice site of a PEXI RIC pre-mRNA comprising the retained intron 19. In some embodiments, the ASO targets an exon 20 sequence about 2 to about 157 nucleotides downstream (or 3 ') from the 3 ' splice site of a PEXI RIC pre-mRNA comprising the retained intron 19.
  • the ASO targets intron 19 in a PEXI RIC pre-mRNA comprising a retained intron 19, wherein the intron numbering correspond to the mRNA sequence at NM OO 1282678.
  • the ASO targets an intron 19 sequence downstream (or 3 ') from the 5' splice site of a PEXI RIC pre-mRNA comprising the retained intron 19.
  • the ASO targets an intron 19 sequence about 6 to about 496 nucleotides downstream (or 3 ') from the 5' splice site of a PEXI RIC pre-mRNA comprising the retained intron 19.
  • the ASO targets an intron 19 sequence upstream (or 5') from the 3 ' splice site of a PEXI RIC pre-mRNA comprising the retained intron 19. In some embodiments, the ASO targets an intron 19 sequence about 16 to about 496 nucleotides upstream (or 5') from the 3 ' splice site of a PEXI RIC pre-mRNA comprising the retained intron 19.
  • the ASO targets exon 21 or exon 22 of a PEXI RIC pre-mRNA comprising a retained intron 21, wherein the intron numbering correspond to the mRNA sequence at NM_001282678.
  • the ASO targets an exon 21 sequence upstream (or 5') from the 5' splice site of a PEXI RIC pre-mRNA comprising the retained intron 21.
  • the ASO targets an exon 21 sequence about 4 to about 214 nucleotides upstream (or 5') from the 5' splice site of a PEXI RIC pre-mRNA comprising the retained intron 21.
  • the ASO targets an exon 22 sequence downstream (or 3') from the 3' splice site of a PEXI RIC pre-mRNA comprising the retained intron 21. In some embodiments, the ASO targets an exon 22 sequence about 2 to about 177 nucleotides downstream (or 3 ') from the 3' splice site of a PEXI RIC pre-mRNA comprising the retained intron 21.
  • the ASO targets intron 21 in a PEXI RIC pre-mRNA comprising a retained intron 21, wherein the intron numbering correspond to the mRNA sequence at NM OO 1282678.
  • the ASO targets an intron 21 sequence downstream (or 3') from the 5' splice site of a PEXI RIC pre-mRNA comprising the retained intron 21.
  • the ASO targets an intron 21 sequence about 6 to about 496 nucleotides downstream (or 3 ') from the 5' splice site of a PEXI RIC pre-mRNA comprising the retained intron 21.
  • the ASO targets an intron 21 sequence upstream (or 5') from the 3' splice site of a PEXI RIC pre-mRNA comprising the retained intron 21. In some embodiments, the ASO targets an intron 21 sequence about 16 to about 497 nucleotides upstream (or 5') from the 3' splice site of a PEXI RIC pre-mRNA comprising the retained intron 21.
  • the ASO targets exon 14 or exon 15 of a PEXI RIC pre-mRNA comprising a retained intron 14, wherein the intron numbering correspond to the mRNA sequence at NM_001282678.
  • the ASO targets an exon 14 sequence upstream (or 5') from the 5' splice site of a PEXI RIC pre-mRNA comprising the retained intron 14.
  • the ASO targets an exon 14 sequence about 4 to about 169 nucleotides upstream (or 5') from the 5' splice site of a PEXI RIC pre-mRNA comprising the retained intron 14.
  • the ASO targets an exon 15 sequence downstream (or 3') from the 3' splice site of a PEXI RIC pre-mRNA comprising the retained intron 14. In some embodiments, the ASO targets an exon 15 sequence about 2 to about 147 nucleotides downstream (or 3 ') from the 3' splice site of a PEXI RIC pre-mRNA comprising the retained intron 14.
  • the ASO targets intron 14 in a PEXI RIC pre-mRNA comprising a retained intron 14, wherein the intron numbering correspond to the mRNA sequence at NM OO 1282678.
  • the ASO targets an intron 14 sequence downstream (or 3') from the 5' splice site of a PEXI RIC pre-mRNA comprising the retained intron 14.
  • the ASO targets an intron 14 sequence about 6 to about 121 nucleotides downstream (or 3 ') from the 5' splice site of a PEXI RIC pre-mRNA comprising the retained intron 14.
  • the ASO targets an intron 14 sequence upstream (or 5') from the 3' splice site of a PEXI RIC pre-mRNA comprising the retained intron 14. In some embodiments, the ASO targets an intron 14 sequence about 16 to about 121 nucleotides upstream (or 5') from the 3' splice site of a PEXl RIC pre-mRNA comprising the retained intron 14.
  • the ASOs disclosed herein target a RIC pre-mRNA transcribed from a STXBPl genomic sequence. In some embodiments, the ASO targets a RIC pre-mRNA transcript from a STXBPl genomic sequence comprising a retained intron. In some
  • the ASO targets a RIC pre-mRNA transcript of SEQ ID NO: 7. In some embodiments, the ASO targets a RIC pre-mRNA transcript of SEQ ID NO: 7 comprising a retained intron. In some embodiments, the ASOs disclosed herein target a STXBPl RIC pre- mRNA sequence. In some embodiments, the ASO targets a STXBPl RIC pre-mRNA transcript comprising a retained intron at 18, 19 or a combination thereof, wherein the intron numbering correspond to the mRNA sequence at NM 003165. In some embodiments, the ASO targets a STXBPl RIC pre-mRNA transcript comprising a retained intron at 18, wherein the intron numbering correspond to the mRNA sequence at NM_001032221.
  • the ASO targets a STXBPl RIC pre-mRNA sequence according to SEQ ID NO: 33. In some embodiments, the ASO targets a STXBPl RIC pre-mRNA sequence according to SEQ ID NO: 33 comprising a retained intron 18, a retained intron 19, or a combination thereof. In some embodiments, the ASO targets a STXBPl RIC pre-mRNA sequence according to SEQ ID NO: 34. In some embodiments, the ASO targets a STXBPl RIC pre-mRNA sequence according to SEQ ID NO: 34 comprising a retained intron 18. In some embodiments, the ASOs disclosed herein target SEQ ID NOs: 24354, 24351, or 24360. In some embodiments, the ASO has a sequence according to any one of SEQ ID NOs: 6412-7753.
  • the ASO targets exon 18 or exon 19 of a STXBPl RIC pre-mRNA comprising a retained intron 18, wherein the intron numbering correspond to the mRNA sequence at NM_003165.
  • the ASO targets an exon 18 sequence upstream (or 5') from the 5' splice site of a STXBPl RIC pre-mRNA comprising the retained intron 18.
  • the ASO targets an exon 18 sequence about 4 to about 136 nucleotides upstream (or 5') from the 5' splice site of a STXBPl RIC pre-mRNA comprising the retained intron 18.
  • the ASO targets an exon 19 sequence downstream (or 3 ') from the 3' splice site of a STXBPl RIC pre-mRNA comprising the retained intron 18. In some embodiments, the ASO targets an exon 19 sequence about 2 to about 106 nucleotides downstream (or 3 ') from the 3' splice site of a STXBPl RIC pre-mRNA comprising the retained intron 18.
  • the ASO targets intron 18 in a STXBPl RIC pre-mRNA comprising a retained intron 18, wherein the intron numbering correspond to the mRNA sequence at NM_003165.
  • the ASO targets an intron 18 sequence downstream (or 3 ') from the 5' splice site of a STXBPl RIC pre-mRNA comprising the retained intron 18.
  • the ASO targets an intron 18 sequence about 6 to about 496 nucleotides downstream (or 3') from the 5' splice site of a STXBPl RIC pre-mRNA comprising the retained intron 18.
  • the ASO targets an intron 18 sequence upstream (or 5') from the 3' splice site of a STXBPl RIC pre-mRNA comprising the retained intron 18. In some embodiments, the ASO targets an intron 18 sequence about 16 to about 498 nucleotides upstream (or 5') from the 3' splice site of a STXBPl RIC pre-mRNA comprising the retained intron 18.
  • the ASO targets exon 19 or exon 20 of a STXBPl RIC pre-mRNA comprising a retained intron 19, wherein the intron numbering correspond to the mRNA sequence at NM_003165.
  • the ASO targets an exon 19 sequence upstream (or 5') from the 5' splice site of a STXBPl RIC pre-mRNA comprising the retained intron 19.
  • the ASO targets an exon 19 sequence about 4 to about 109 nucleotides upstream (or 5') from the 5' splice site of a STXBPl RIC pre-mRNA comprising the retained intron 19.
  • the ASO targets an exon 20 sequence downstream (or 3 ') from the 3' splice site of a STXBPl RIC pre-mRNA comprising the retained intron 19. In some embodiments, the ASO targets an exon 20 sequence about 2 to about 1922 nucleotides downstream (or 3 ') from the 3' splice site of a STXBPl RIC pre-mRNA comprising the retained intron 19.
  • the ASO targets intron 19 in a STXBPl RIC pre-mRNA comprising a retained intron 19, wherein the intron numbering correspond to the mRNA sequence at NM 003165.
  • the ASO targets an intron 19 sequence downstream (or 3 ') from the 5' splice site of a STXBPl RIC pre-mRNA comprising the retained intron 19.
  • the ASO targets an intron 19 sequence about 6 to about 499 nucleotides downstream (or 3') from the 5' splice site of a STXBPl RIC pre-mRNA comprising the retained intron 19.
  • the ASO targets an intron 19 sequence upstream (or 5') from the 3' splice site of a STXBPl RIC pre-mRNA comprising the retained intron 19. In some embodiments, the ASO targets an intron 19 sequence about 16 to about 500 nucleotides upstream (or 5') from the 3' splice site of a STXBPl RIC pre-mRNA comprising the retained intron 19.
  • the ASO targets exon 18 or exon 19 of a STXBPl RIC pre-mRNA comprising a retained intron 18, wherein the intron numbering correspond to the mRNA sequence at NM_001032221.
  • the ASO targets an exon 18 sequence upstream (or 5') from the 5' splice site of a STXBPl RIC pre-mRNA comprising the retained intron 18.
  • the ASO targets an exon 18 sequence about 4 to about 136 nucleotides upstream (or 5') from the 5' splice site of a STXBPl RIC pre-mRNA comprising the retained intron 18.
  • the ASO targets an exon 19 sequence downstream (or 3') from the 3' splice site of a STXBPl RIC pre-mRNA comprising the retained intron 18. In some embodiments, the ASO targets an exon 19 sequence about 2 to about 1922 nucleotides downstream (or 3 ') from the 3' splice site of a STXBPl RIC pre-mRNA comprising the retained intron 18.
  • the ASO targets intron 18 in a STXBPl RIC pre-mRNA comprising a retained intron 18, wherein the intron numbering correspond to the mRNA sequence at NM_001032221.
  • the ASO targets an intron 18 sequence downstream (or 3 ') from the 5' splice site of a STXBPl RIC pre-mRNA comprising the retained intron 18.
  • the ASO targets an intron 18 sequence about 6 to about 496 nucleotides downstream (or 3') from the 5' splice site of a STXBPl RIC pre-mRNA comprising the retained intron 18.
  • the ASO targets an intron 18 sequence upstream (or 5') from the 3' splice site of a STXBPl RIC pre-mRNA comprising the retained intron 18. In some embodiments, the ASO targets an intron 18 sequence about 16 to about 500 nucleotides upstream (or 5') from the 3' splice site of a STXBPl RIC pre-mRNA comprising the retained intron 18.
  • the ASOs disclosed herein target a RIC pre-mRNA transcribed from a EIF2B1 genomic sequence. In some embodiments, the ASO targets a RIC pre-mRNA transcript from a EIF2B1 genomic sequence comprising a retained intron. In some
  • the ASO targets a RIC pre-mRNA transcript of SEQ ID NO: 8. In some embodiments, the ASO targets a RIC pre-mRNA transcript of SEQ ID NO: 8 comprising a retained intron. In some embodiments, the ASOs disclosed herein target a EIF2B1 RIC pre- mRNA sequence. In some embodiments, the ASO targets a EIF2B1 RIC pre-mRNA transcript comprising a retained intron at 6, wherein the intron numbering correspond to the mRNA sequence at NM_001414.
  • the ASO targets a EIF2B1 RIC pre-mRNA sequence according to SEQ ID NO: 35. In some embodiments, the ASO targets a EIF2B1 RIC pre-mRNA sequence according to SEQ ID NO: 35 comprising a retained intron 6. In some embodiments, the ASOs disclosed herein target SEQ ID NO: 24353. In some embodiments, the ASO has a sequence according to any one of SEQ ID NOs: 7754-7964.
  • the ASO targets exon 6 or exon 7 of a EIF2B1 RIC pre-mRNA comprising a retained intron 6, wherein the intron numbering correspond to the mRNA sequence at NM 001414.
  • the ASO targets an exon 6 sequence upstream (or 5') from the 5' splice site of a EIF2B1 RIC pre-mRNA comprising the retained intron 6.
  • the ASO targets an exon 6 sequence about 4 to about 49 nucleotides upstream (or 5') from the 5' splice site of a EIF2Bl RIC pre-mRNA comprising the retained intron 6.
  • the ASO targets an exon 7 sequence downstream (or 3 ') from the 3' splice site of a EIF2B1 RIC pre-mRNA comprising the retained intron 6. In some embodiments, the ASO targets an exon 7 sequence about 2 to about 57 nucleotides downstream (or 3') from the 3' splice site of a EIF2B1 RIC pre-mRNA comprising the retained intron 6.
  • the ASO targets intron 6 in a EIF2Bl RIC pre-mRNA comprising a retained intron 6, wherein the intron numbering correspond to the mRNA sequence at
  • the ASO targets an intron 6 sequence downstream (or 3 ') from the 5' splice site of a EIF2B1 RIC pre-mRNA comprising the retained intron 6. In some embodiments, the ASO targets an intron 6 sequence about 19 to about 496 nucleotides downstream (or 3 ') from the 5' splice site of a EIF2Bl RIC pre-mRNA comprising the retained intron 6. In some embodiments, the ASO targets an intron 6 sequence upstream (or 5') from the 3' splice site of a EIF2B1 RIC pre-mRNA comprising the retained intron 6. In some embodiments, the ASO targets an intron 6 sequence about 16 to about 498 nucleotides upstream (or 5') from the 3' splice site of a EIF2B1 RIC pre-mRNA comprising the retained intron 6.
  • the ASOs disclosed herein target a RIC pre-mRNA transcribed from a EIF2B2 genomic sequence. In some embodiments, the ASO targets a RIC pre-mRNA transcript from a EIF2B2 genomic sequence comprising a retained intron. In some
  • the ASO targets a RIC pre-mRNA transcript of SEQ ID NO: 9. In some embodiments, the ASO targets a RIC pre-mRNA transcript of SEQ ID NO: 9 comprising a retained intron. In some embodiments, the ASOs disclosed herein target a EIF2B2 RIC pre- mRNA sequence. In some embodiments, the ASO targets a EIF2B2 RIC pre-mRNA transcript comprising a retained intron at 1, wherein the intron numbering correspond to the mRNA sequence at NM_014239.
  • the ASO targets a EIF2B2 RIC pre-mRNA sequence according to SEQ ID NO: 36. In some embodiments, the ASO targets a EIF2B2 RIC pre-mRNA sequence according to SEQ ID NO: 36 comprising a retained intron 1. In some embodiments, the ASOs disclosed herein target SEQ ID NO: 24358. In some embodiments, the ASO has a sequence according to any one of SEQ ID NOs: 7965-8053.
  • the ASO targets exon 1 or exon 2 of a EIF2B2 RIC pre-mRNA comprising a retained intron 1, wherein the intron numbering correspond to the mRNA sequence at NM_014239.
  • the ASO targets an exon 1 sequence upstream (or 5') from the 5' splice site of a EIF2B2 RIC pre-mRNA comprising the retained intron 1.
  • the ASO targets an exon 1 sequence about 4 to about 219 nucleotides upstream (or 5') from the 5' splice site of a EIF2B2 RIC pre-mRNA comprising the retained intron 1.
  • the ASO targets an ex on 2 sequence downstream (or 3 ') from the 3' splice site of a EIF2B2 RIC pre-mRNA comprising the retained intron 1. In some embodiments, the ASO targets an exon 2 sequence about 2 to about 102 nucleotides downstream (or 3') from the 3' splice site of a EIF2B2 RIC pre-mRNA comprising the retained intron 1.
  • the ASO targets intron 1 in a EIF2B2 RIC pre-mRNA comprising a retained intron 1, wherein the intron numbering correspond to the mRNA sequence at
  • the ASO targets an intron 1 sequence downstream (or 3 ') from the 5' splice site of a EIF2B2 RIC pre-mRNA comprising the retained intron 1. In some embodiments, the ASO targets an intron 1 sequence about 6 to about 70 nucleotides downstream (or 3') from the 5' splice site of a EIF2B2 RIC pre-mRNA comprising the retained intron 1. In some embodiments, the ASO targets an intron 1 sequence upstream (or 5') from the 3' splice site of a EIF2B2 RIC pre-mRNA comprising the retained intron 1. In some embodiments, the ASO targets an intron 1 sequence about 16 to about 70 nucleotides upstream (or 5') from the 3' splice site of a EIF2B2 RIC pre-mRNA comprising the retained intron 1.
  • the ASOs disclosed herein target a RIC pre-mRNA transcribed from a PRRT2 genomic sequence. In some embodiments, the ASO targets a RIC pre-mRNA transcript from a PRRT2 genomic sequence comprising a retained intron. In some embodiments, the ASO targets a RIC pre-mRNA transcript of SEQ ID NO: 10. In some embodiments, the ASO targets a RIC pre-mRNA transcript of SEQ ID NO: 10 comprising a retained intron. In some embodiments, the ASOs disclosed herein target a PRRT2 RIC pre-mRNA sequence. In some embodiments, the ASO targets a PRRT2 RIC pre-mRNA transcript comprising a retained intron at 1, wherein the intron numbering correspond to the mRNA sequence at
  • the ASO targets a PRRT2 RIC pre-mRNA transcript comprising a retained intron at 1, wherein the intron numbering correspond to the mRNA sequence at NM_145239. In some embodiments, the ASO targets a PRRT2 RIC pre-mRNA transcript comprising a retained intron at 1, wherein the intron numbering correspond to the mRNA sequence at NM_001256442.
  • the ASO targets a PRRT2 RIC pre-mRNA sequence according to SEQ ID NO: 37. In some embodiments, the ASO targets a PRRT2 RIC pre-mRNA sequence according to SEQ ID NO: 37 comprising a retained intron 1. In some embodiments, the ASO targets a PRRT2 RIC pre-mRNA sequence according to SEQ ID NO: 38. In some embodiments, the ASO targets a PRRT2 RIC pre-mRNA sequence according to SEQ ID NO: 38 comprising a retained intron 1. In some embodiments, the ASO targets a PRRT2 RIC pre-mRNA sequence according to SEQ ID NO: 39.
  • the ASO targets a PRRT2 RIC pre-mRNA sequence according to SEQ ID NO: 39 comprising a retained intron 1.
  • the ASOs disclosed herein target SEQ ID NOs: 24369 or 24365.
  • the ASO has a sequence according to any one of SEQ ID NOs: 8054-9332.
  • the ASO targets exon 1 or exon 2 of a PRRT2 RIC pre-mRNA comprising a retained intron 1, wherein the intron numbering correspond to the mRNA sequence at NM_001256443.
  • the ASO targets an exon 1 sequence upstream (or 5') from the 5' splice site of a PRRT2 RIC pre-mRNA comprising the retained intron 1.
  • the ASO targets an exon 1 sequence about 4 to about 244 nucleotides upstream (or 5') from the 5' splice site of a PRRT2 RIC pre-mRNA comprising the retained intron 1.
  • the ASO targets an exon 2 sequence downstream (or 3 ') from the 3' splice site of a PRRT2 RIC pre-mRNA comprising the retained intron 1. In some embodiments, the ASO targets an exon 2 sequence about 2 to about 2875 nucleotides downstream (or 3 ') from the 3' splice site of a PRRT2 RIC pre-mRNA comprising the retained intron 1.
  • the ASO targets intron 1 in a PRRT2 RIC pre-mRNA comprising a retained intron 1, wherein the intron numbering correspond to the mRNA sequence at
  • the ASO targets an intron 1 sequence downstream (or 3') from the 5' splice site of a PRRT2 RIC pre-mRNA comprising the retained intron 1. In some embodiments, the ASO targets an intron 1 sequence about 6 to about 333 nucleotides downstream (or 3 ') from the 5' splice site of a PRRT2 RIC pre-mRNA comprising the retained intron 1. In some embodiments, the ASO targets an intron 1 sequence upstream (or 5') from the 3' splice site of a PRRT2 RIC pre-mRNA comprising the retained intron 1. In some
  • the ASO targets an intron 1 sequence about 16 to about 330 or about 26 to about 330 nucleotides upstream (or 5') from the 3' splice site of a PRRT2 RIC pre-mRNA comprising the retained intron 1.
  • the ASO targets exon 1 or exon 2 of a PRRT2 RIC pre-mRNA comprising a retained intron 1, wherein the intron numbering correspond to the mRNA sequence at NM_145239.
  • the ASO targets an exon 1 sequence upstream (or 5') from the 5' splice site of a PRRT2 RIC pre-mRNA comprising the retained intron 1.
  • the ASO targets an exon 1 sequence about 4 to about 219 nucleotides upstream (or 5') from the 5' splice site of a PRRT2 RIC pre-mRNA comprising the retained intron 1.
  • the ASO targets an exon 2 sequence downstream (or 3 ') from the 3' splice site of a PRRT2 RIC pre-mRNA comprising the retained intron 1. In some embodiments, the ASO targets an exon 2 sequence about 2 to about 924 nucleotides downstream (or 3') from the 3' splice site of a PRRT2 RIC pre-mRNA comprising the retained intron 1. [0244] In some embodiments, the ASO targets intron 1 in a PRRT2 RIC pre-mRNA comprising a retained intron 1, wherein the intron numbering correspond to the mRNA sequence at
  • the ASO targets an intron 1 sequence downstream (or 3 ') from the 5' splice site of a PRRT2 RIC pre-mRNA comprising the retained intron 1. In some embodiments, the ASO targets an intron 1 sequence about 6 to about 346 nucleotides downstream (or 3 ') from the 5' splice site of a PRRT2 RIC pre-mRNA comprising the retained intron 1. In some embodiments, the ASO targets an intron 1 sequence upstream (or 5') from the 3' splice site of a PRRT2 RIC pre-mRNA comprising the retained intron 1. In some
  • the ASO targets an intron 1 sequence about 16 to about 345 nucleotides upstream (or 5') from the 3' splice site of a PRRT2 RIC pre-mRNA comprising the retained intron 1.
  • the ASO targets exon 1 or exon 2 of a PRRT2 RIC pre-mRNA comprising a retained intron 1, wherein the intron numbering correspond to the mRNA sequence at NM_001256442.
  • the ASO targets an exon 1 sequence upstream (or 5') from the 5' splice site of a PRRT2 RIC pre-mRNA comprising the retained intron 1.
  • the ASO targets an exon 1 sequence about 4 to about 219 nucleotides upstream (or 5') from the 5' splice site of a PRRT2 RIC pre-mRNA comprising the retained intron 1.
  • the ASO targets an exon 2 sequence downstream (or 3 ') from the 3' splice site of a PRRT2 RIC pre-mRNA comprising the retained intron 1. In some embodiments, the ASO targets an exon 2 sequence about 2 to about 924 nucleotides downstream (or 3') from the 3' splice site of a PRRT2 RIC pre-mRNA comprising the retained intron 1.
  • the ASO targets intron 1 in a PRRT2 RIC pre-mRNA comprising a retained intron 1, wherein the intron numbering correspond to the mRNA sequence at
  • the ASO targets an intron 1 sequence downstream (or 3') from the 5' splice site of a PRRT2 RIC pre-mRNA comprising the retained intron 1. In some embodiments, the ASO targets an intron 1 sequence about 6 to about 346 nucleotides downstream (or 3 ') from the 5' splice site of a PRRT2 RIC pre-mRNA comprising the retained intron 1. In some embodiments, the ASO targets an intron 1 sequence upstream (or 5') from the 3' splice site of a PRRT2 RIC pre-mRNA comprising the retained intron 1. In some
  • the ASO targets an intron 1 sequence about 16 to about 345 or about 26 to about 345 nucleotides upstream (or 5') from the 3' splice site of a PRRT2 RIC pre-mRNA comprising the retained intron 1.
  • the ASOs disclosed herein target a RIC pre-mRNA transcribed from a STX1B genomic sequence. In some embodiments, the ASO targets a RIC pre-mRNA transcript from a STX1B genomic sequence comprising a retained intron. In some embodiments, the ASO targets a RIC pre-mRNA transcript of SEQ ID NO: 11. In some embodiments, the ASO targets a RIC pre-mRNA transcript of SEQ ID NO: 11 comprising a retained intron. In some embodiments, the ASOs disclosed herein target a STXIB RIC pre-mRNA sequence. In some embodiments, the ASO targets a STXIB RIC pre-mRNA transcript comprising a retained intron at 6, 7 or a combination thereof, wherein the intron numbering correspond to the mRNA sequence at NM_052874.
  • the ASO targets a STXIB RIC pre-mRNA sequence according to SEQ ID NO: 40. In some embodiments, the ASO targets a STXIB RIC pre-mRNA sequence according to SEQ ID NO: 40 comprising a retained intron 6, a retained intron 7, or a
  • the ASOs disclosed herein target SEQ ID NO: 1
  • the ASO has a sequence according to any one of SEQ ID NOs: 9333-9600.
  • the ASO targets exon 6 or exon 7 of a STXIB RIC pre-mRNA comprising a retained intron 6, wherein the intron numbering correspond to the mRNA sequence at NM 052874.
  • the ASO targets an exon 6 sequence upstream (or 5') from the 5' splice site of a STXIB RIC pre-mRNA comprising the retained intron 6.
  • the ASO targets an exon 6 sequence about 4 to about 89 nucleotides upstream (or 5') from the 5' splice site of a STXIB RIC pre-mRNA comprising the retained intron 6.
  • the ASO targets an exon 7 sequence downstream (or 3') from the 3' splice site of a STXIB RIC pre-mRNA comprising the retained intron 6. In some embodiments, the ASO targets an exon 7 sequence about 2 to about 57 nucleotides downstream (or 3') from the 3' splice site of a STXIB RIC pre-mRNA comprising the retained intron 6.
  • the ASO targets intron 6 in a STXIB RIC pre-mRNA comprising a retained intron 6, wherein the intron numbering correspond to the mRNA sequence at
  • the ASO targets an intron 6 sequence downstream (or 3 ') from the 5' splice site of a STXIB RIC pre-mRNA comprising the retained intron 6. In some embodiments, the ASO targets an intron 6 sequence about 6 to about 99 nucleotides downstream (or 3') from the 5' splice site of a STXIB RIC pre-mRNA comprising the retained intron 6. In some embodiments, the ASO targets an intron 6 sequence upstream (or 5') from the 3' splice site of a STXIB RIC pre-mRNA comprising the retained intron 6. In some embodiments, the ASO targets an intron 6 sequence about 16 to about 94 nucleotides upstream (or 5') from the 3' splice site of a STXIB RIC pre-mRNA comprising the retained intron 6.
  • the ASO targets exon 7 or exon 8 of a STXIB RIC pre-mRNA comprising a retained intron 7, wherein the intron numbering correspond to the mRNA sequence at NM_052874.
  • the ASO targets an exon 7 sequence upstream (or 5') from the 5' splice site of a STXIB RIC pre-mRNA comprising the retained intron 7.
  • the ASO targets an exon 7 sequence about 4 to about 54 nucleotides upstream (or 5') from the 5' splice site of a STXIB RIC pre-mRNA comprising the retained intron 7.
  • the ASO targets an exon 8 sequence downstream (or 3') from the 3' splice site of a STXIB RIC pre-mRNA comprising the retained intron 7. In some embodiments, the ASO targets an exon 8 sequence about 2 to about 117 nucleotides downstream (or 3') from the 3' splice site of a STXIB RIC pre-mRNA comprising the retained intron 7.
  • the ASO targets intron 7 in a STXIB RIC pre-mRNA comprising a retained intron 7, wherein the intron numbering correspond to the mRNA sequence at
  • the ASO targets an intron 7 sequence downstream (or 3') from the 5' splice site of a STXIB RIC pre-mRNA comprising the retained intron 7. In some embodiments, the ASO targets an intron 7 sequence about 6 to about 500 nucleotides downstream (or 3 ') from the 5' splice site of a STXIB RIC pre-mRNA comprising the retained intron 7. In some embodiments, the ASO targets an intron 7 sequence upstream (or 5') from the 3' splice site of a STXIB RIC pre-mRNA comprising the retained intron 7. In some embodiments,
  • the ASO targets an intron 7 sequence about 16 to about 496 nucleotides upstream (or 5') from the 3' splice site of a STXIB RIC pre-mRNA comprising the retained intron 7.
  • the ASOs disclosed herein target a RIC pre-mRNA transcribed from a RAI1 genomic sequence. In some embodiments, the ASO targets a RIC pre-mRNA transcript from a RAI1 genomic sequence comprising a retained intron. In some embodiments, the ASO targets a RIC pre-mRNA transcript of SEQ ID NO: 12. In some embodiments, the ASO targets a RIC pre-mRNA transcript of SEQ ID NO: 12 comprising a retained intron. In some embodiments, the ASOs disclosed herein target a RAI1 RIC pre-mRNA sequence. In some embodiments, the ASO targets a RAI1 RIC pre-mRNA transcript comprising a retained intron at 4, wherein the intron numbering correspond to the mRNA sequence at NM 030665.
  • the ASO targets a RAI1 RIC pre-mRNA sequence according to SEQ ID NO: 41. In some embodiments, the ASO targets a RAI1 RIC pre-mRNA sequence according to SEQ ID NO: 41 comprising a retained intron 4. In some embodiments, the ASOs disclosed herein target SEQ ID NO: 24382. In some embodiments, the ASO has a sequence according to any one of SEQ ID NOs: 9601-9803.
  • the ASO targets exon 4 or exon 5 of a RAI1 RIC pre-mRNA comprising a retained intron 4, wherein the intron numbering correspond to the mRNA sequence at NM 030665.
  • the ASO targets an exon 4 sequence upstream (or 5') from the 5' splice site of a RAI1 RIC pre-mRNA comprising the retained intron 4.
  • the ASO targets an exon 4 sequence about 4 to about 74 nucleotides upstream (or 5') from the 5' splice site of a RAII RIC pre-mRNA comprising the retained intron 4.
  • the ASO targets an exon 5 sequence downstream (or 3') from the 3' splice site of a RAIl RIC pre-mRNA comprising the retained intron 4. In some embodiments, the ASO targets an exon 5 sequence about 2 to about 32 nucleotides downstream (or 3') from the 3 ' splice site of a RAIl RIC pre-mRNA comprising the retained intron 4.
  • the ASO targets intron 4 in a RAIl RIC pre-mRNA comprising a retained intron 4, wherein the intron numbering correspond to the mRNA sequence at
  • the ASO targets an intron 4 sequence downstream (or 3 ') from the 5' splice site of a RAIl RIC pre-mRNA comprising the retained intron 4. In some embodiments, the ASO targets an intron 4 sequence about 6 to about 500 nucleotides
  • the ASO targets an intron 4 sequence upstream (or 5') from the 3' splice site of a RAIl RIC pre-mRNA comprising the retained intron 4. In some embodiments, the ASO targets an intron 4 sequence about 16 to about 499 nucleotides upstream (or 5') from the 3' splice site of a RAIl RIC pre-mRNA comprising the retained intron 4.
  • the ASOs disclosed herein target a RIC pre-mRNA transcribed from a TCF4 genomic sequence. In some embodiments, the ASO targets a RIC pre-mRNA transcript from a TCF4 genomic sequence comprising a retained intron. In some embodiments, the ASO targets a RIC pre-mRNA transcript of SEQ ID NO: 13. In some embodiments, the ASO targets a RIC pre-mRNA transcript of SEQ ID NO: 13 comprising a retained intron. In some embodiments, the ASOs disclosed herein target a TCF4 RIC pre-mRNA sequence. In some embodiments, the ASO targets a TCF4 RIC pre-mRNA transcript comprising a retained intron at 10, wherein the intron numbering correspond to the mRNA sequence at
  • the ASO targets a TCF4 RIC pre-mRNA transcript comprising a retained intron at 10, wherein the intron numbering correspond to the mRNA sequence at NM_001243235. In some embodiments, the ASO targets a TCF4 RIC pre-mRNA transcript comprising a retained intron at 10, wherein the intron numbering correspond to the mRNA sequence at NM_001243234. In some embodiments, the ASO targets a TCF4 RIC pre- mRNA transcript comprising a retained intron at 13, wherein the intron numbering correspond to the mRNA sequence at NM_001243233.
  • the ASO targets a TCF4 RIC pre-mRNA transcript comprising a retained intron at 13, wherein the intron numbering correspond to the mRNA sequence at NM_001243232. In some embodiments, the ASO targets a TCF4 RIC pre-mRNA transcript comprising a retained intron at 15, wherein the intron numbering correspond to the mRNA sequence at NM_001243231. In some embodiments, the ASO targets a TCF4 RIC pre-mRNA transcript comprising a retained intron at 17, wherein the intron numbering correspond to the mRNA sequence at NM 003199.
  • the ASO targets a TCF4 RIC pre-mRNA transcript comprising a retained intron at 16, wherein the intron numbering correspond to the mRNA sequence at NM_001306207. In some embodiments, the ASO targets a TCF4 RIC pre-mRNA transcript comprising a retained intron at 13, wherein the intron numbering correspond to the mRNA sequence at NM 001306208. In some embodiments, the ASO targets a TCF4 RIC pre-mRNA transcript comprising a retained intron at 16, wherein the intron numbering correspond to the mRNA sequence at NM_001243227. In some embodiments, the ASO targets a TCF4 RIC pre-mRNA transcript comprising a retained intron at 17, wherein the intron numbering correspond to the mRNA sequence at
  • the ASO targets a TCF4 RIC pre-mRNA transcript comprising a retained intron at 16, wherein the intron numbering correspond to the mRNA sequence at NM_001243230. In some embodiments, the ASO targets a TCF4 RIC pre-mRNA transcript comprising a retained intron at 18, wherein the intron numbering correspond to the mRNA sequence at NM_001243226. In some embodiments, the ASO targets a TCF4 RIC pre- mRNA transcript comprising a retained intron at 17, wherein the intron numbering correspond to the mRNA sequence at NM 001083962.
  • the ASO targets a TCF4 RIC pre-mRNA transcript comprising a retained intron at 12, wherein the intron numbering correspond to the mRNA sequence at NM OO 1330605. In some embodiments, the ASO targets a TCF4 RIC pre-mRNA transcript comprising a retained intron at 17, wherein the intron numbering correspond to the mRNA sequence at NM_001330604.
  • the ASO targets a TCF4 RIC pre-mRNA sequence according to SEQ ID NO: 42. In some embodiments, the ASO targets a TCF4 RIC pre-mRNA sequence according to SEQ ID NO: 42 comprising a retained intron 10. In some embodiments, the ASO targets a TCF4 RIC pre-mRNA sequence according to SEQ ID NO: 43. In some embodiments, the ASO targets a TCF4 RIC pre-mRNA sequence according to SEQ ID NO: 43 comprising a retained intron 10. In some embodiments, the ASO targets a TCF4 RIC pre-mRNA sequence according to SEQ ID NO: 44.
  • the ASO targets a TCF4 RIC pre-mRNA sequence according to SEQ ID NO: 44 comprising a retained intron 10. In some embodiments, the ASO targets a TCF4 RIC pre-mRNA sequence according to SEQ ID NO: 45. In some embodiments, the ASO targets a TCF4 RIC pre-mRNA sequence according to SEQ ID NO: 45 comprising a retained intron 13. In some embodiments, the ASO targets a TCF4 RIC pre-mRNA sequence according to SEQ ID NO: 46. In some embodiments, the ASO targets a TCF4 RIC pre-mRNA sequence according to SEQ ID NO: 46 comprising a retained intron 13.
  • the ASO targets a TCF4 RIC pre-mRNA sequence according to SEQ ID NO: 47. In some embodiments, the ASO targets a TCF4 RIC pre-mRNA sequence according to SEQ ID NO: 47 comprising a retained intron 15. In some embodiments, the ASO targets a TCF4 RIC pre-mRNA sequence according to SEQ ID NO: 48. In some embodiments, the ASO targets a TCF4 RIC pre-mRNA sequence according to SEQ ID NO: 48 comprising a retained intron 17. In some embodiments, the ASO targets a TCF4 RIC pre-mRNA sequence according to SEQ ID NO: 49.
  • the ASO targets a TCF4 RIC pre-mRNA sequence according to SEQ ID NO: 49 comprising a retained intron 16. In some embodiments, the ASO targets a TCF4 RIC pre-mRNA sequence according to SEQ ID NO: 50. In some embodiments, the ASO targets a TCF4 RIC pre-mRNA sequence according to SEQ ID NO: 50 comprising a retained intron 13. In some embodiments, the ASO targets a TCF4 RIC pre-mRNA sequence according to SEQ ID NO: 51. In some embodiments, the ASO targets a TCF4 RIC pre-mRNA sequence according to SEQ ID NO: 51 comprising a retained intron 16.
  • the ASO targets a TCF4 RIC pre-mRNA sequence according to SEQ ID NO: 52. In some embodiments, the ASO targets a TCF4 RIC pre-mRNA sequence according to SEQ ID NO: 52 comprising a retained intron 17. In some embodiments, the ASO targets a TCF4 RIC pre-mRNA sequence according to SEQ ID NO: 53. In some embodiments, the ASO targets a TCF4 RIC pre-mRNA sequence according to SEQ ID NO: 53 comprising a retained intron 16. In some embodiments, the ASO targets a TCF4 RIC pre-mRNA sequence according to SEQ ID NO: 54.
  • the ASO targets a TCF4 RIC pre-mRNA sequence according to SEQ ID NO: 54 comprising a retained intron 18. In some embodiments, the ASO targets a TCF4 RIC pre-mRNA sequence according to SEQ ID NO: 55. In some embodiments, the ASO targets a TCF4 RIC pre-mRNA sequence according to SEQ ID NO: 55 comprising a retained intron 17. In some embodiments, the ASO targets a TCF4 RIC pre-mRNA sequence according to SEQ ID NO: 56. In some embodiments, the ASO targets a TCF4 RIC pre-mRNA sequence according to SEQ ID NO: 56 comprising a retained intron 12.
  • the ASO targets a TCF4 RIC pre-mRNA sequence according to SEQ ID NO: 57. In some embodiments, the ASO targets a TCF4 RIC pre-mRNA sequence according to SEQ ID NO: 57 comprising a retained intron 17. In some embodiments, the ASOs disclosed herein target SEQ ID NOs: 28515 or 28516. In some embodiments, the ASO has a sequence according to any one of SEQ ID NOs: 24387-24643.
  • the ASO targets exon 10 or exon 11 of a TCF4 RIC pre-mRNA comprising a retained intron 10, wherein the intron numbering correspond to the mRNA sequence at NM_001243236.
  • the ASO targets an exon 10 sequence upstream (or 5') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 10.
  • the ASO targets an exon 10 sequence about 4 to about 134 nucleotides upstream (or 5') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 10.
  • the ASO targets an exon 11 sequence downstream (or 3') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 10. In some embodiments, the ASO targets an exon 11 sequence about 2 to about 212 nucleotides downstream (or 3 ') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 10.
  • the ASO targets intron 10 in a TCF4 RIC pre-mRNA comprising a retained intron 10, wherein the intron numbering correspond to the mRNA sequence at NM 001243236.
  • the ASO targets an intron 10 sequence downstream (or 3') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 10.
  • the ASO targets an intron 10 sequence about 6 to about 496 nucleotides downstream (or 3 ') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 10.
  • the ASO targets an intron 10 sequence upstream (or 5') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 10. In some embodiments, the ASO targets an intron 10 sequence about 16 to about 496 nucleotides upstream (or 5') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 10.
  • the ASO targets exon 10 or exon 11 of a TCF4 RIC pre-mRNA comprising a retained intron 10, wherein the intron numbering correspond to the mRNA sequence at NM_001243235.
  • the ASO targets an exon 10 sequence upstream (or 5') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 10.
  • the ASO targets an exon 10 sequence about 4 to about 134 nucleotides upstream (or 5') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 10.
  • the ASO targets an exon 11 sequence downstream (or 3') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 10. In some embodiments, the ASO targets an exon 11 sequence about 2 to about 212 nucleotides downstream (or 3 ') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 10.
  • the ASO targets intron 10 in a TCF4 RIC pre-mRNA comprising a retained intron 10, wherein the intron numbering correspond to the mRNA sequence at NM_001243235.
  • the ASO targets an intron 10 sequence downstream (or 3') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 10.
  • the ASO targets an intron 10 sequence about 6 to about 496 nucleotides downstream (or 3 ') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 10.
  • the ASO targets an intron 10 sequence upstream (or 5') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 10. In some embodiments, the ASO targets an intron 10 sequence about 16 to about 496 nucleotides upstream (or 5') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 10.
  • the ASO targets exon 10 or exon 11 of a TCF4 RIC pre-mRNA comprising a retained intron 10, wherein the intron numbering correspond to the mRNA sequence at NM_001243234.
  • the ASO targets an exon 10 sequence upstream (or 5') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 10.
  • the ASO targets an exon 10 sequence about 4 to about 144 nucleotides upstream (or 5') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 10.
  • the ASO targets an exon 11 sequence downstream (or 3') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 10. In some embodiments, the ASO targets an exon 11 sequence about 2 to about 212 nucleotides downstream (or 3 ') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 10.
  • the ASO targets intron 10 in a TCF4 RIC pre-mRNA comprising a retained intron 10, wherein the intron numbering correspond to the mRNA sequence at NM_001243234.
  • the ASO targets an intron 10 sequence downstream (or 3') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 10.
  • the ASO targets an intron 10 sequence about 6 to about 496 nucleotides downstream (or 3 ') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 10.
  • the ASO targets an intron 10 sequence upstream (or 5') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 10. In some embodiments, the ASO targets an intron 10 sequence about 16 to about 496 nucleotides upstream (or 5') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 10.
  • the ASO targets exon 13 or exon 14 of a TCF4 RIC pre-mRNA comprising a retained intron 13, wherein the intron numbering correspond to the mRNA sequence at NM_001243233.
  • the ASO targets an exon 13 sequence upstream (or 5') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 13.
  • the ASO targets an exon 13 sequence about 4 to about 134 nucleotides upstream (or 5') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 13.
  • the ASO targets an exon 14 sequence downstream (or 3') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 13. In some embodiments, the ASO targets an exon 14 sequence about 2 to about 212 nucleotides downstream (or 3 ') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 13. [0266] In some embodiments, the ASO targets intron 13 in a TCF4 RIC pre-mRNA comprising a retained intron 13, wherein the intron numbering correspond to the mRNA sequence at NM_001243233.
  • the ASO targets an intron 13 sequence downstream (or 3') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 13. In some embodiments, the ASO targets an intron 13 sequence about 6 to about 496 nucleotides downstream (or 3 ') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 13. In some embodiments, the ASO targets an intron 13 sequence upstream (or 5') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 13. In some embodiments, the ASO targets an intron 13 sequence about 16 to about 496 nucleotides upstream (or 5') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 13.
  • the ASO targets exon 13 or exon 14 of a TCF4 RIC pre-mRNA comprising a retained intron 13, wherein the intron numbering correspond to the mRNA sequence at NM_001243232.
  • the ASO targets an exon 13 sequence upstream (or 5') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 13.
  • the ASO targets an exon 13 sequence about 4 to about 144 nucleotides upstream (or 5') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 13.
  • the ASO targets an exon 14 sequence downstream (or 3') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 13. In some embodiments, the ASO targets an exon 14 sequence about 2 to about 212 nucleotides downstream (or 3 ') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 13.
  • the ASO targets intron 13 in a TCF4 RIC pre-mRNA comprising a retained intron 13, wherein the intron numbering correspond to the mRNA sequence at NM_001243232.
  • the ASO targets an intron 13 sequence downstream (or 3') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 13.
  • the ASO targets an intron 13 sequence about 6 to about 496 nucleotides downstream (or 3 ') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 13.
  • the ASO targets an intron 13 sequence upstream (or 5') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 13. In some embodiments, the ASO targets an intron 13 sequence about 16 to about 496 nucleotides upstream (or 5') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 13.
  • the ASO targets exon 15 or exon 16 of a TCF4 RIC pre-mRNA comprising a retained intron 15, wherein the intron numbering correspond to the mRNA sequence at M_001243231.
  • the ASO targets an exon 15 sequence upstream (or 5') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 15.
  • the ASO targets an exon 15 sequence about 4 to about 134 nucleotides upstream (or 5') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 15.
  • the ASO targets an exon 16 sequence downstream (or 3') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 15. In some embodiments, the ASO targets an exon 16 sequence about 2 to about 212 nucleotides downstream (or 3 ') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 15.
  • the ASO targets intron 15 in a TCF4 RIC pre-mRNA comprising a retained intron 15, wherein the intron numbering correspond to the mRNA sequence at NM_001243231.
  • the ASO targets an intron 15 sequence downstream (or 3') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 15.
  • the ASO targets an intron 15 sequence about 6 to about 496 nucleotides downstream (or 3 ') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 15.
  • the ASO targets an intron 15 sequence upstream (or 5') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 15. In some embodiments, the ASO targets an intron 15 sequence about 16 to about 496 nucleotides upstream (or 5') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 15.
  • the ASO targets exon 17 or exon 18 of a TCF4 RIC pre-mRNA comprising a retained intron 17, wherein the intron numbering correspond to the mRNA sequence at NM_003199.
  • the ASO targets an exon 17 sequence upstream (or 5') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 17.
  • the ASO targets an exon 17 sequence about 4 to about 134 nucleotides upstream (or 5') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 17.
  • the ASO targets an exon 18 sequence downstream (or 3') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 17. In some embodiments, the ASO targets an exon 18 sequence about 2 to about 212 nucleotides downstream (or 3 ') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 17.
  • the ASO targets intron 17 in a TCF4 RIC pre-mRNA comprising a retained intron 17, wherein the intron numbering correspond to the mRNA sequence at NM 003199.
  • the ASO targets an intron 17 sequence downstream (or 3') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 17.
  • the ASO targets an intron 17 sequence about 6 to about 496 nucleotides downstream (or 3 ') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 17.
  • the ASO targets an intron 17 sequence upstream (or 5') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 17. In some embodiments, the ASO targets an intron 17 sequence about 16 to about 496 nucleotides upstream (or 5') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 17.
  • the ASO targets exon 16 or exon 17 of a TCF4 RIC pre-mRNA comprising a retained intron 16, wherein the intron numbering correspond to the mRNA sequence at NM_001306207.
  • the ASO targets an exon 16 sequence upstream (or 5') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 16.
  • the ASO targets an exon 16 sequence about 4 to about 134 nucleotides upstream (or 5') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 16.
  • the ASO targets an exon 17 sequence downstream (or 3') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 16. In some embodiments, the ASO targets an exon 17 sequence about 2 to about 212 nucleotides downstream (or 3 ') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 16.
  • the ASO targets intron 16 in a TCF4 RIC pre-mRNA comprising a retained intron 16, wherein the intron numbering correspond to the mRNA sequence at NM OO 1306207.
  • the ASO targets an intron 16 sequence downstream (or 3') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 16.
  • the ASO targets an intron 16 sequence about 6 to about 496 nucleotides downstream (or 3 ') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 16.
  • the ASO targets an intron 16 sequence upstream (or 5') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 16. In some embodiments, the ASO targets an intron 16 sequence about 16 to about 496 nucleotides upstream (or 5') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 16.
  • the ASO targets exon 13 or exon 14 of a TCF4 RIC pre-mRNA comprising a retained intron 13, wherein the intron numbering correspond to the mRNA sequence at NM_001306208.
  • the ASO targets an exon 13 sequence upstream (or 5') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 13.
  • the ASO targets an exon 13 sequence about 4 to about 134 nucleotides upstream (or 5') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 13.
  • the ASO targets an exon 14 sequence downstream (or 3') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 13. In some embodiments, the ASO targets an exon 14 sequence about 2 to about 212 nucleotides downstream (or 3 ') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 13.
  • the ASO targets intron 13 in a TCF4 RIC pre-mRNA comprising a retained intron 13, wherein the intron numbering correspond to the mRNA sequence at NM OO 1306208.
  • the ASO targets an intron 13 sequence downstream (or 3') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 13.
  • the ASO targets an intron 13 sequence about 6 to about 496 nucleotides downstream (or 3 ') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 13.
  • the ASO targets an intron 13 sequence upstream (or 5') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 13. In some embodiments, the ASO targets an intron 13 sequence about 16 to about 496 nucleotides upstream (or 5') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 13.
  • the ASO targets exon 16 or exon 17 of a TCF4 RIC pre-mRNA comprising a retained intron 16, wherein the intron numbering correspond to the mRNA sequence at NM_001243227.
  • the ASO targets an exon 16 sequence upstream (or 5') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 16.
  • the ASO targets an exon 16 sequence about 4 to about 144 nucleotides upstream (or 5') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 16.
  • the ASO targets an exon 17 sequence downstream (or 3') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 16. In some embodiments, the ASO targets an exon 17 sequence about 2 to about 212 nucleotides downstream (or 3 ') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 16.
  • the ASO targets intron 16 in a TCF4 RIC pre-mRNA comprising a retained intron 16, wherein the intron numbering correspond to the mRNA sequence at NM_001243227.
  • the ASO targets an intron 16 sequence downstream (or 3') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 16.
  • the ASO targets an intron 16 sequence about 6 to about 496 nucleotides downstream (or 3 ') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 16.
  • the ASO targets an intron 16 sequence upstream (or 5') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 16. In some embodiments, the ASO targets an intron 16 sequence about 16 to about 496 nucleotides upstream (or 5') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 16.
  • the ASO targets ex on 17 or exon 18 of a TCF4 RIC pre-mRNA comprising a retained intron 17, wherein the intron numbering correspond to the mRNA sequence at NM_001243228.
  • the ASO targets an exon 17 sequence upstream (or 5') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 17.
  • the ASO targets an exon 17 sequence about 4 to about 144 nucleotides upstream (or 5') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 17.
  • the ASO targets an exon 18 sequence downstream (or 3') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 17. In some embodiments, the ASO targets an exon 18 sequence about 2 to about 212 nucleotides downstream (or 3 ') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 17.
  • the ASO targets intron 17 in a TCF4 RIC pre-mRNA comprising a retained intron 17, wherein the intron numbering correspond to the mRNA sequence at NM_001243228.
  • the ASO targets an intron 17 sequence downstream (or 3') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 17.
  • the ASO targets an intron 17 sequence about 6 to about 496 nucleotides downstream (or 3 ') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 17.
  • the ASO targets an intron 17 sequence upstream (or 5') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 17. In some embodiments, the ASO targets an intron 17 sequence about 16 to about 496 nucleotides upstream (or 5') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 17.
  • the ASO targets exon 16 or exon 17 of a TCF4 RIC pre-mRNA comprising a retained intron 16, wherein the intron numbering correspond to the mRNA sequence at NM_001243230.
  • the ASO targets an exon 16 sequence upstream (or 5') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 16.
  • the ASO targets an exon 16 sequence about 4 to about 134 nucleotides upstream (or 5') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 16.
  • the ASO targets an exon 17 sequence downstream (or 3') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 16. In some embodiments, the ASO targets an exon 17 sequence about 2 to about 212 nucleotides downstream (or 3 ') from the 3 ' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 16.
  • the ASO targets intron 16 in a TCF4 RIC pre-mRNA comprising a retained intron 16, wherein the intron numbering correspond to the mRNA sequence at NM OO 1243230.
  • the ASO targets an intron 16 sequence downstream (or 3 ') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 16.
  • the ASO targets an intron 16 sequence about 6 to about 496 nucleotides downstream (or 3 ') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 16.
  • the ASO targets an intron 16 sequence upstream (or 5') from the 3 ' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 16. In some embodiments, the ASO targets an intron 16 sequence about 16 to about 496 nucleotides upstream (or 5') from the 3 ' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 16.
  • the ASO targets exon 18 or ex on 19 of a TCF4 RIC pre-mRNA comprising a retained intron 18, wherein the intron numbering correspond to the mRNA sequence at NM_001243226.
  • the ASO targets an exon 18 sequence upstream (or 5') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 18.
  • the ASO targets an exon 18 sequence about 4 to about 144 nucleotides upstream (or 5') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 18.
  • the ASO targets an exon 19 sequence downstream (or 3 ') from the 3 ' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 18. In some embodiments, the ASO targets an exon 19 sequence about 2 to about 212 nucleotides downstream (or 3 ') from the 3 ' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 18.
  • the ASO targets intron 18 in a TCF4 RIC pre-mRNA comprising a retained intron 18, wherein the intron numbering correspond to the mRNA sequence at NM OO 1243226.
  • the ASO targets an intron 18 sequence downstream (or 3 ') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 18.
  • the ASO targets an intron 18 sequence about 6 to about 496 nucleotides downstream (or 3 ') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 18.
  • the ASO targets an intron 18 sequence upstream (or 5') from the 3 ' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 18. In some embodiments, the ASO targets an intron 18 sequence about 16 to about 496 nucleotides upstream (or 5') from the 3 ' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 18. [0285] In some embodiments, the ASO targets exon 17 or exon 18 of a TCF4 RIC pre-mRNA comprising a retained intron 17, wherein the intron numbering correspond to the mRNA sequence at NM_001083962.
  • the ASO targets an exon 17 sequence upstream (or 5') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 17. In some embodiments, the ASO targets an exon 17 sequence about 4 to about 144 nucleotides upstream (or 5') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 17. In some embodiments, the ASO targets an exon 18 sequence downstream (or 3') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 17. In some embodiments, the ASO targets an exon 18 sequence about 2 to about 212 nucleotides downstream (or 3 ') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 17.
  • the ASO targets intron 17 in a TCF4 RIC pre-mRNA comprising a retained intron 17, wherein the intron numbering correspond to the mRNA sequence at NM 001083962.
  • the ASO targets an intron 17 sequence downstream (or 3') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 17.
  • the ASO targets an intron 17 sequence about 6 to about 496 nucleotides downstream (or 3 ') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 17.
  • the ASO targets an intron 17 sequence upstream (or 5') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 17. In some embodiments, the ASO targets an intron 17 sequence about 16 to about 496 nucleotides upstream (or 5') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 17.
  • the ASO targets exon 12 or exon 13 of a TCF4 RIC pre-mRNA comprising a retained intron 12, wherein the intron numbering correspond to the mRNA sequence at NM OO 1330605.
  • the ASO targets an exon 12 sequence upstream (or 5') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 12.
  • the ASO targets an exon 12 sequence about 4 to about 144 nucleotides upstream (or 5') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 12.
  • the ASO targets an exon 13 sequence downstream (or 3') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 12. In some embodiments, the ASO targets an exon 13 sequence about 2 to about 212 nucleotides downstream (or 3 ') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 12.
  • the ASO targets intron 12 in a TCF4 RIC pre-mRNA comprising a retained intron 12, wherein the intron numbering correspond to the mRNA sequence at NM 001330605.
  • the ASO targets an intron 12 sequence downstream (or 3') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 12.
  • the ASO targets an intron 12 sequence about 6 to about 496 nucleotides downstream (or 3 ') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 12.
  • the ASO targets an intron 12 sequence upstream (or 5') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 12. In some embodiments, the ASO targets an intron 12 sequence about 16 to about 496 nucleotides upstream (or 5') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 12.
  • the ASO targets exon 17 or exon 18 of a TCF4 RIC pre-mRNA comprising a retained intron 17, wherein the intron numbering correspond to the mRNA sequence at NM_001330604.
  • the ASO targets an exon 17 sequence upstream (or 5') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 17.
  • the ASO targets an exon 17 sequence about 4 to about 144 nucleotides upstream (or 5') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 17.
  • the ASO targets an exon 18 sequence downstream (or 3') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 17. In some embodiments, the ASO targets an exon 18 sequence about 2 to about 212 nucleotides downstream (or 3 ') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 17.
  • the ASO targets intron 17 in a TCF4 RIC pre-mRNA comprising a retained intron 17, wherein the intron numbering correspond to the mRNA sequence at NM OO 1330604.
  • the ASO targets an intron 17 sequence downstream (or 3') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 17.
  • the ASO targets an intron 17 sequence about 6 to about 496 nucleotides downstream (or 3 ') from the 5' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 17.
  • the ASO targets an intron 17 sequence upstream (or 5') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 17. In some embodiments, the ASO targets an intron 17 sequence about 16 to about 496 nucleotides upstream (or 5') from the 3' splice site of a TCF4 RIC pre-mRNA comprising the retained intron 17.
  • the ASOs disclosed herein target a RIC pre-mRNA transcribed from a NPC1 genomic sequence. In some embodiments, the ASO targets a RIC pre-mRNA transcript from a NPCl genomic sequence comprising a retained intron. In some embodiments, the ASO targets a RIC pre-mRNA transcript of SEQ ID NO: 14. In some embodiments, the ASO targets a RIC pre-mRNA transcript of SEQ ID NO: 14 comprising a retained intron. In some embodiments, the ASOs disclosed herein target a NPC1 RIC pre-mRNA sequence. In some embodiments, the ASO targets a NPC1 RIC pre-mRNA transcript comprising a retained intron at 15, wherein the intron numbering correspond to the mRNA sequence at NM_000271.
  • the ASO targets a NPC1 RIC pre-mRNA sequence according to SEQ ID NO: 58. In some embodiments, the ASO targets a NPC1 RIC pre-mRNA sequence according to SEQ ID NO: 58 comprising a retained intron 15. In some embodiments, the ASOs disclosed herein target SEQ ID NO: 24382. In some embodiments, the ASO has a sequence according to any one of SEQ ID NOs: 13692-13760.
  • the ASO targets exon 15 or exon 16 of a NPCl RIC pre-mRNA comprising a retained intron 15, wherein the intron numbering correspond to the mRNA sequence at NM_000271.
  • the ASO targets an exon 15 sequence upstream (or 5') from the 5' splice site of a NPC1 RIC pre-mRNA comprising the retained intron 15.
  • the ASO targets an exon 15 sequence about 4 to about 109 nucleotides upstream (or 5') from the 5' splice site of a NPCl RIC pre-mRNA comprising the retained intron 15.
  • the ASO targets an exon 16 sequence downstream (or 3 ') from the 3' splice site of a NPC1 RIC pre-mRNA comprising the retained intron 15. In some embodiments, the ASO targets an exon 16 sequence about 2 to about 122 nucleotides downstream (or 3 ') from the 3' splice site of a NPCl RIC pre-mRNA comprising the retained intron 15.
  • the ASO targets intron 15 in a NPCl RIC pre-mRNA comprising a retained intron 15, wherein the intron numbering correspond to the mRNA sequence at NM 000271.
  • the ASO targets an intron 15 sequence downstream (or 3') from the 5' splice site of a NPC1 RIC pre-mRNA comprising the retained intron 15.
  • the ASO targets an intron 15 sequence about 6 to about 61 nucleotides downstream (or 3 ') from the 5' splice site of a NPCl RIC pre-mRNA comprising the retained intron 15.
  • the ASO targets an intron 15 sequence upstream (or 5') from the 3' splice site of a NPCl RIC pre-mRNA comprising the retained intron 15. In some embodiments, the ASO targets an intron 15 sequence about 16 to about 61 nucleotides upstream (or 5') from the 3' splice site of a NPCl RIC pre-mRNA comprising the retained intron 15.
  • the ASOs disclosed herein target a RIC pre-mRNA transcribed from a CACNAIA genomic sequence. In some embodiments, the ASO targets a RIC pre-mRNA transcript from a CACNAIA genomic sequence comprising a retained intron. In some embodiments, the ASO targets a RIC pre-mRNA transcript of SEQ ID NO: 15. In some embodiments, the ASO targets a RIC pre-mRNA transcript of SEQ ID NO: 15 comprising a retained intron. In some embodiments, the ASOs disclosed herein target a CACNA1A RIC pre- mRNA sequence.
  • the ASO targets a CACNA1A RIC pre-mRNA transcript comprising a retained intron at 36, 37 or a combination thereof, wherein the intron numbering correspond to the mRNA sequence at NM 000068. In some embodiments, the ASO targets a CACNA1A RIC pre-mRNA transcript comprising a retained intron at 36, 37 or a combination thereof, wherein the intron numbering correspond to the mRNA sequence at NM_023035. In some embodiments, the ASO targets a CACNA1A RIC pre-mRNA transcript comprising a retained intron at 36, 37 or a combination thereof, wherein the intron numbering correspond to the mRNA sequence at NM_001174080.
  • the ASO targets a CACNA1A RIC pre-mRNA transcript comprising a retained intron at 36, 37 or a combination thereof, wherein the intron numbering correspond to the mRNA sequence at NM_001127222. In some embodiments, the ASO targets a CACNA1A RIC pre-mRNA transcript comprising a retained intron at 36, 37 or a combination thereof, wherein the intron numbering correspond to the mRNA sequence at NM_001127221.
  • the ASO targets a CACNA1A RIC pre-mRNA sequence according to SEQ ID NO: 59. In some embodiments, the ASO targets a CACNA1A RIC pre-mRNA sequence according to SEQ ID NO: 59 comprising a retained intron 36, a retained intron 37, or a combination thereof. In some embodiments, the ASO targets a CACNA1A RIC pre-mRNA sequence according to SEQ ID NO: 60. In some embodiments, the ASO targets a CACNA1A RIC pre-mRNA sequence according to SEQ ID NO: 69 comprising a retained intron 36, a retained intron 37, or a combination thereof. In some embodiments, the ASO targets a
  • CACNA1A RIC pre-mRNA sequence according to SEQ ID NO: 61 In some embodiments, the ASO targets a CACNA1A RIC pre-mRNA sequence according to SEQ ID NO: 61 comprising a retained intron 36, a retained intron 37, or a combination thereof. In some embodiments, the ASO targets a CACNA1A RIC pre-mRNA sequence according to SEQ ID NO: 62. In some embodiments, the ASO targets a CACNA1A RIC pre-mRNA sequence according to SEQ ID NO: 62 comprising a retained intron 36, a retained intron 37, or a combination thereof.
  • the ASO targets a CACNA1A RIC pre-mRNA sequence according to SEQ ID NO: 63. In some embodiments, the ASO targets a CACNA1A RIC pre-mRNA sequence according to SEQ ID NO: 63 comprising a retained intron 36, a retained intron 37, or a combination thereof. In some embodiments, the ASOs disclosed herein target SEQ ID NOs: 24366, 24374, 24377, or 24384. In some embodiments, the ASO has a sequence according to any one of SEQ ID NOs: 13761-15914.
  • the ASO targets exon 36 or exon 37 of a CACNA1A RIC pre- mRNA comprising a retained intron 36, wherein the intron numbering correspond to the mRNA sequence at NM_000068.
  • the ASO targets an exon 36 sequence upstream (or 5') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 36.
  • the ASO targets an exon 36 sequence about 4 to about 110 nucleotides upstream (or 5') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 36.
  • the ASO targets an exon 37 sequence downstream (or 3') from the 3' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 36. In some embodiments, the ASO targets an exon 37 sequence about 2 to about 79 nucleotides downstream (or 3 ') from the 3' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 36.
  • the ASO targets intron 36 in a CACNA1A RIC pre-mRNA comprising a retained intron 36, wherein the intron numbering correspond to the mRNA sequence at NM_000068.
  • the ASO targets an intron 36 sequence downstream (or 3 ') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 36.
  • the ASO targets an intron 36 sequence about 6 to about 499 nucleotides downstream (or 3 ') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 36.
  • the ASO targets an intron 36 sequence upstream (or 5') from the 3' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 36. In some embodiments, the ASO targets an intron 36 sequence about 16 to about 498 nucleotides upstream (or 5') from the 3' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 36.
  • the ASO targets exon 37 or exon 38 of a CACNA1A RIC pre- mRNA comprising a retained intron 37, wherein the intron numbering correspond to the mRNA sequence at NM_000068.
  • the ASO targets an exon 37 sequence upstream (or 5') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37.
  • the ASO targets an exon 37 sequence about 4 to about 78 nucleotides upstream (or 5') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37.
  • the ASO targets an exon 38 sequence downstream (or 3') from the 3' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37. In some embodiments, the ASO targets an exon 38 sequence about 2 to about 87 nucleotides downstream (or 3 ') from the 3' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37.
  • the ASO targets intron 37 in a CACNA1A RIC pre-mRNA comprising a retained intron 37, wherein the intron numbering correspond to the mRNA sequence at NM_000068.
  • the ASO targets an intron 37 sequence downstream (or 3 ') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37.
  • the ASO targets an intron 37 sequence about 6 to about 500 nucleotides downstream (or 3 ') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37.
  • the ASO targets an intron 37 sequence upstream (or 5') from the 3' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37. In some embodiments, the ASO targets an intron 37 sequence about 16 to about 498 nucleotides upstream (or 5') from the 3' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37.
  • the ASO targets exon 36 or exon 37 of a CACNA1A RIC pre- mRNA comprising a retained intron 36, wherein the intron numbering correspond to the mRNA sequence at NM_023035.
  • the ASO targets an exon 36 sequence upstream (or 5') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 36.
  • the ASO targets an exon 36 sequence about 4 to about 110 nucleotides upstream (or 5') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 36.
  • the ASO targets an exon 37 sequence downstream (or 3') from the 3' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 36. In some embodiments, the ASO targets an exon 37 sequence about 2 to about 79 nucleotides downstream (or 3 ') from the 3' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 36.
  • the ASO targets intron 36 in a CACNA1A RIC pre-mRNA comprising a retained intron 36, wherein the intron numbering correspond to the mRNA sequence at NM_023035.
  • the ASO targets an intron 36 sequence downstream (or 3 ') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 36.
  • the ASO targets an intron 36 sequence about 6 to about 499 nucleotides downstream (or 3 ') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 36.
  • the ASO targets an intron 36 sequence upstream (or 5') from the 3' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 36. In some embodiments, the ASO targets an intron 36 sequence about 16 to about 498 nucleotides upstream (or 5') from the 3' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 36.
  • the ASO targets exon 37 or exon 38 of a CACNA1A RIC pre- mRNA comprising a retained intron 37, wherein the intron numbering correspond to the mRNA sequence at NM_023035.
  • the ASO targets an exon 37 sequence upstream (or 5') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37.
  • the ASO targets an exon 37 sequence about 4 to about 78 nucleotides upstream (or 5') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37.
  • the ASO targets an exon 38 sequence downstream (or 3') from the 3' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37. In some embodiments, the ASO targets an exon 38 sequence about 2 to about 87 nucleotides downstream (or 3 ') from the 3' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37.
  • the ASO targets intron 37 in a CACNA1A RIC pre-mRNA comprising a retained intron 37, wherein the intron numbering correspond to the mRNA sequence at NM_023035.
  • the ASO targets an intron 37 sequence downstream (or 3 ') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37.
  • the ASO targets an intron 37 sequence about 6 to about 500 nucleotides downstream (or 3 ') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37.
  • the ASO targets an intron 37 sequence upstream (or 5') from the 3' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37. In some embodiments, the ASO targets an intron 37 sequence about 16 to about 498 nucleotides upstream (or 5') from the 3' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37.
  • the ASO targets exon 36 or exon 37 of a CACNA1A RIC pre- mRNA comprising a retained intron 36, wherein the intron numbering correspond to the mRNA sequence at NM OO 1174080.
  • the ASO targets an exon 36 sequence upstream (or 5') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 36.
  • the ASO targets an exon 36 sequence about 4 to about 110 nucleotides upstream (or 5') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 36.
  • the ASO targets an exon 37 sequence downstream (or 3') from the 3' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 36. In some embodiments, the ASO targets an exon 37 sequence about 2 to about 79 nucleotides downstream (or 3 ') from the 3' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 36.
  • the ASO targets intron 36 in a CACNA1A RIC pre-mRNA comprising a retained intron 36, wherein the intron numbering correspond to the mRNA sequence at NM OOl 174080.
  • the ASO targets an intron 36 sequence downstream (or 3 ') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 36.
  • the ASO targets an intron 36 sequence about 6 to about 499 or about 16 to about 499 nucleotides downstream (or 3 ') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 36.
  • the ASO targets an intron 36 sequence upstream (or 5') from the 3' splice site of a CACNA1A RIC pre- mRNA comprising the retained intron 36. In some embodiments, the ASO targets an intron 36 sequence about 16 to about 498 nucleotides upstream (or 5') from the 3' splice site of a
  • CACNA1A RIC pre-mRNA comprising the retained intron 36.
  • the ASO targets exon 37 or exon 38 of a CACNA1A RIC pre- mRNA comprising a retained intron 37, wherein the intron numbering correspond to the mRNA sequence at NM_001174080.
  • the ASO targets an exon 37 sequence upstream (or 5') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37.
  • the ASO targets an exon 37 sequence about 4 to about 78 nucleotides upstream (or 5') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37.
  • the ASO targets an exon 38 sequence downstream (or 3') from the 3' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37. In some embodiments, the ASO targets an exon 38 sequence about 2 to about 87 nucleotides downstream (or 3 ') from the 3' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37.
  • the ASO targets intron 37 in a CACNA1A RIC pre-mRNA comprising a retained intron 37, wherein the intron numbering correspond to the mRNA sequence at NM OOl 174080.
  • the ASO targets an intron 37 sequence downstream (or 3 ') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37.
  • the ASO targets an intron 37 sequence about 6 to about 500 nucleotides downstream (or 3 ') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37.
  • the ASO targets an intron 37 sequence upstream (or 5') from the 3' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37. In some embodiments, the ASO targets an intron 37 sequence about 16 to about 498 nucleotides upstream (or 5') from the 3' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37.
  • the ASO targets exon 36 or exon 37 of a CACNA1A RIC pre- mRNA comprising a retained intron 36, wherein the intron numbering correspond to the mRNA sequence at NM_001127222.
  • the ASO targets an exon 36 sequence upstream (or 5') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 36.
  • the ASO targets an exon 36 sequence about 4 to about 110 or about 14 to about 110 nucleotides upstream (or 5') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 36.
  • the ASO targets an exon 37 sequence downstream (or 3') from the 3' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 36. In some embodiments, the ASO targets an exon 37 sequence about 2 to about 79 nucleotides downstream (or 3') from the 3' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 36.
  • the ASO targets intron 36 in a CACNAJA RIC pre-mRNA comprising a retained intron 36, wherein the intron numbering correspond to the mRNA sequence at NM_001127222.
  • the ASO targets an intron 36 sequence downstream (or 3 ') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 36.
  • the ASO targets an intron 36 sequence about 6 to about 499 or about 16 to about 499 nucleotides downstream (or 3') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 36.
  • the ASO targets an intron 36 sequence upstream (or 5') from the 3' splice site of a CACNA1A RIC pre- mRNA comprising the retained intron 36. In some embodiments, the ASO targets an intron 36 sequence about 16 to about 498 nucleotides upstream (or 5') from the 3' splice site of a
  • CACNA1A RIC pre-mRNA comprising the retained intron 36.
  • the ASO targets exon 37 or exon 38 of a CACNA1A RIC pre- mRNA comprising a retained intron 37, wherein the intron numbering correspond to the mRNA sequence at NM_001127222.
  • the ASO targets an exon 37 sequence upstream (or 5') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37.
  • the ASO targets an exon 37 sequence about 4 to about 78 nucleotides upstream (or 5') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37.
  • the ASO targets an exon 38 sequence downstream (or 3') from the 3' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37. In some embodiments, the ASO targets an exon 38 sequence about 2 to about 87 nucleotides downstream (or 3 ') from the 3' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37.
  • the ASO targets intron 37 in a CACNA1A RIC pre-mRNA comprising a retained intron 37, wherein the intron numbering correspond to the mRNA sequence at NM_001127222.
  • the ASO targets an intron 37 sequence downstream (or 3 ') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37.
  • the ASO targets an intron 37 sequence about 6 to about 500 nucleotides downstream (or 3 ') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37.
  • the ASO targets an intron 37 sequence upstream (or 5') from the 3' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37. In some embodiments, the ASO targets an intron 37 sequence about 16 to about 498 nucleotides upstream (or 5') from the 3' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37. [0313] In some embodiments, the ASO targets exon 36 or exon 37 of a CACNA1A RIC pre- mRNA comprising a retained intron 36, wherein the intron numbering correspond to the mRNA sequence at NM_001127221.
  • the ASO targets an exon 36 sequence upstream (or 5') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 36. In some embodiments, the ASO targets an exon 36 sequence about 14 to about 110 nucleotides upstream (or 5') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 36. In some embodiments, the ASO targets an exon 37 sequence downstream (or 3') from the 3' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 36. In some embodiments, the ASO targets an exon 37 sequence about 2 to about 77 nucleotides downstream (or 3 ') from the 3' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 36.
  • the ASO targets intron 36 in a CACNAJA RIC pre-mRNA comprising a retained intron 36, wherein the intron numbering correspond to the mRNA sequence at NM_001127221.
  • the ASO targets an intron 36 sequence downstream (or 3 ') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 36.
  • the ASO targets an intron 36 sequence about 6 to about 499 or about 16 to about 499 nucleotides downstream (or 3 ') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 36.
  • the ASO targets an intron 36 sequence upstream (or 5') from the 3' splice site of a CACNA1A RIC pre- mRNA comprising the retained intron 36. In some embodiments, the ASO targets an intron 36 sequence about 16 to about 499 or about 21 to about 499 nucleotides upstream (or 5') from the 3' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 36.
  • the ASO targets exon 37 or exon 38 of a CACNA1A RIC pre- mRNA comprising a retained intron 37, wherein the intron numbering correspond to the mRNA sequence at NM_001127221.
  • the ASO targets an exon 37 sequence upstream (or 5') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37.
  • the ASO targets an exon 37 sequence about 4 to about 79 nucleotides upstream (or 5') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37.
  • the ASO targets an exon 38 sequence downstream (or 3') from the 3' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37. In some embodiments, the ASO targets an exon 38 sequence about 2 to about 87 nucleotides downstream (or 3 ') from the 3' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37.
  • the ASO targets intron 37 in a CACNA1A RIC pre-mRNA comprising a retained intron 37, wherein the intron numbering correspond to the mRNA sequence at NM_001127221.
  • the ASO targets an intron 37 sequence downstream (or 3 ') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37.
  • the ASO targets an intron 37 sequence about 6 to about 500 nucleotides downstream (or 3 ') from the 5' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37.
  • the ASO targets an intron 37 sequence upstream (or 5') from the 3' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37. In some embodiments, the ASO targets an intron 37 sequence about 16 to about 498 nucleotides upstream (or 5') from the 3' splice site of a CACNA1A RIC pre-mRNA comprising the retained intron 37.
  • the ASOs disclosed herein target a RIC pre-mRNA transcribed from a DNMTl genomic sequence. In some embodiments, the ASO targets a RIC pre-mRNA transcript from a DNMTl genomic sequence comprising a retained intron. In some
  • the ASO targets a RIC pre-mRNA transcript of SEQ ID NO: 16. In some embodiments, the ASO targets a RIC pre-mRNA transcript of SEQ ID NO: 16 comprising a retained intron. In some embodiments, the ASOs disclosed herein target a DNMTl RIC pre- mRNA sequence. In some embodiments, the ASO targets a DNMTl RIC pre-mRNA transcript comprising a retained intron at 14, 29 or a combination thereof, wherein the intron numbering correspond to the mRNA sequence at NM 001379.
  • the ASO targets a DNMTl RIC pre-mRNA transcript comprising a retained intron at 15, 30 or a combination thereof, wherein the intron numbering correspond to the mRNA sequence at NM 001130823. In some embodiments, the ASO targets a DNMTl RIC pre-mRNA transcript comprising a retained intron at 14, 29 or a combination thereof, wherein the intron numbering correspond to the mRNA sequence at NM_001318730. In some embodiments, the ASO targets a DNMTl RIC pre-mRNA transcript comprising a retained intron at 15, 30 or a combination thereof, wherein the intron numbering correspond to the mRNA sequence at NM_001318731.
  • the ASO targets a, DNMTl RIC pre-mRNA sequence according to SEQ ID NO: 64. In some embodiments, the ASO targets a DNMTl RIC pre-mRNA sequence according to SEQ ID NO: 64 comprising a retained intron 14, a retained intron 29, or a combination thereof. In some embodiments, the ASO targets a DNMTl RIC pre-mRNA sequence according to SEQ ID NO: 65. In some embodiments, the ASO targets a DNMTl RIC pre-mRNA sequence according to SEQ ID NO: 65 comprising a retained intron 15, a retained intron 30, or a combination thereof.
  • the ASO targets a DNMTl RIC pre- mRNA sequence according to SEQ ID NO: 66. In some embodiments, the ASO targets a DNMTl RIC pre-mRNA sequence according to SEQ ID NO: 66 comprising a retained intron 14, a retained intron 29, or a combination thereof. In some embodiments, the ASO targets a DNMTl RIC pre-mRNA sequence according to SEQ ID NO: 67. In some embodiments, the ASO targets a DNMTl RIC pre-mRNA sequence according to SEQ ID NO: 67 comprising a retained intron 15, a retained intron 30, or a combination thereof. In some embodiments, the ASOs disclosed herein target SEQ ID NOs: 24362 or 24371. In some embodiments, the ASO has a sequence according to any one of SEQ ID NOs: 15915-16930.
  • the ASO targets exon 29 or exon 30 of a DNMTl RIC pre-mRNA comprising a retained intron 29, wherein the intron numbering correspond to the mRNA sequence at NM_001379.
  • the ASO targets an exon 29 sequence upstream (or 5') from the 5' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 29.
  • the ASO targets an exon 29 sequence about 4 to about 173 nucleotides upstream (or 5') from the 5' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 29.
  • the ASO targets an exon 30 sequence downstream (or 3') from the 3' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 29. In some embodiments, the ASO targets an exon 30 sequence about 2 to about 67 nucleotides downstream (or 3') from the 3' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 29.
  • the ASO targets intron 29 in a DNMTl RIC pre-mRNA comprising a retained intron 29, wherein the intron numbering correspond to the mRNA sequence at NM_001379.
  • the ASO targets an intron 29 sequence downstream (or 3 ') from the 5' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 29.
  • the ASO targets an intron 29 sequence about 6 to about 429 nucleotides downstream (or 3') from the 5' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 29.
  • the ASO targets an intron 29 sequence upstream (or 5') from the 3' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 29. In some embodiments, the ASO targets an intron 29 sequence about 16 to about 433 nucleotides upstream (or 5') from the 3' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 29.
  • the ASO targets exon 14 or exon 15 of a DNMTl RIC pre-mRNA comprising a retained intron 14, wherein the intron numbering correspond to the mRNA sequence at NM_001379.
  • the ASO targets an exon 14 sequence upstream (or 5') from the 5' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 14.
  • the ASO targets an exon 14 sequence about 4 to about 29 nucleotides upstream (or 5') from the 5' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 14.
  • the ASO targets an exon 15 sequence downstream (or 3') from the 3' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 14. In some embodiments, the ASO targets an ex on 15 sequence about 2 to about 62 nucleotides downstream (or 3') from the 3' splice site of a DNMT1 RIC pre-mRNA comprising the retained intron 14.
  • the ASO targets intron 14 in a DNMT1 RIC pre-mRNA comprising a retained intron 14, wherein the intron numbering correspond to the mRNA sequence at M_001379.
  • the ASO targets an intron 14 sequence downstream (or 3 ') from the 5' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 14.
  • the ASO targets an intron 14 sequence about 6 to about 61 nucleotides downstream (or 3') from the 5' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 14.
  • the ASO targets an intron 14 sequence upstream (or 5') from the 3' splice site of a DNMT1 RIC pre-mRNA comprising the retained intron 14. In some embodiments, the ASO targets an intron 14 sequence about 16 to about 61 nucleotides upstream (or 5') from the 3' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 14.
  • the ASO targets exon 30 or exon 31 of a DNMTl RIC pre-mRNA comprising a retained intron 30, wherein the intron numbering correspond to the mRNA sequence at NM OO 1130823.
  • the ASO targets an exon 30 sequence upstream (or 5') from the 5' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 30.
  • the ASO targets an exon 30 sequence about 4 to about 173 nucleotides upstream (or 5') from the 5' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 30.
  • the ASO targets an exon 31 sequence downstream (or 3') from the 3' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 30. In some embodiments, the ASO targets an exon 31 sequence about 2 to about 67 nucleotides downstream (or 3 ') from the 3' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 30.
  • the ASO targets intron 30 in a DNMTl RIC pre-mRNA comprising a retained intron 30, wherein the intron numbering correspond to the mRNA sequence at NM OOl 130823.
  • the ASO targets an intron 30 sequence downstream (or 3 ') from the 5' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 30.
  • the ASO targets an intron 30 sequence about 6 to about 429 or about 11 to about 429 nucleotides downstream (or 3') from the 5' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 30.
  • the ASO targets an intron 30 sequence upstream (or 5') from the 3' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 30. In some embodiments, the ASO targets an intron 30 sequence about 16 to about 433 nucleotides upstream (or 5') from the 3' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 30. [0325] In some embodiments, the ASO targets exon 15 or exon 16 of a DNMTl RIC pre-mRNA comprising a retained intron 15, wherein the intron numbering correspond to the mRNA sequence at NM OO 1130823.
  • the ASO targets an exon 15 sequence upstream (or 5') from the 5' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 15. In some embodiments, the ASO targets an exon 15 sequence about 4 to about 29 nucleotides upstream (or 5') from the 5' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 15. In some embodiments, the ASO targets an exon 16 sequence downstream (or 3') from the 3' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 15. In some embodiments, the ASO targets an exon 16 sequence about 2 to about 62 nucleotides downstream (or 3 ') from the 3' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 15.
  • the ASO targets intron 15 in a DNMTl RIC pre-mRNA comprising a retained intron 15, wherein the intron numbering correspond to the mRNA sequence at NM OOl 130823.
  • the ASO targets an intron 15 sequence downstream (or 3 ') from the 5' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 15.
  • the ASO targets an intron 15 sequence about 6 to about 61 nucleotides downstream (or 3') from the 5' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 15.
  • the ASO targets an intron 15 sequence upstream (or 5') from the 3' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 15. In some embodiments, the ASO targets an intron 15 sequence about 16 to about 61 nucleotides upstream (or 5') from the 3' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 15.
  • the ASO targets exon 29 or exon 30 of a DNMTl RIC pre-mRNA comprising a retained intron 29, wherein the intron numbering correspond to the mRNA sequence at NM 001318730.
  • the ASO targets an exon 29 sequence upstream (or 5') from the 5' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 29.
  • the ASO targets an exon 29 sequence about 4 to about 173 nucleotides upstream (or 5') from the 5' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 29.
  • the ASO targets an exon 30 sequence downstream (or 3') from the 3' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 29. In some embodiments, the ASO targets an exon 30 sequence about 2 to about 67 nucleotides downstream (or 3 ') from the 3' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 29.
  • the ASO targets intron 29 in a DNMTl RIC pre-mRNA comprising a retained intron 29, wherein the intron numbering correspond to the mRNA sequence at M 001318730.
  • the ASO targets an intron 29 sequence downstream (or 3 ') from the 5' splice site of a, DNMTl RIC pre-mRNA comprising the retained intron 29.
  • the ASO targets an intron 29 sequence about 6 to about 429 or about 11 to about 429 nucleotides downstream (or 3') from the 5' splice site of a, DNMTl RIC pre-mRNA comprising the retained intron 29.
  • the ASO targets an intron 29 sequence upstream (or 5') from the 3' splice site of a, DNMTl RIC pre-mRNA comprising the retained intron 29. In some embodiments, the ASO targets an intron 29 sequence about 16 to about 433 nucleotides upstream (or 5') from the 3' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 29.
  • the ASO targets exon 14 or exon 15 of a DNMTl RIC pre-mRNA comprising a retained intron 14, wherein the intron numbering correspond to the mRNA sequence at NM 001318730.
  • the ASO targets an exon 14 sequence upstream (or 5') from the 5' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 14.
  • the ASO targets an exon 14 sequence about 4 to about 29 nucleotides upstream (or 5') from the 5' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 14.
  • the ASO targets an exon 15 sequence downstream (or 3') from the 3' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 14. In some embodiments, the ASO targets an exon 15 sequence about 2 to about 62 nucleotides downstream (or 3 ') from the 3' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 14.
  • the ASO targets intron 14 in a DNMTl RIC pre-mRNA comprising a retained intron 14, wherein the intron numbering correspond to the mRNA sequence at NM 001318730.
  • the ASO targets an intron 14 sequence downstream (or 3 ') from the 5' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 14.
  • the ASO targets an intron 14 sequence about 6 to about 61 nucleotides downstream (or 3') from the 5' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 14.
  • the ASO targets an intron 14 sequence upstream (or 5') from the 3' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 14. In some embodiments, the ASO targets an intron 14 sequence about 16 to about 61 nucleotides upstream (or 5') from the 3' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 14.
  • the ASO targets exon 30 or exon 31 of a DNMTl RIC pre-mRNA comprising a retained intron 30, wherein the intron numbering correspond to the mRNA sequence at NM 001318731.
  • the ASO targets an exon 30 sequence upstream (or 5') from the 5' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 30.
  • the ASO targets an exon 30 sequence about 4 to about 173 nucleotides upstream (or 5') from the 5' splice site of a DNMTI RIC pre-mRNA comprising the retained intron 30.
  • the ASO targets an exon 31 sequence downstream (or 3') from the 3' splice site of a DNMTI RIC pre-mRNA comprising the retained intron 30. In some embodiments, the ASO targets an exon 31 sequence about 2 to about 67 nucleotides downstream (or 3 ') from the 3' splice site of a DNMTI RIC pre-mRNA comprising the retained intron 30.
  • the ASO targets intron 30 in a DNMTI RIC pre-mRNA comprising a retained intron 30, wherein the intron numbering correspond to the mRNA sequence at NM 001318731.
  • the ASO targets an intron 30 sequence downstream (or 3 ') from the 5' splice site of a DNMTI RIC pre-mRNA comprising the retained intron 30.
  • the ASO targets an intron 30 sequence about 6 to about 429 or about 11 to about 429 nucleotides downstream (or 3') from the 5' splice site of a DNMTI RIC pre-mRNA comprising the retained intron 30.
  • the ASO targets an intron 30 sequence upstream (or 5') from the 3' splice site of a DNMTI RIC pre-mRNA comprising the retained intron 30. In some embodiments, the ASO targets an intron 30 sequence about 16 to about 433 nucleotides upstream (or 5') from the 3' splice site of a DNMTI RIC pre-mRNA comprising the retained intron 30.
  • the ASO targets exon 15 or exon 16 of a DNMTI RIC pre-mRNA comprising a retained intron 15, wherein the intron numbering correspond to the mRNA sequence at NM 001318731.
  • the ASO targets an exon 15 sequence upstream (or 5') from the 5' splice site of a DNMTI RIC pre-mRNA comprising the retained intron 15.
  • the ASO targets an exon 15 sequence about 4 to about 29 nucleotides upstream (or 5') from the 5' splice site of a DNMTI RIC pre-mRNA comprising the retained intron 15.
  • the ASO targets an exon 16 sequence downstream (or 3') from the 3' splice site of a DNMTI RIC pre-mRNA comprising the retained intron 15. In some embodiments, the ASO targets an exon 16 sequence about 2 to about 62 nucleotides downstream (or 3 ') from the 3' splice site of a DNMTI RIC pre-mRNA comprising the retained intron 15.
  • the ASO targets intron 15 in a DNMTI RIC pre-mRNA comprising a retained intron 15, wherein the intron numbering correspond to the mRNA sequence at NM 001318731.
  • the ASO targets an intron 15 sequence downstream (or 3 ') from the 5' splice site of a DNMTI RIC pre-mRNA comprising the retained intron 15.
  • the ASO targets an intron 15 sequence about 6 to about 61 nucleotides downstream (or 3') from the 5' splice site of a DNMTI RIC pre-mRNA comprising the retained intron 15.
  • the ASO targets an intron 15 sequence upstream (or 5') from the 3' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 15. In some embodiments, the ASO targets an intron 15 sequence about 16 to about 61 nucleotides upstream (or 5') from the 3' splice site of a DNMTl RIC pre-mRNA comprising the retained intron 15.
  • the ASOs disclosed herein target a RIC pre-mRNA transcribed from a NF2 genomic sequence. In some embodiments, the ASO targets a RIC pre-mRNA transcript from a NF2 genomic sequence comprising a retained intron. In some embodiments, the ASO targets a RIC pre-mRNA transcript of SEQ ID NO: 17. In some embodiments, the ASO targets a RIC pre-mRNA transcript of SEQ ID NO: 17 comprising a retained intron. In some embodiments, the ASOs disclosed herein target a NF2 RIC pre-mRNA sequence. In some embodiments, the ASO targets a NF2 RIC pre-mRNA transcript comprising a retained intron at
  • the ASO targets a NF2 RIC pre-mRNA transcript comprising a retained intron at
  • the ASO targets a NF2 RIC pre-mRNA transcript comprising a retained intron at 4, wherein the intron numbering correspond to the mRNA sequence at NM_181833. In some embodiments, the ASO targets a NF2 RIC pre-mRNA transcript comprising a retained intron at
  • the ASO targets a NF2 RIC pre-mRNA transcript comprising a retained intron at
  • the ASO targets a NF2 RIC pre-mRNA transcript comprising a retained intron at
  • the ASO targets a NF2 RIC pre-mRNA transcript comprising a retained intron at 15, wherein the intron numbering correspond to the mRNA sequence at NM_000268.
  • the ASO targets a NF2 RIC pre-mRNA sequence according to SEQ ID NO: 68. In some embodiments, the ASO targets a NF2 RIC pre-mRNA sequence according to SEQ ID NO: 68 comprising a retained intron 14. In some embodiments, the ASO targets a NF2 RIC pre-mRNA sequence according to SEQ ID NO: 69. In some embodiments, the ASO targets a NF2 RIC pre-mRNA sequence according to SEQ ID NO: 69 comprising a retained intron 15. In some embodiments, the ASO targets a NF2 RIC pre-mRNA sequence according to SEQ ID NO: 70.
  • the ASO targets a NF2 RIC pre-mRNA sequence according to SEQ ID NO: 70 comprising a retained intron 4. In some embodiments, the ASO targets a NF2 RIC pre-mRNA sequence according to SEQ ID NO: 71. In some embodiments, the ASO targets a NF2 RIC pre-mRNA sequence according to SEQ ID NO: 71
  • the ASO targets a NF2 RIC pre-mRNA sequence according to SEQ ID NO: 72. In some embodiments, the ASO targets a NF2 RIC pre- mRNA sequence according to SEQ ID NO: 72 comprising a retained intron 15. In some embodiments, the ASO targets a NF2 RIC pre-mRNA sequence according to SEQ ID NO: 73. In some embodiments, the ASO targets a NF2 RIC pre-mRNA sequence according to SEQ ID NO: 73 comprising a retained intron 16. In some embodiments, the ASO targets a NF2 RIC pre- mRNA sequence according to SEQ ID NO: 74.
  • the ASO targets a NF2 RIC pre-mRNA sequence according to SEQ ID NO: 74 comprising a retained intron 15.
  • the ASOs disclosed herein target SEQ ID NOs: 24373, 24367, 24352 or 24368.
  • the ASO has a sequence according to any one of SEQ ID NOs: 16931- 23347.
  • the ASO targets exon 14 or exon 15 of a NF2 RIC pre-mRNA comprising a retained intron 14, wherein the intron numbering correspond to the mRNA sequence at NM_181830.
  • the ASO targets an exon 14 sequence upstream (or 5') from the 5' splice site of a NF2 RIC pre-mRNA comprising the retained intron 14.
  • the ASO targets an exon 14 sequence about 4 to about 24 nucleotides upstream (or 5') from the 5' splice site of a NF2 RIC pre-mRNA comprising the retained intron 14.
  • the ASO targets an exon 15 sequence downstream (or 3') from the 3' splice site of a NF2 RIC pre-mRNA comprising the retained intron 14. In some embodiments, the ASO targets an exon 15 sequence about 2 to about 3828 nucleotides downstream (or 3 ') from the 3' splice site of a NF2 RIC pre-mRNA comprising the retained intron 14.
  • the ASO targets intron 14 in a NF2 RIC pre-mRNA comprising a retained intron 14, wherein the intron numbering correspond to the mRNA sequence at
  • the ASO targets an intron 14 sequence downstream (or 3') from the 5' splice site of a NF2 RIC pre-mRNA comprising the retained intron 14. In some embodiments, the ASO targets an intron 14 sequence about 6 to about 499 nucleotides downstream (or 3 ') from the 5' splice site of a NF2 RIC pre-mRNA comprising the retained intron 14. In some embodiments, the ASO targets an intron 14 sequence upstream (or 5') from the 3' splice site of a NF2 RIC pre-mRNA comprising the retained intron 14. In some embodiments, the ASO targets an intron 14 sequence about 16 to about 500 nucleotides upstream (or 5') from the 3' splice site of a NF2 RIC pre-mRNA comprising the retained intron 14.
  • the ASO targets exon 15 or exon 16 of a NF2 RIC pre-mRNA comprising a retained intron 15, wherein the intron numbering correspond to the mRNA sequence at NM_181829.
  • the ASO targets an exon 15 sequence upstream (or 5') from the 5' splice site of a NF2 RIC pre-mRNA comprising the retained intron 15.
  • the ASO targets an exon 15 sequence about 4 to about 24 nucleotides upstream (or 5') from the 5' splice site of a NF2 RIC pre-mRNA comprising the retained intron 15.
  • the ASO targets an exon 16 sequence downstream (or 3') from the 3' splice site of a NF2 RIC pre-mRNA comprising the retained intron 15. In some embodiments, the ASO targets an exon 16 sequence about 2 to about 3828 nucleotides downstream (or 3 ') from the 3' splice site of a NF2 RIC pre-mRNA comprising the retained intron 15.
  • the ASO targets intron 15 in a NF2 RIC pre-mRNA comprising a retained intron 15, wherein the intron numbering correspond to the mRNA sequence at
  • the ASO targets an intron 15 sequence downstream (or 3') from the 5' splice site of a NF2 RIC pre-mRNA comprising the retained intron 15. In some embodiments, the ASO targets an intron 15 sequence about 6 to about 499 nucleotides downstream (or 3 ') from the 5' splice site of a NF2 RIC pre-mRNA comprising the retained intron 15. In some embodiments, the ASO targets an intron 15 sequence upstream (or 5') from the 3' splice site of a NF2 RIC pre-mRNA comprising the retained intron 15. In some embodiments, the ASO targets an intron 15 sequence about 16 to about 500 nucleotides upstream (or 5') from the 3' splice site of a NF2 RIC pre-mRNA comprising the retained intron 15.
  • the ASO targets exon 4 or exon 5 of a NF2 RIC pre-mRNA comprising a retained intron 4, wherein the intron numbering correspond to the mRNA sequence at NM_181833.
  • the ASO targets an exon 4 sequence upstream (or 5') from the 5' splice site of a NF2 RIC pre-mRNA comprising the retained intron 4.
  • the ASO targets an exon 4 sequence about 4 to about 64 nucleotides upstream (or 5') from the 5' splice site of a NF2 RIC pre-mRNA comprising the retained intron 4.
  • the ASO targets an exon 5 sequence downstream (or 3') from the 3' splice site of a NF2 RIC pre-mRNA comprising the retained intron 4. In some embodiments, the ASO targets an exon 5 sequence about 2 to about 3828 nucleotides downstream (or 3') from the 3' splice site of a NF2 RIC pre-mRNA comprising the retained intron 4.
  • the ASO targets intron 4 in a NF2 RIC pre-mRNA comprising a retained intron 4, wherein the intron numbering correspond to the mRNA sequence at
  • the ASO targets an intron 4 sequence downstream (or 3 ') from the 5' splice site of a NF2 RIC pre-mRNA comprising the retained intron 4. In some embodiments, the ASO targets an intron 4 sequence about 6 to about 496 nucleotides downstream (or 3 ') from the 5' splice site of a NF2 RIC pre-mRNA comprising the retained intron 4. In some embodiments, the ASO targets an intron 4 sequence upstream (or 5') from the 3' splice site of a NF2 RIC pre-mRNA comprising the retained intron 4. In some embodiments, the ASO targets an intron 4 sequence about 16 to about 500 nucleotides upstream (or 5') from the 3' splice site of a NF2 RIC pre-mRNA comprising the retained intron 4.
  • the ASO targets exon 16 or exon 17 of a NF2 RIC pre-mRNA comprising a retained intron 16, wherein the intron numbering correspond to the mRNA sequence at NM_181832.
  • the ASO targets an exon 16 sequence upstream (or 5') from the 5' splice site of a NF2 RIC pre-mRNA comprising the retained intron 16.
  • the ASO targets an exon 16 sequence about 4 to about 39 nucleotides upstream (or 5') from the 5' splice site of a NF2 RIC pre-mRNA comprising the retained intron 16.
  • the ASO targets an exon 17 sequence downstream (or 3') from the 3' splice site of a NF2 RIC pre-mRNA comprising the retained intron 16. In some embodiments, the ASO targets an exon 17 sequence about 2 to about 3828 nucleotides downstream (or 3 ') from the 3' splice site of a NF2 RIC pre-mRNA comprising the retained intron 16.
  • the ASO targets intron 16 in a NF2 RIC pre-mRNA comprising a retained intron 16, wherein the intron numbering correspond to the mRNA sequence at
  • the ASO targets an intron 16 sequence downstream (or 3') from the 5' splice site of a NF2 RIC pre-mRNA comprising the retained intron 16. In some embodiments, the ASO targets an intron 16 sequence about 6 to about 499 nucleotides downstream (or 3 ') from the 5' splice site of a NF2 RIC pre-mRNA comprising the retained intron 16. In some embodiments, the ASO targets an intron 16 sequence upstream (or 5') from the 3' splice site of a NF2 RIC pre-mRNA comprising the retained intron 16. In some embodiments, the ASO targets an intron 16 sequence about 16 to about 500 nucleotides upstream (or 5') from the 3' splice site of a NF2 RIC pre-mRNA comprising the retained intron 16.
  • the ASO targets exon 15 or exon 16 of a NF2 RIC pre-mRNA comprising a retained intron 15, wherein the intron numbering correspond to the mRNA sequence at NM_181828.
  • the ASO targets an exon 15 sequence upstream (or 5') from the 5' splice site of a NF2 RIC pre-mRNA comprising the retained intron 15.
  • the ASO targets an exon 15 sequence about 4 to about 24 nucleotides upstream (or 5') from the 5' splice site of a NF2 RIC pre-mRNA comprising the retained intron 15.
  • the ASO targets an exon 16 sequence downstream (or 3') from the 3' splice site of a NF2 RIC pre-mRNA comprising the retained intron 15. In some embodiments, the ASO targets an exon 16 sequence about 2 to about 3828 nucleotides downstream (or 3 ') from the 3' splice site of a NF2 RIC pre-mRNA comprising the retained intron 15. [0346] In some embodiments, the ASO targets intron 15 in a NF2 RIC pre-mRNA comprising a retained intron 15, wherein the intron numbering correspond to the mRNA sequence at
  • the ASO targets an intron 15 sequence downstream (or 3') from the 5' splice site of a NF2 RIC pre-mRNA comprising the retained intron 15. In some embodiments, the ASO targets an intron 15 sequence about 6 to about 499 nucleotides downstream (or 3 ') from the 5' splice site of a NF2 RIC pre-mRNA comprising the retained intron 15. In some embodiments, the ASO targets an intron 15 sequence upstream (or 5') from the 3' splice site of a NF2 RIC pre-mRNA comprising the retained intron 15. In some embodiments, the ASO targets an intron 15 sequence about 16 to about 500 nucleotides upstream (or 5') from the 3' splice site of a NF2 RIC pre-mRNA comprising the retained intron 15.
  • the ASO targets exon 16 or exon 17 of a NF2 RIC pre-mRNA comprising a retained intron 16, wherein the intron numbering correspond to the mRNA sequence at NM_016418.
  • the ASO targets an exon 16 sequence upstream (or 5') from the 5' splice site of a NF2 RIC pre-mRNA comprising the retained intron 16.
  • the ASO targets an exon 16 sequence about 4 to about 24 nucleotides upstream (or 5') from the 5' splice site of a NF2 RIC pre-mRNA comprising the retained intron 16.
  • the ASO targets an exon 17 sequence downstream (or 3') from the 3' splice site of a NF2 RIC pre-mRNA comprising the retained intron 16. In some embodiments, the ASO targets an exon 17 sequence about 2 to about 3828 nucleotides downstream (or 3 ') from the 3' splice site of a NF2 RIC pre-mRNA comprising the retained intron 16.
  • the ASO targets intron 16 in a NF2 RIC pre-mRNA comprising a retained intron 16, wherein the intron numbering correspond to the mRNA sequence at
  • the ASO targets an intron 16 sequence downstream (or 3') from the 5' splice site of a NF2 RIC pre-mRNA comprising the retained intron 16. In some embodiments, the ASO targets an intron 16 sequence about 6 to about 499 nucleotides downstream (or 3 ') from the 5' splice site of a NF2 RIC pre-mRNA comprising the retained intron 16. In some embodiments, the ASO targets an intron 16 sequence upstream (or 5') from the 3' splice site of a NF2 RIC pre-mRNA comprising the retained intron 16. In some embodiments, the ASO targets an intron 16 sequence about 16 to about 500 nucleotides upstream (or 5') from the 3' splice site of a NF2 RIC pre-mRNA comprising the retained intron 16.
  • the ASO targets exon 15 or exon 16 of a NF2 RIC pre-mRNA comprising a retained intron 15, wherein the intron numbering correspond to the mRNA sequence at NM_000268.
  • the ASO targets an exon 15 sequence upstream (or 5') from the 5' splice site of a NF2 RIC pre-mRNA comprising the retained intron 15.
  • the ASO targets an exon 15 sequence about 4 to about 144 nucleotides upstream (or 5') from the 5' splice site of a NF2 RIC pre-mRNA comprising the retained intron 15.
  • the ASO targets an exon 16 sequence downstream (or 3') from the 3' splice site of a NF2 RIC pre-mRNA comprising the retained intron 15. In some embodiments, the ASO targets an exon 16 sequence about 2 to about 3828 nucleotides downstream (or 3') from the 3' splice site of a NF2 RIC pre-mRNA comprising the retained intron 15.
  • the ASO targets intron 15 in a NF2 RIC pre-mRNA comprising a retained intron 15, wherein the intron numbering correspond to the mRNA sequence at
  • the ASO targets an intron 15 sequence downstream (or 3') from the 5' splice site of a NF2 RIC pre-mRNA comprising the retained intron 15. In some embodiments, the ASO targets an intron 15 sequence about 6 to about 500 nucleotides downstream (or 3 ') from the 5' splice site of a NF2 RIC pre-mRNA comprising the retained intron 15. In some embodiments, the ASO targets an intron 15 sequence upstream (or 5') from the 3' splice site of a NF2 RIC pre-mRNA comprising the retained intron 15. In some embodiments, the ASO targets an intron 15 sequence about 16 to about 500 nucleotides upstream (or 5') from the 3' splice site of a NF2 RIC pre-mRNA comprising the retained intron 15.
  • the ASOs disclosed herein target a RIC pre-mRNA transcribed from a SHANK3 genomic sequence. In some embodiments, the ASO targets a RIC pre-mRNA transcript from a SHANK3 genomic sequence comprising a retained intron. In some
  • the ASO targets a RIC pre-mRNA transcript of SEQ ID NO: 18. In some embodiments, the ASO targets a RIC pre-mRNA transcript of SEQ ID NO: 18 comprising a retained intron. In some embodiments, the ASOs disclosed herein target a SHANK3 RIC pre- mRNA sequence. In some embodiments, the ASO targets a SHANK3 RIC pre-mRNA transcript comprising a retained intron at 16, wherein the intron numbering correspond to the mRNA sequence at NM_033517.
  • the ASO targets a SHANK3 RIC pre-mRNA sequence according to SEQ ID NO: 75. In some embodiments, the ASO targets a SHANK3 RIC pre-mRNA sequence according to SEQ ID NO: 75 comprising a retained intron 16. In some embodiments, the ASOs disclosed herein target SEQ ID NO: 24357. In some embodiments, the ASO has a sequence according to any one of SEQ ID NOs: 23348-23535.
  • the ASO targets exon 16 or exon 17 of a SHANK3 RIC pre- mRNA comprising a retained intron 16, wherein the intron numbering correspond to the mRNA sequence at NM_000214.
  • the ASO targets an exon 16 sequence upstream (or 5') from the 5' splice site of a SHANK3 RIC pre-mRNA comprising the retained intron 16.
  • the ASO targets an exon 16 sequence about 4 to about 114 nucleotides upstream (or 5') from the 5' splice site of a SHANK3 RIC pre-mRNA comprising the retained intron 16.
  • the ASO targets an exon 17 sequence downstream (or 3') from the 3' splice site of a SHANK3 RIC pre-mRNA comprising the retained intron 16. In some embodiments, the ASO targets an exon 17 sequence about 2 to about 62 or about 7 to about 62 nucleotides downstream (or 3') from the 3' splice site of a SHANK3 RIC pre-mRNA comprising the retained intron 16.
  • the ASO targets intron 16 in a SHANK3 RIC pre-mRNA comprising a retained intron 16, wherein the intron numbering correspond to the mRNA sequence at NM_000214.
  • the ASO targets an intron 16 sequence downstream (or 3 ') from the 5' splice site of a SHANK3 RIC pre-mRNA comprising the retained intron 16.
  • the ASO targets an intron 16 sequence about 6 to about 499 nucleotides downstream (or 3') from the 5' splice site of a SHANK3 RIC pre-mRNA comprising the retained intron 16.
  • the ASO targets an intron 16 sequence upstream (or 5') from the 3' splice site of a SHANK3 RIC pre-mRNA comprising the retained intron 16. In some embodiments, the ASO targets an intron 16 sequence about 16 to about 498 nucleotides upstream (or 5') from the 3' splice site of a SHANK3 RIC pre-mRNA comprising the retained intron 16.
  • the ASOs disclosed herein target a RIC pre-mRNA transcribed from a ARSA genomic sequence. In some embodiments, the ASO targets a RIC pre-mRNA transcript from a ARSA genomic sequence comprising a retained intron. In some embodiments, the ASO targets a RIC pre-mRNA transcript of SEQ ID NO: 19. In some embodiments, the ASO targets a RIC pre-mRNA transcript of SEQ ID NO: 19 comprising a retained intron. In some embodiments, the ASOs disclosed herein target a ARSA RIC pre-mRNA sequence.
  • the ASO targets a ARSA RIC pre-mRNA transcript comprising a retained intron at 2, 3 or a combination thereof, wherein the intron numbering correspond to the mRNA sequence at NM_000487. In some embodiments, the ASO targets a ARSA RIC pre-mRNA transcript comprising a retained intron at 3, 4 or a combination thereof, wherein the intron numbering correspond to the mRNA sequence at NM_001085425. In some embodiments, the ASO targets a ARSA RIC pre-mRNA transcript comprising a retained intron at 3, 4 or a combination thereof, wherein the intron numbering correspond to the mRNA sequence at NM_001085426.
  • the ASO targets a ARSA RIC pre-mRNA transcript comprising a retained intron at 3, 4 or a combination thereof, wherein the intron numbering correspond to the mRNA sequence at NM_001085427. In some embodiments, the ASO targets a ARSA RIC pre-mRNA transcript comprising a retained intron at 2, 3 or a combination thereof, wherein the intron numbering correspond to the mRNA sequence at NM_001085428.
  • the ASO targets a ARSA RIC pre-mRNA sequence according to SEQ ID NO: 76. In some embodiments, the ASO targets a ARSA RIC pre-mRNA sequence according to SEQ ID NO: 76 comprising a retained intron 2, a retained intron 3, or a
  • the ASO targets a ARSA RIC pre-mRNA sequence according to SEQ ID NO: 77. In some embodiments, the ASO targets a ARSA RIC pre-mRNA sequence according to SEQ ID NO: 77 comprising a retained intron 3, a retained intron 4, or a combination thereof. In some embodiments, the ASO targets a ARSA RIC pre-mRNA sequence according to SEQ ID NO: 78. In some embodiments, the ASO targets a ARSA RIC pre-mRNA sequence according to SEQ ID NO: 78 comprising a retained intron 3, a retained intron 4, or a combination thereof. In some embodiments, the ASO targets a ARSA RIC pre-mRNA sequence according to SEQ ID NO: 79.
  • the ASO targets a ARSA RIC pre-mRNA sequence according to SEQ ID NO: 79 comprising a retained intron 3, a retained intron 4, or a combination thereof. In some embodiments, the ASO targets a ARSA RIC pre-mRNA sequence according to SEQ ID NO: 80. In some embodiments, the ASO targets a ARSA RIC pre-mRNA sequence according to SEQ ID NO: 80 comprising a retained intron 2, a retained intron 3, or a combination thereof. In some embodiments, the ASOs disclosed herein target SEQ ID NO: 79 comprising a retained intron 3, a retained intron 4, or a combination thereof. In some embodiments, the ASO targets a ARSA RIC pre-mRNA sequence according to SEQ ID NO: 80 comprising a retained intron 2, a retained intron 3, or a combination thereof. In some embodiments, the ASOs disclosed herein target SEQ ID NO: 79 comprising a retained intron 3, a retained intron 4, or a combination thereof. In some embodiments
  • the ASO has a sequence according to any one of SEQ ID NOs: 23536-24350.
  • the ASO targets exon 2 or exon 3 of a ARSA RIC pre-mRNA comprising a retained intron 2, wherein the intron numbering correspond to the mRNA sequence at NM_000487.
  • the ASO targets an exon 2 sequence upstream (or 5') from the 5' splice site of a ARSA RIC pre-mRNA comprising the retained intron 2.
  • the ASO targets an exon 2 sequence about 4 to about 222 nucleotides upstream (or 5') from the 5' splice site of a ARSA RIC pre-mRNA comprising the retained intron 2.
  • the ASO targets an exon 3 sequence downstream (or 3 ') from the 3' splice site of a ARSA RIC pre-mRNA comprising the retained intron 2. In some embodiments, the ASO targets an exon 3 sequence about 2 to about 202 or about 7 to about 202 nucleotides downstream (or 3 ') from the 3' splice site of a ARSA RIC pre-mRNA comprising the retained intron 2.
  • the ASO targets intron 2 in a ARSA RIC pre-mRNA comprising a retained intron 2, wherein the intron numbering correspond to the mRNA sequence at
  • the ASO targets an intron 2 sequence downstream (or 3 ') from the 5' splice site of a ARSA RIC pre-mRNA comprising the retained intron 2. In some embodiments, the ASO targets an intron 2 sequence about 6 to about 56 nucleotides downstream (or 3') from the 5' splice site of a ARSA RIC pre-mRNA comprising the retained intron 2. In some embodiments, the ASO targets an intron 2 sequence upstream (or 5') from the 3' splice site of a ARSA RIC pre-mRNA comprising the retained intron 2. In some embodiments, the ASO targets an intron 2 sequence about 16 to about 71 nucleotides upstream (or 5') from the 3' splice site of a ARSA RIC pre-mRNA comprising the retained intron 2.
  • the ASO targets exon 3 or exon 4 of a ARSA RIC pre-mRNA comprising a retained intron 3, wherein the intron numbering correspond to the mRNA sequence at NM 000487.
  • the ASO targets an exon 3 sequence upstream (or 5') from the 5' splice site of a ARSA RIC pre-mRNA comprising the retained intron 3.
  • the ASO targets an exon 3 sequence about 4 to about 199 nucleotides upstream (or 5') from the 5' splice site of a ARSA RIC pre-mRNA comprising the retained intron 3.
  • the ASO targets an exon 4 sequence downstream (or 3 ') from the 3' splice site of a ARSA RIC pre-mRNA comprising the retained intron 3. In some embodiments, the ASO targets an exon 4 sequence about 2 to about 152 nucleotides downstream (or 3') from the 3' splice site of a ARSA RIC pre-mRNA comprising the retained intron 3.
  • the ASO targets intron 3 in a ARSA RIC pre-mRNA comprising a retained intron 3, wherein the intron numbering correspond to the mRNA sequence at
  • the ASO targets an intron 3 sequence downstream (or 3 ') from the 5' splice site of a ARSA RIC pre-mRNA comprising the retained intron 3. In some embodiments, the ASO targets an intron 3 sequence about 6 to about 49 nucleotides downstream (or 3') from the 5' splice site of a ARSA RIC pre-mRNA comprising the retained intron 3. In some embodiments, the ASO targets an intron 3 sequence upstream (or 5') from the 3' splice site of a ARSA RIC pre-mRNA comprising the retained intron 3. In some embodiments, the ASO targets an intron 3 sequence about 16 to about 35 nucleotides upstream (or 5') from the 3' splice site of a ARSA RIC pre-mRNA comprising the retained intron 3.
  • the ASO targets exon 3 or exon 4 of a ARSA RIC pre-mRNA comprising a retained intron 3, wherein the intron numbering correspond to the mRNA sequence at NM_001085425.
  • the ASO targets an exon 3 sequence upstream (or 5') from the 5' splice site of a ARSA RIC pre-mRNA comprising the retained intron 3.
  • the ASO targets an exon 3 sequence about 4 to about 222 nucleotides upstream (or 5') from the 5' splice site of a ARSA RIC pre-mRNA comprising the retained intron 3.
  • the ASO targets an exon 4 sequence downstream (or 3 ') from the 3' splice site of a ARSA RIC pre-mRNA comprising the retained intron 3. In some embodiments, the ASO targets an exon 4 sequence about 2 to about 202 or about 7 to about 202 nucleotides downstream (or 3 ') from the 3' splice site of aARSA RIC pre-mRNA comprising the retained intron 3.
  • the ASO targets intron 3 in a ARSA RIC pre-mRNA comprising a retained intron 3, wherein the intron numbering correspond to the mRNA sequence at
  • the ASO targets an intron 3 sequence downstream (or 3') from the 5' splice site of aARSA RIC pre-mRNA comprising the retained intron 3. In some embodiments, the ASO targets an intron 3 sequence about 6 to about 56 nucleotides downstream (or 3') from the 5' splice site of a ARSA RIC pre-mRNA comprising the retained intron 3. In some embodiments, the ASO targets an intron 3 sequence upstream (or 5') from the 3' splice site of a ARSA RIC pre-mRNA comprising the retained intron 3. In some embodiments, the ASO targets an intron 3 sequence about 16 to about 71 nucleotides upstream (or 5') from the 3' splice site of a ARSA RIC pre-mRNA comprising the retained intron 3.
  • the ASO targets ex on 4 or exon 5 of a ARSA RIC pre-mRNA comprising a retained intron 4, wherein the intron numbering correspond to the mRNA sequence at NM_001085425.
  • the ASO targets an exon 4 sequence upstream (or 5') from the 5' splice site of a ARSA RIC pre-mRNA comprising the retained intron 4.
  • the ASO targets an exon 4 sequence about 4 to about 199 nucleotides upstream (or 5') from the 5' splice site of a ARSA RIC pre-mRNA comprising the retained intron 4.
  • the ASO targets an exon 5 sequence downstream (or 3 ') from the 3' splice site of a ARSA RIC pre-mRNA comprising the retained intron 4. In some embodiments, the ASO targets an exon 5 sequence about 2 to about 152 nucleotides downstream (or 3') from the 3' splice site of a ARSA RIC pre-mRNA comprising the retained intron 4.
  • the ASO targets intron 4 in a ARSA RIC pre-mRNA comprising a retained intron 4, wherein the intron numbering correspond to the mRNA sequence at
  • the ASO targets an intron 4 sequence downstream (or 3') from the 5' splice site of aARSA RIC pre-mRNA comprising the retained intron 4. In some embodiments, the ASO targets an intron 4 sequence about 5 to about 49 or about 6 to about 49 nucleotides downstream (or 3') from the 5' splice site of a ARSA RIC pre-mRNA comprising the retained intron 4. In some embodiments, the ASO targets an intron 4 sequence upstream (or 5') from the 3' splice site of a ARSA RIC pre-mRNA comprising the retained intron 4. In some embodiments, the ASO targets an intron 4 sequence about 16 to about 35 nucleotides upstream (or 5') from the 3' splice site of a ARSA RIC pre-mRNA comprising the retained intron 4.
  • the ASO targets exon 3 or exon 4 of aARSA RIC pre-mRNA comprising a retained intron 3, wherein the intron numbering correspond to the mRNA sequence at NM_001085426.
  • the ASO targets an exon 3 sequence upstream (or 5') from the 5' splice site of a ARSA RIC pre-mRNA comprising the retained intron 3.
  • the ASO targets an exon 3 sequence about 4 to about 222 nucleotides upstream (or 5') from the 5' splice site of a ARSA RIC pre-mRNA comprising the retained intron 3.
  • the ASO targets an exon 4 sequence downstream (or 3 ') from the 3 ' splice site of a ARSA RIC pre-mRNA comprising the retained intron 3. In some embodiments, the ASO targets an exon 4 sequence about 2 to about 202 or about 7 to about 202 nucleotides downstream (or 3 ') from the 3 ' splice site of a ARSA RIC pre-mRNA comprising the retained intron 3.
  • the ASO targets intron 3 in a ARSA RIC pre-mRNA comprising a retained intron 3, wherein the intron numbering correspond to the mRNA sequence at
  • the ASO targets an intron 3 sequence downstream (or 3 ') from the 5' splice site of a ARSA RIC pre-mRNA comprising the retained intron 3. In some embodiments, the ASO targets an intron 3 sequence about 6 to about 56 nucleotides downstream (or 3 ') from the 5' splice site of a ARSA RIC pre-mRNA comprising the retained intron 3. In some embodiments, the ASO targets an intron 3 sequence upstream (or 5') from the 3 ' splice site of a ARSA RIC pre-mRNA comprising the retained intron 3. In some embodiments, the ASO targets an intron 3 sequence about 16 to about 71 nucleotides upstream (or 5') from the 3 ' splice site of a ARSA RIC pre-mRNA comprising the retained intron 3.
  • the ASO targets exon 4 or exon 5 of a ARSA RIC pre-mRNA comprising a retained intron 4, wherein the intron numbering correspond to the mRNA sequence at NM_001085426.
  • the ASO targets an exon 4 sequence upstream (or 5 ') from the 5' splice site of a ARSA RIC pre-mRNA comprising the retained intron 4.
  • the ASO targets an exon 4 sequence about 4 to about 199 nucleotides upstream (or 5') from the 5' splice site of a ARSA RIC pre-mRNA comprising the retained intron 4.
  • the ASO targets an exon 5 sequence downstream (or 3 ') from the 3 ' splice site of a ARSA RIC pre-mRNA comprising the retained intron 4. In some embodiments, the ASO targets an exon 5 sequence about 2 to about 152 nucleotides downstream (or 3 ') from the 3 ' splice site of a ARSA RIC pre-mRNA comprising the retained intron 4.
  • the ASO targets intron 4 in a ARSA RIC pre-mRNA comprising a retained intron 4, wherein the intron numbering correspond to the mRNA sequence at
  • the ASO targets an intron 4 sequence downstream (or 3 ') from the 5' splice site of a ARSA RIC pre-mRNA comprising the retained intron 4. In some embodiments, the ASO targets an intron 4 sequence about 5 toa bout 49 or about 6 to about 49 nucleotides downstream (or 3 ') from the 5' splice site of a ARSA RIC pre-mRNA comprising the retained intron 4. In some embodiments, the ASO targets an intron 4 sequence upstream (or 5') from the 3' splice site of a ARSA RIC pre-mRNA comprising the retained intron 4. In some embodiments, the ASO targets an intron 4 sequence about 16 to about 35 nucleotides upstream (or 5') from the 3' splice site of a ARSA RIC pre-mRNA comprising the retained intron 4.
  • the ASO targets exon 3 or exon 4 of a ARSA RIC pre-mRNA comprising a retained intron 3, wherein the intron numbering correspond to the mRNA sequence at NM_001085427.
  • the ASO targets an exon 3 sequence upstream (or 5') from the 5' splice site of a ARSA RIC pre-mRNA comprising the retained intron 3.
  • the ASO targets an exon 3 sequence about 4 to about 222 nucleotides upstream (or 5') from the 5' splice site of a ARSA RIC pre-mRNA comprising the retained intron 3.
  • the ASO targets an exon 4 sequence downstream (or 3') from the 3' splice site of a ARSA RIC pre-mRNA comprising the retained intron 3. In some embodiments, the ASO targets an exon 4 sequence about 2 to about 202 or about 7 to about 202 nucleotides downstream (or 3 ') from the 3' splice site of aARSA RIC pre-mRNA comprising the retained intron 3.
  • the ASO targets intron 3 in a ARSA RIC pre-mRNA comprising a retained intron 3, wherein the intron numbering correspond to the mRNA sequence at
  • the ASO targets an intron 3 sequence downstream (or 3') from the 5' splice site of aARSA RIC pre-mRNA comprising the retained intron 3. In some embodiments, the ASO targets an intron 3 sequence about 6 to about 56 nucleotides downstream (or 3') from the 5' splice site of a ARSA RIC pre-mRNA comprising the retained intron 3. In some embodiments, the ASO targets an intron 3 sequence upstream (or 5') from the 3' splice site of a ARSA RIC pre-mRNA comprising the retained intron 3. In some embodiments, the ASO targets an intron 3 sequence about 16 to about 71 nucleotides upstream (or 5') from the 3' splice site of a ARSA RIC pre-mRNA comprising the retained intron 3.
  • the ASO targets exon 4 or exon 5 of a ARSA RIC pre-mRNA comprising a retained intron 4, wherein the intron numbering correspond to the mRNA sequence at NM_001085427.
  • the ASO targets an exon 4 sequence upstream (or 5') from the 5' splice site of a ARSA RIC pre-mRNA comprising the retained intron 4.
  • the ASO targets an exon 4 sequence about 4 to about 199 nucleotides upstream (or 5') from the 5' splice site of a ARSA RIC pre-mRNA comprising the retained intron 4.
  • the ASO targets an exon 5 sequence downstream (or 3') from the 3' splice site of a ARSA RIC pre-mRNA comprising the retained intron 4. In some embodiments, the ASO targets an exon 5 sequence about 2 to about 152 nucleotides downstream (or 3') from the 3' splice site of a ARSA RIC pre-mRNA comprising the retained intron 4. [0372] In some embodiments, the ASO targets intron 4 in a ARSA RIC pre-mRNA comprising a retained intron 4, wherein the intron numbering correspond to the mRNA sequence at
  • the ASO targets an intron 4 sequence downstream (or 3') from the 5' splice site of aARSA RIC pre-mRNA comprising the retained intron 4. In some embodiments, the ASO targets an intron 4 sequence about 5 to about 49 or about 6 to about 49 nucleotides downstream (or 3') from the 5' splice site of a ARSA RIC pre-mRNA comprising the retained intron 4. In some embodiments, the ASO targets an intron 4 sequence upstream (or 5') from the 3' splice site of a ARSA RIC pre-mRNA comprising the retained intron 4. In some embodiments, the ASO targets an intron 4 sequence about 16 to about 35 nucleotides upstream (or 5') from the 3' splice site of a ARSA RIC pre-mRNA comprising the retained intron 4.
  • the ASO targets exon 2 or exon 3 of a ARSA RIC pre-mRNA comprising a retained intron 2, wherein the intron numbering correspond to the mRNA sequence at NM_001085428.
  • the ASO targets an exon 2 sequence upstream (or 5') from the 5' splice site of a ARSA RIC pre-mRNA comprising the retained intron 2.
  • the ASO targets an exon 2 sequence about 4 to about 222 nucleotides upstream (or 5') from the 5' splice site of a ARSA RIC pre-mRNA comprising the retained intron 2.
  • the ASO targets an exon 3 sequence downstream (or 3 ') from the 3' splice site of a ARSA RIC pre-mRNA comprising the retained intron 2. In some embodiments, the ASO targets an exon 3 sequence about 2 to about 202 or about 7 to about 202 nucleotides downstream (or 3 ') from the 3' splice site of aARSA RIC pre-mRNA comprising the retained intron 2.
  • the ASO targets intron 2 in a ARSA RIC pre-mRNA comprising a retained intron 2, wherein the intron numbering correspond to the mRNA sequence at
  • the ASO targets an intron 2 sequence downstream (or 3') from the 5' splice site of aARSA RIC pre-mRNA comprising the retained intron 2. In some embodiments, the ASO targets an intron 2 sequence about 6 to about 56 nucleotides downstream (or 3') from the 5' splice site of a ARSA RIC pre-mRNA comprising the retained intron 2. In some embodiments, the ASO targets an intron 2 sequence upstream (or 5') from the 3' splice site of a ARSA RIC pre-mRNA comprising the retained intron 2. In some embodiments, the ASO targets an intron 2 sequence about 16 to about 71 nucleotides upstream (or 5') from the 3' splice site of a ARSA RIC pre-mRNA comprising the retained intron 2.
  • the ASO targets exon 3 or exon 4 of a ARSA RIC pre-mRNA comprising a retained intron 3, wherein the intron numbering correspond to the mRNA sequence at NM_001085428.
  • the ASO targets an exon 3 sequence upstream (or 5') from the 5' splice site of a ARSA RIC pre-mRNA comprising the retained intron 3.
  • the ASO targets an ex on 3 sequence about 4 to about 199 nucleotides upstream (or 5') from the 5' splice site of a ARSA RIC pre-mRNA comprising the retained intron 3.
  • the ASO targets an ex on 4 sequence downstream (or 3 ') from the 3' splice site of a ARSA RIC pre-mRNA comprising the retained intron 3. In some embodiments, the ASO targets an exon 4 sequence about 2 to about 152 nucleotides downstream (or 3') from the 3' splice site of a ARSA RIC pre-mRNA comprising the retained intron 3.
  • the ASO targets intron 3 in a ARSA RIC pre-mRNA comprising a retained intron 3, wherein the intron numbering correspond to the mRNA sequence at
  • the ASO targets an intron 3 sequence downstream (or 3') from the 5' splice site of aARSA RIC pre-mRNA comprising the retained intron 3. In some embodiments, the ASO targets an intron 3 sequence about 5 to about 49 or about 6 to about 49 nucleotides downstream (or 3') from the 5' splice site of a ARSA RIC pre-mRNA comprising the retained intron 3. In some embodiments, the ASO targets an intron 3 sequence upstream (or 5') from the 3' splice site of a ARSA RIC pre-mRNA comprising the retained intron 3. In some embodiments, the ASO targets an intron 3 sequence about 16 to about 35 nucleotides upstream (or 5') from the 3' splice site of a ARSA RIC pre-mRNA comprising the retained intron 3.
  • the targeted portion of the MFSD8 RIC pre-mRNA is in intron 12.
  • the MFSD8 intron numbering used herein corresponds to the mRNA sequence at NM l 52778.
  • the percent retained intron can be 42.
  • hybridization of an ASO to the targeted portion of the RIC pre-mRNA results in enhanced splicing at the splice site (5' splice site or 3' splice site) of retained intron 12 and subsequently increases MFSD8 protein production. It is understood that the intron numbering may change in reference to a different MFSD8 isoform sequence.
  • One of skill in the art can determine the corresponding intron number in any isoform based on an intron sequence provided herein or using the number provided in reference to the mRNA sequence at NM l 52778.
  • One of skill in the art also can determine the sequences of flanking exons in any MFSD8 isoform for targeting using the methods of the invention, based on an intron sequence provided herein or using the intron number provided in reference to the mRNA sequence at NM_152778.
  • the targeted portion of the IDUA RIC pre-mRNA is in intron 3, 4, 5, 6 or 7.
  • the IDUA intron numbering used herein corresponds to the mRNA sequence at
  • the percent retained intron can be 25, 63 or 16.
  • hybridization of an ASO to the targeted portion of the RIC pre-mRNA results in enhanced splicing at the splice site (5' splice site or 3' splice site) of retained intron 3, 4, 5, 6 or 7 and subsequently increases IDUA protein production. It is understood that the intron numbering may change in reference to a different IDUA isoform sequence.
  • One of skill in the art can determine the corresponding intron number in any isoform based on an intron sequence provided herein or using the number provided in reference to the mRNA sequence at NM 000203.
  • One of skill in the art also can determine the sequences of flanking exons in any IDUA isoform for targeting using the methods of the invention, based on an intron sequence provided herein or using the intron number provided in reference to the mRNA sequence at NM_000203.
  • the targeted portion of the ATP1A2, CACNA1A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEX1, ARSA, EIF2B5, EIF2B1, EIF2B2, NPC1, ADAR, MFSD8, STXBP1, PRICKLE2, PRRT2, IDUA, or STXIB pre-mRNA is in intron 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 or 38.
  • hybridization of an ASO to the targeted portion of the RIC pre- mRNA results in enhanced splicing at the splice site (5' splice site or 3' splice site) of at least one of retained introns 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 or 38, and subsequently increases ATP1A2, CACNA1A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEX1, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, MFSD8, STXBP1, PRICKLE2, PRRT2, IDUA, or STXIB protein production.
  • STXBP1, PRICKLE2, PRRT2, or STXIB pre-mRNA is in intron 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 or 38.
  • hybridization of an ASO to the targeted portion of the RIC pre-mRNA results in enhanced splicing at the splice site (5' splice site or 3' splice site) of at least one of retained introns 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 or 38, and subsequently increases ATP1A2, CACNA1A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEX1, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, STXBP1, PRICKLE2, PRRT2, or STXIB protein production.
  • the targeted portion of the ATP1A2, CACNA1A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEX1, ARSA, EIF2B5, EIF2B2, NPCl, ADAR, STXBP1, PRICKLE2, PRRT2, or STXIB pre-mRNA is in intron 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 or 38.
  • hybridization of an ASO to the targeted portion of the RIC pre-mRNA results in enhanced splicing at the splice site (5' splice site or 3' splice site) of at least one of retained introns 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 or 38, and subsequently increases ATP1A2, CACNA1A, SETD5, SHA K3, F2, D MT1, TCF4, RAI1, PEX1, ARSA, EIF2B5, EIF2B2, NPCl, ADAR, STXBPl, PRICKLE2, PRRT2, or STXIB protein production.
  • the degree of intron retention can be expressed as percent intron retention (PIR), the percentage of transcripts in which a given intron is retained.
  • PIR percent intron retention
  • PIR can be calculated as the percentage of the average number of reads mapping to the exon-intron junctions, over the sum of the average of the exon-intron junction reads plus the ex on-ex on junction reads.
  • the methods described herein are used to increase the production of a functional ATP1A2, CACNA1A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEX1, ARSA, EIF2B5, , EIF2B2, NPCl, ADAR, MFSD8, STXBPl, PRICKLE2, PRRT2, IDUA, STXIB protein, or any combinations thereof.
  • the term "functional" refers to the amount of activity or function of a ATP1A2, CACNA1A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEX1, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, MFSD8, STXBPl, PRICKLE2, PRRT2, IDUA, STXIB protein or any combination thereof that is necessary to eliminate any one or more symptoms of a treated condition.
  • the methods are used to increase the production of a partially functional ATP1 A2, CACNA1 A, SETD5,
  • the term “partially functional” refers to any amount of activity or function of the ATP1A2, CACNA1A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEX1, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, MFSD8, STXBPl, PRICKLE2, PRRT2, IDUA, or STXIB protein that is less than the amount of activity or function that is necessary to eliminate or prevent any one or more symptoms of a disease or condition.
  • a partially functional protein or RNA will have at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, 85%, at least 90%), or at least 95% less activity relative to the fully functional protein or RNA.
  • the method is a method of increasing the expression of the ATP1A2, CACNA1A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEX1, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, MFSD8, STXBPl, PRICKLE2, PRRT2, IDUA, STXIB protein or any combination thereof by cells of a subject having a RIC pre-mRNA encoding the ATP1 A2, CACNA1A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEX1, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, MFSD8, STXBPl, PRICKLE2, PRRT2, IDUA, or STXIB protein, wherein the subject has a deficient amount of activity of ATP1A2, CACNA1A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEX1, ARSA, E
  • the subject has a first allele encoding a functional ATP1 A2, CACNA1 A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEXl, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, MFSD8, STXBPl, PRICKLE2, PRRT2, IDUA, or STXIB protein, and a second allele from which the ATP1 A2, CACNA1 A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEXl, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, MFSD8, STXBPl, PRICKLE2, PRRT2, IDUA, or STXIB protein is not produced.
  • the subject has a first allele encoding a functional ATP1A2, CACNA1A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEXl, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, MFSD8, STXBPl, PRICKLE2, PRRT2, IDUA, or STXIB protein, and a second allele encoding a nonfunctional ATP1 A2, CACNA1A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEXl, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, MFSD8, STXBPl, PRICKLE2, PRRT2, IDUA, or STXIB protein.
  • the subject has a first allele encoding a functional ATP1 A2,
  • CACNA1A SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEXl, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, MFSD8, STXBPl, PRICKLE2, PRRT2, IDUA, or STXIB protein, and a second allele encoding a partially functional ATP1A2, CACNA1A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEXl, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, MFSD8, STXBPl, PRICKLE2, PRRT2, IDUA, or STXIB protein.
  • the antisense oligomer binds to a targeted portion of the RIC pre-mRNA transcribed from the first allele (encoding functional ATP1A2, CACNA1A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEXl, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, MFSD8, STXBPl, PRICKLE2, PRRT2, IDUA, or STXIB protein), thereby inducing constitutive splicing of the retained intron from the RIC pre-mRNA, and causing an increase in the level of mature mRNA encoding functional ATP1A2, CACNA1A, SETD5, SHANK3, NF2, DNMT1, TCF4, RAI1, PEXl, ARSA, EIF2B5, EIF2B1, EIF2B2, NPCl, ADAR, MFSD8, STXBPl, PRICKLE2, PRRT2, IDUA, or STXIB

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