Antisense oligomers for treatment of autosomal dominant mental retardation-5 and dravet syndrome

Abstract

Provided herein are methods and compositions for treating a subject in need thereof, such as a subject with deficient SYNGAP1 protein or SCN1A protein expression or a subject having AD mental retardation 5 or Dravet syndrome.

1 - 188 . (canceled) 
     
     
         189 . A pharmaceutical composition comprising an antisense oligomer (ASO) or a vector encoding the ASO, wherein the ASO is complementary to a targeted portion of a retained-intron-containing pre-mRNA (RIC pre-mRNA) that encodes a target protein, wherein the RIC pre-mRNA comprises a retained intron, an exon flanking a 5′ splice site of the retained intron, and an exon flanking a 3′ splice site of the retained intron, wherein the ASO induces constitutive splicing of the retained intron from the RIC pre-mRNA encoding the target protein, and wherein the target protein is Ras/Rap GTPase-activating protein SynGAP (SYNGAP1) or Nav1.1. 
     
     
         190 . The pharmaceutical composition of  claim 189 , wherein the targeted portion of the RIC pre-mRNA is within the retained intron. 
     
     
         191 . The pharmaceutical composition of  claim 189 , wherein the targeted portion of the RIC pre-mRNA is within a region +6 relative to the 5′ splice site of the retained intron to −16 relative to the 3′ splice site of the retained intron. 
     
     
         192 . The pharmaceutical composition of  claim 191 , wherein the targeted portion of the RIC pre-mRNA is within:
 (a) a region +6 to +499 relative to the 5′ splice site of the retained intron; or   (b) a region −16 to −496 relative to the 3′ splice site of the retained intron.   
     
     
         193 . The pharmaceutical composition of  claim 189 , wherein the target protein is Nav1.1. 
     
     
         194 . The pharmaceutical composition of  claim 193 , wherein the RIC pre-mRNA comprises a sequence with at least 90% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 4-7. 
     
     
         195 . The pharmaceutical composition of  claim 193 , wherein the targeted portion of the RIC pre-mRNA comprises a sequence with at least 8 contiguous nucleic acids of SEQ ID NO: 2593. 
     
     
         196 . pharmaceutical composition of  claim 193 , wherein the ASO comprises a sequence selected from the group consisting of SEQ ID NOs: 10-1037. 
     
     
         197 . The pharmaceutical composition of  claim 196 , wherein the ASO comprises a sequence selected from the group consisting of SEQ ID NOs: 63, 69, 246, 247, 251, 255-258, 2599-2601, 2607 and 2608. 
     
     
         198 . The pharmaceutical composition of  claim 189 , wherein the target protein is SYNGAP1. 
     
     
         199 . The pharmaceutical composition of  claim 198 , wherein the RIC pre-mRNA comprises a sequence with at least 90% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 8 and 9. 
     
     
         200 . The pharmaceutical composition of  claim 198 , wherein the targeted portion of the RIC pre-mRNA comprises a sequence with at least 8 contiguous nucleic acids of a sequence selected from the group consisting of SEQ ID NO: 2592, 2594, and 2595. 
     
     
         201 . The pharmaceutical composition of  claim 198 , wherein the ASO comprises a sequence selected from the group consisting of SEQ ID NOs: 1038-2591. 
     
     
         202 . The pharmaceutical composition of  claim 201 , wherein the ASO comprises a sequence selected from the group consisting of SEQ ID NOs: 1052-1054, 1056, 1688, 1689, 1694, 1778-1781, 1783-1785, 1998-2000 and 2004. 
     
     
         203 . The pharmaceutical composition of  claim 189 , wherein the pharmaceutical composition is formulated for administration to a human subject via intravitreal injection, intrathecal injection, intraperitoneal injection, subcutaneous injection, intravenous injection, subretinal injection, intracerebroventricular injection, intramuscular injection, topical application, or implantation. 
     
     
         204 . The pharmaceutical composition of  claim 198 , wherein when the pharmaceutical composition is administered to a subject the ASO increases the amount of the target protein in cells of the subject by at least about 1.1 fold. 
     
     
         205 . The pharmaceutical composition of  claim 201 , wherein when the pharmaceutical composition is administered to a subject the ASO increases the amount of the target protein in cells of the subject by at least about 1.5 fold. 
     
     
         206 . The pharmaceutical composition of  claim 202 , wherein when the pharmaceutical composition is administered to a subject the ASO increases the amount of the target protein in cells of the subject by at least about 2 fold. 
     
     
         207 . The pharmaceutical composition of  claim 189 , wherein the target protein is produced in a form having reduced function compared to an equivalent wild-type protein. 
     
     
         208 . The pharmaceutical composition of  claim 189 , wherein the target protein is produced in a form that is fully-functional compared to an equivalent wild-type protein. 
     
     
         209 . The pharmaceutical composition of  claim 189 , wherein the pharmaceutical composition comprises the ASO. 
     
     
         210 . The pharmaceutical composition of  claim 209 , wherein the ASO comprises a backbone modification comprising a phosphorothioate linkage or a phosphorodiamidate linkage. 
     
     
         211 . The pharmaceutical composition of  claim 209 , wherein the ASO comprises a phosphorodiamidate morpholino, a locked nucleic acid, a peptide nucleic acid, a 2′-O-methyl, a 2′-Fluoro, or a 2′-O-methoxyethyl moiety. 
     
     
         212 . The pharmaceutical composition of  claim 189 , wherein the ASO consists of from 8 to 50 nucleobases. 
     
     
         213 . The pharmaceutical composition of  claim 189 , wherein the pharmaceutical composition comprises the vector encoding the ASO. 
     
     
         214 . The pharmaceutical composition of  claim 213 , wherein the vector is a viral vector. 
     
     
         215 . The pharmaceutical composition of  claim 189 , wherein the targeted portion of the RIC pre-mRNA is a wild-type sequence. 
     
     
         216 . The pharmaceutical composition of  claim 189 , wherein the ASO is complementary to at least 8 contiguous nucleic acids of the targeted portion of the RIC pre-mRNA. 
     
     
         217 . The pharmaceutical composition of  claim 189 , wherein when the pharmaceutical composition is administered to a subject:
 (i) the ASO does not increase the amount of the target protein in cells of the subject by modulating alternative splicing resulting from mutation of a gene encoding the target protein, and   (ii) the ASO does not increase the amount of the target protein in cells of the subject by modulating aberrant splicing resulting from mutation of a gene encoding the target protein.