Therapeutics for Syngap haploinsufficiency
The invention relates to therapeutic compositions for disorders associated with haploinsufficiency. The invention provides antisense oligonucleotides useful for treating neurodevelopmental disorders associated with mutations in the SYNGAP gene. The invention provides compositions that include synthetic antisense oligonucleotides (ASOs) that promote expression of the SynGAP protein by one or any combination of (i) preventing one or more miRNAs from interfering with production of the SynGAP protein; (ii) binding to 5′-UTR of the SYNGAP1 transcript and augmenting translation of the Syngap protein; and (iii) promoting RNAseH cleavage of antisense long non-coding RNAs that are anticorrelated with SYNGAP expression. When the composition is delivered to a patient with SYNGAP haploinsufficiency, the ASOs promote expression of the SynGAP protein.
1 . A composition comprising: at least one nucleic acid that promotes expression of a SynGAP protein from a transcript of the SYNGAP gene, wherein the nucleic acid comprises a gapmer structure having a central DNA segment flanked by modified RNA wings, and wherein the nucleic acid has the sequence of one of SEQ ID Nos: 28-29, wherein a majority of inter-base linkages in the nucleic acid are phosphorothioate bonds, a majority of instances of U and C in the nucleic acid are methylated at position 5, and a majority of the bases in the nucleic acid comprise 2′-O-methoxyethyl ribose sugars.
2 . The composition of claim 1 , wherein all instances of U and C are methylated at position 5; and all inter-base linkages in the nucleic acid are phosphorothioate bonds.
3 . The composition of claim 1 , wherein the nucleic acid mediates digestion of a long, non-coding RNA antisense to the transcript.
4 . The composition of claim 3 , wherein the composition comprises a plurality of nucleic acids, each of the nucleic acids having one of SEQ ID NOs: 28-29.
5 . The composition of claim 3 , wherein the central DNA segment comprises at least 9 DNA bases.
6 . The composition of claim 5 , wherein each RNA wing comprises 2′-O-methoxyethyl RNA.
7 . The composition of claim 3 , wherein the oligonucleotide comprises a central 12 DNA bases flanked by a 5′ RNA wing and a 3′ RNA wing, the 5′ wing and the 3′ wing each comprising four consecutive 2′ modified RNA bases.
8 . The composition of claim 7 , further comprising a plurality of the nucleic acids, wherein a plurality of the nucleic acids tile along the long, non-coding RNA antisense to the transcript; and/or in which the oligonucleotide has the sequence of one of SEQ ID NOs: 28-29 and in which both RNA wings consist of four 2′-O-methoxyethyl-modified RNA bases.