THERAPEUTICS FOR HAPLOINSUFFICIENCY CONDITIONS
The invention relates to therapeutic compositions for disorders associated with haploinsufficiency. The invention provides antisense oligonucleotides useful for treating early-onset epileptic encephalopathy by promoting expression of Syntaxin-binding protein 1 (STXBP1). The invention provides compositions that include synthetic antisense oligonucleotides (ASOs) that prevent certain miRNAs from interfering with production of the STXBP1 protein or bind to the 5′-UTR of the STXBP1 transcript and augment translation of the STXBP1 protein. When the composition is delivered to a patient with STXBP1 haploinsufficiency, the ASOs prevent miRNA from downregulating synthesis of STXBP1 protein.
1 . A composition comprising:
at least one nucleic acid that promotes expression of Syntaxin binding protein 1 (STXBP1) and has:
at least 50% sequence similarity to one of SEQ ID Nos: 1-3, 7-13, 15-18, and 23-107;
at least 60% sequence similarity to SEQ ID NO: 19;
at least 70% sequence similarity to SEQ ID NO: 22;
at least 75% sequence similarity to SEQ ID NO: 6;
at least 80% sequence similarity to SEQ ID NO: 21;
at least 85% sequence similarity to one of SEQ ID NOS: 14 and 20; or
at least 90% sequence similarity to one of SEQ ID NOS: 4 and 5.
2 . The composition of claim 1 , wherein the nucleic acid has a length between about 5 and about 50 bases.
3 . The composition of claim 1 , wherein the nucleic acid has a region of at least about 5 contiguous bases with a 100% match to a segment within one of SEQ ID Nos: 1-25.
4 . The composition of claim 1 , wherein the nucleic acid comprises at least about 50% RNA
bases with a 2′ modification on a ribose sugar.
5 . The composition of claim 1 , wherein the at least about 50% of the inter-base linkages in the nucleic acid are not phosphodiester bonds.
6 . The composition of claim 1 , wherein at least about 12 contiguous bases in the nucleic acid have at least 90% sequence identity to a corresponding about 12 contiguous bases in one of SEQ ID Nos: 1-25.
7 . The composition of claim 6 , wherein a majority of the bases of the nucleic acid have a 2′-O-methoxyethyl-modified ribose.
8 . The composition of claim 7 , wherein a majority of inter-base linkages in the nucleic acid are phosphorothioate bonds.
9 . The composition of claim 1 , wherein all of the bases in the nucleic acid comprise 2′-O-methoxyethyl ribose sugars.
10 . The composition of claim 1 , wherein the nucleic acid has at least 88% sequence similarity to one of SEQ ID Nos: 1-25 and wherein all of the bases in the nucleic acid comprise 2′-O-methoxyethyl ribose sugars.
11 . The composition of claim 1 , the nucleic acid has at least 94% sequence similarity to one of SEQ ID Nos: 1-25 and wherein all of the bases in the nucleic acid comprise 2′-O-methoxyethyl ribose sugars.
12 . The composition of claim 10 or 11 , wherein at least about 90% of inter-base linkages in the nucleic acid are phosphorothioate bonds.
13 . The composition of claim 1 , wherein: the nucleic acid has 100% sequence similarity to one of SEQ ID Nos: 1-25; all of the bases in the nucleic acid comprise 2′-O-methoxyethyl ribose sugars; all instances of U and Care methylated at position 5; and wherein all inter-base linkages in the nucleic acid are phosphorothioate bonds.
14 . The composition of claim 1 , further comprising one of the following features (a) through (1):
(a) the nucleic acid hybridizes to a binding site of, and blocks binding of an miR 3p and the nucleic acid has at least 75% sequence similarity to one selecting from the group consisting of SEQ ID Nos: 1, 2, and 3;
(b) the nucleic acid hybridizes to a binding site of, and blocks binding of miR-491-5p and the nucleic acid has at least 90% sequence similarity to one selecting from the group consisting of SEQ ID Nos: 4 and 5;
(c) the nucleic acid hybridizes to a binding site of, and blocks binding of miR-338-3p and the nucleic acid has at least 75% sequence similarity to SEQ ID NO: 6;
(d) the nucleic acid hybridizes to a binding site of, and blocks binding of miR-1-3p and the nucleic acid has at least 75% sequence similarity to one selecting from the group consisting of SEQ ID Nos: 7, 8, 9, 23, 24, and 25;
(e) the nucleic acid hybridizes to a binding site of, and blocks binding of miR-423-5p and the nucleic acid has at least 75% sequence similarity to SEQ ID NO: 10;
(f) the nucleic acid hybridizes to a binding site of, and blocks binding of miR-154-5p and the nucleic acid has at least 75% sequence similarity to one selecting from the group consisting of SEQ ID Nos: 11 and 12;
(g) the nucleic acid hybridizes to a binding site of, and blocks binding of miR-219a-5p and the nucleic acid has at least 75% sequence similarity to SEQ ID NO: 13;
(h) the nucleic acid hybridizes to a binding site of, and blocks binding of miR-424-5p and the nucleic acid has at least 85% sequence similarity to SEQ ID NO: 14;
(i) the nucleic acid hybridizes to a binding site of, and blocks binding of miR-30b-5p and the nucleic acid has at least 75% sequence similarity to one selecting from the group consisting of SEQ ID Nos: 15, 16, and 17;
(j) the nucleic acid hybridizes to a binding site of, and blocks binding of miR-141-3p and the nucleic acid has at least 75% sequence similarity to one selecting from the group consisting of SEQ ID Nos: 18 and 19;
(k) the nucleic acid hybridizes to a binding site of, and blocks binding of miR-218-5p and the nucleic acid has at least 85% sequence similarity to SEQ ID NO: 20 or at least 80% sequence similarity to SEQ ID NO: 21; and
(l) the nucleic acid hybridizes to a binding site of, and blocks binding of miR-143-3p and the nucleic acid has at least 75% sequence similarity to SEQ ID NO: 22.
15 . The composition of claim 14 , wherein: the nucleic acid has 100% sequence similarity to the one of SEQ ID Nos: 1-25
16 - 17 . (canceled)
18 . The composition of claim 1 , wherein the nucleic acid has at least 80% sequence identity to one of SEQ ID NOs: 26-49.
19 . The composition of claim 18 , wherein all of the inter-base linkages are phosphodiester.
20 . The composition of claim 1 , wherein the nucleic acid has at least 80% sequence identity to one of SEQ ID NOs: 50-73.
21 . The composition of claim 20 , wherein all of the inter-base linkages are phosphorothioate.
22 - 29 . (canceled)