Treatment of MST1 related diseases and disorders
Disclosed herein are compositions comprising an oligonucleotide that targets MST1. The oligonucleotide may include a small interfering RNA (siRNA) or an antisense oligonucleotide (ASO). Also provided herein are methods of treating conditions associated with MST1 variants that include providing an oligonucleotide that targets MST1 to a subject.
1. A composition
for modulating an expression of MST1 (macrophage-stimulating 1), the composition comprising an oligonucleotide comprising an siRNA comprising a sense strand and an antisense strand,
wherein
each strand is independently 12-30 nucleosides in length;
the sense strand comprises an oligonucleotide sequence of SEQ ID NO: 2999 or 6385; and the antisense strand comprises an oligonucleotide sequence of SEQ ID NO: 6023 or 6415; and
(a) the sense strand comprises modification pattern 30S 5′-snnnnnnNfnNfNfnnnnnnnnnsnsn-3′;
(b) the antisense strand comprises modification pattern 15AS 5′-nsNfsnnnnNfnnNfnNfnNfnNfnNfnsnsn-3′; or
(c) both (a) and (b),
wherein
n is 2′-O-methyl (2′-OMe) A, G, C, and U, respectively;
Nf is 2′-fluoro (2′-F) A, G, C, and U, respectively; and
s is a phosphorothioate linkage.
2. A composition
for modulating an expression of MST1 (macrophage-stimulating 1), the composition comprising a modified oligonucleotide comprising an siRNA comprising a sense strand and an antisense strand, each strand is independently 12-30 nucleosides in length, at least one of the sense strand and the antisense strand comprises a nucleoside sequence comprising 12-30 contiguous nucleosides of SEQ ID NO: 6185; and
(a) the sense strand comprises modification pattern 30S (5′-snnnnnnNfnNfNfnnnnnnnnnsnsn-3′);
(b) the antisense strand comprises modification pattern 15AS (5′-nsNfsnnnnNfnnNfnNfnNfnNfnNfnsnsn-3′); or
(c) both (a) and (b),
wherein
n is 2′-O-methyl (2′-OMe) A, G, C, and U, respectively;
Nf is 2′-fluoro (2′-F) A, G, C, and U, respectively; and
s is a phosphorothioate linkage.
3. The composition of claim 2 , wherein the modified oligonucleotide is conjugated to a ligand.
4. The composition of claim 3 , wherein the ligand comprises a sugar moiety.
5. The composition of claim 4 , wherein the sugar moiety comprises N-acetylgalactosamine (GalNAc), N-acetylglucosamine (GlcNAc), or mannose.
6. The composition of claim 3 , wherein the ligand is conjugated to the 5′ or 3′ terminus of the sense strand or antisense strand.
7. The composition of claim 3 , wherein the ligand is conjugated to the 5′ terminus of the sense strand.
8. A double stranded ribonucleic acid (dsRNA) for inhibiting expression of MST1 (macrophage-stimulating 1) in a cell, or a pharmaceutically acceptable salt thereof, comprising:
a sense strand and an antisense strand forming a double stranded region, wherein the sense strand comprises the nucleotide sequence:
5′-[ETL17]sacuucuUfgUfCfagacauaaasusu-3′ (SEQ ID NO: 6538), and wherein the antisense strand comprises the nucleotide sequence:
5′-usUfsuaugUfcuGfaCfaAfgAfaGfususu-3′ (SEQ ID NO: 6570), wherein
a, g, c, and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively;
Af, Gf, Cf, and Uf are 2′-fluoro (2′-F) A, G, C, and U, respectively;
s is a phosphorothioate linkage, and
[ETL17] is
wherein J is the attachment point to the 5′ phosphorothioate linkage of the sense strand.