Compositions and methods for inhibiting GYS2 expression
AssigneeDicerna Pharmaceuticals, Inc.
InventorsBob D. Brown, Natalie Pursell, Henryk T. Dudek, Cheng Lai
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Abstract
This disclosure relates to oligonucleotides, compositions and methods useful for reducing GYS2 expression, particularly in hepatocytes. Disclosed oligonucleotides for the reduction of GYS2 expression may be double-stranded or single-stranded, and may be modified for improved characteristics such as stronger resistance to nucleases and lower immunogenicity. Disclosed oligonucleotides for the reduction of GYS2 expression may also include targeting ligands to target a particular cell or organ, such as the hepatocytes of the liver, and may be used to treat glycogen storage diseases (e.g., GSDIa, GSDIII, GSDIV, GSDVI, and GSDIX) and related conditions.
Claims35
An oligonucleotide for reducing expression of GYS2, the oligonucleotide comprising an antisense strand of 15 to 30 nucleotides in length and a sense strand of 36 to 40 nucleotides in length, wherein the sense strand forms a duplex region with the antisense strand, and wherein:
- the antisense strand has a region of complementarity to a target sequence of GYS2 as set forth in any one of SEQ ID NOs:
- 599-608, wherein the region of complementarity is at least 15 contiguous nucleotides in length;
- and
- the sense strand comprises a sequence as set forth in any one of SEQ ID NOs:
- 385-416, 569-574, 581-585, and 612-619.
An oligonucleotide for reducing expression of GYS2, the oligonucleotide comprising an antisense strand of 15 to 30 nucleotides in length and a sense strand of 15 to 40 nucleotides in length, wherein the sense strand forms a duplex region with the antisense strand, and wherein:
- the antisense strand has a region of complementarity to a target sequence of GYS2 as set forth in any one of SEQ ID NOs:
- 599-608, wherein the region of complementarity is at least 15 contiguous nucleotides in length;
- and
- the sense strand comprises at its 3′-end a stem-loop set forth as:
- S1-L-S2, wherein S1 is complementary to S2;
- L forms a loop between S1 and S2;
- and L is a tetraloop.
An oligonucleotide for reducing expression of GYS2, wherein:
- the antisense strand has a region of complementarity to a target sequence of GYS2 as set forth in any one of SEQ ID NOs:
- 599-608, wherein the region of complementarity is at least 15 contiguous nucleotides in length;
- the oligonucleotide comprises a 3′-overhang sequence of two nucleotides in length, wherein the 3′-overhang sequence is present on the antisense strand;
- the sense strand is 21 nucleotides in length and the antisense strand is 23 nucleotides in length, such that the sense strand and antisense strand form a duplex of 21 nucleotides in length;
- the oligonucleotide comprises at least one modified nucleotide and wherein the modified nucleotide comprises a 2′-modification selected from:
- 2′-aminoethyl, 2′-fluoro, 2′-O-methyl, 2′-O-methoxyethyl, and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid;
- and
- wherein the 4′-carbon of the sugar of the 5′-nucleotide of the antisense strand comprises a phosphate analog, and wherein the phosphate analog is oxymethylphosphonate, vinylphosphonate, or malonylphosphonate.
Dependencies are inferred from the claim text.