JPWO2020097044A5 - - Google Patents

Claims (15)

comprising a sense strand and an antisense strand having a length of 15-35 nucleotides; comprising at least two phosphorothioate internucleotide linkages between the first five nucleotides counted from the 5' end of said antisense strand; said sense strand and/or A dsRNA agent comprising at least 3, 4, 5, or 6 2'-deoxy modifications on the antisense strand, wherein the double-stranded region is 19-25 base pairs, and wherein the dsRNA agent is a ligand wherein said sense strand does not contain glycol nucleic acid (GNA). 2. The dsRNA agent of claim 1, wherein the dsRNA agent contains all natural nucleotides or less than 20% non-natural nucleotides. 2. The dsRNA agent of claim 1, wherein said dsRNA comprises a sense strand having a length of 18-30 nucleotides and has at least two 2'-deoxy modifications in the central region of said sense strand. 4. The dsRNA agent of claim 3, wherein the central region is within positions 7-13 counting from the 5' end of the sense strand. 2. The dsRNA agent of claim 1, wherein said dsRNA comprises an antisense strand having a length of 18-30 nucleotides and has at least two 2'-deoxy modifications in the central region of said antisense strand. 6. The dsRNA agent of claim 5, wherein the central region is within positions 10-16 counting from the 5' end of the antisense strand. said dsRNA comprises an antisense strand having a length of 18-23 nucleotides, and said at least five 2'-deoxy modifications at positions 2, 5, 7, 12 and 14 counting from the 5' end of said antisense strand; 2. The dsRNA agent of claim 1, in the antisense strand. at least two of said 2'-deoxy modifications are at positions 2 and 14 of said antisense strand counting from the 5' end of said antisense strand, and at least one of said 2'-deoxy modifications are at positions 5 of said sense strand 2. The dsRNA agent of claim 1, wherein the dsRNA agent of claim 1 is at position 11 of the sense strand, counting from the 'end. at least three of said 2'-deoxy modifications are at positions 2, 12 and 14 of said antisense strand, counting from the 5' end of said antisense strand, and at least two of said 2'-deoxy modifications are located on said sense strand 2. The dsRNA agent of claim 1, at positions 9 and 11 of the sense strand, counting from the 5' end of the dsRNA agent of claim 1. at least five of said 2'-deoxy modifications are at positions 2, 5, 7, 12 and 14 of said antisense strand, counting from the 5' end of said antisense strand, and at least two of said 2'-deoxy modifications are , at positions 9 and 11 of the sense strand, counting from the 5' end of the sense strand. The non-natural nucleotide is a non-cyclic nucleotide, locked nucleic acid (LNA) nucleotide, hexitol nucleic acid (HNA) nucleotide, cyclohexenyl nucleic acid (CeNA) nucleotide, 2'-methoxyethyl nucleotide, 2'-O-allyl nucleotide, 2'- C-allyl nucleotide, 2′-fluoro nucleotide, 2′-ON-methylacetamide (2′-O-NMA) nucleotide, 2′-O-dimethylaminoethoxyethyl (2′-O-DMAEOE) nucleotide, 2 3. The dsRNA agent of claim 2 , which is selected from the group consisting of '-O-aminopropyl (2'-O-AP) nucleotides and 2'-ara-F nucleotides. 3. The dsRNA agent of claim 2 , wherein said natural nucleotides are 2'-OH, 2'-OMe, and 2'-deoxy. 13. The dsRNA agent of any one of claims 1-12, wherein said ligand is an ASGPR ligand. a 17-30 nucleotide long sense strand having at least one 2'-deoxy modification in the central region of the sense strand; a 17-30 nucleotide long antisense strand having at least two 2'-deoxy modifications in the central region of the antisense strand. A dsRNA agent comprising a strand. a 17-30 nucleotide long sense strand having at least two 2'-deoxy modifications in the central region of the sense strand; a 17-30 nucleotide long antisense strand having at least one 2'-deoxy modification in the central region of the antisense strand. A dsRNA agent comprising a strand.