Cell death-inducing DFFA-like effector B (CIDEB) iRNA compositions and methods of use thereof
The invention relates to double-stranded ribonucleic acid (dsRNA) compositions targeting the CIDEB gene, as well as methods of inhibiting expression of CIDEB, and methods of treating subjects that would benefit from reduction in expression of CIDEB, such as subjects having a CIDEB-associated disease, disorder, or condition, using such dsRNA compositions.
1. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of cell death-inducing DFFA-like effector b (CIDEB) in a cell, or a salt thereof,
wherein said dsRNA agent, or a salt thereof, comprises a sense strand and an antisense strand forming a double stranded region,
wherein the sense strand consists of the nucleotide sequence
(SEQ ID NO: 705)
5′-AGUAUCUAAUAUAAGCUCGGU-3′ of
and the antisense strand consists of the nucleotide sequence
(SEQ ID NO: 1153)
5′-ACCGAGCUUAUAUUAGAUACUGA-3′ of
wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand comprise a nucleotide modification;
wherein a ligand is conjugated to the 3′ end of the sense strand; and
wherein the ligand is
2. The dsRNA agent, or a salt thereof, of claim 1 , wherein the dsRNA agent, or a salt thereof, is conjugated to the ligand as shown in the following schematic
wherein X is O or S.
3. The dsRNA agent, or a salt thereof, of claim 2 , wherein X is O.
4. The dsRNA agent, or a salt thereof, of claim 1 , wherein the dsRNA agent, or a salt thereof, further comprises at least one phosphorothioate or methylphosphonate internucleotide linkage.
5. The dsRNA agent, or a salt thereof, of claim 4 , wherein the phosphorothioate or methylphosphonate internucleotide linkage is at the 3′-terminus of the sense strand or the antisense strand.
6. The dsRNA agent, or a salt thereof, of claim 4 , wherein the phosphorothioate or methylphosphonate internucleotide linkage is at the 5′-terminus of the sense strand or the antisense strand.
7. The dsRNA agent, or a salt thereof, of claim 4 , wherein the dsRNA agent comprises 6-8 phosphorothioate internucleotide linkages.
8. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of cell death-inducing DFFA-like effector b (CIDEB) in a cell, or a salt thereof, comprising a sense strand and an antisense strand forming a double stranded region,
wherein the antisense strand comprises the nucleotide sequence 5′-asdCscgdAgdCuuaudAuUfagauacusgsa-3′ of SEQ ID. NO: 2049,
wherein
s is a phosphorothioate linkage;
a, c, g, and u are 2′-O-methyl (2′-OMe) A, C, G, and U, respectively;
dA is 2′-deoxyadenosine-3′-phosphate;
dC is 2′-deoxycytidine-3′-phosphate; and
Uf is 2′-fluoro U.
9. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of cell death-inducing DFFA-like effector b (CIDEB) in a cell, or a salt thereof, comprising a sense strand and an antisense strand forming a double stranded region,
wherein the sense strand consists of the nucleotide sequence, 5′-asgsuaucuaAfUfAfuaagcucggu-3′ of SEQ ID. NO: 1601 and the antisense strand consists of the nucleotide sequence 5′-asdCscgdAgdCuuaudAuUfagauacusgsa-3′ of SEQ ID. NO: 2049,
wherein
s is a phosphorothioate linkage;
a, c, g, and u are 2′-O-methyl (2′-OMe) A, C, G, and U, respectively;
dA is 2′-deoxyadenosine-3′-phosphate;
dC is 2′-deoxycytidine-3′-phosphate; and
Af and Uf are 2′-fluoro A and U, respectively, and
wherein the 3′-end of the sense strand is conjugated to a ligand as shown in the following schematic
wherein X is O.
10. The dsRNA agent of claim 9 which is in sodium salt form.
11. A pharmaceutical composition for inhibiting expression of cell death-inducing DFFA-like effector b (CIDEB) gene, comprising the dsRNA agent, or a salt thereof, of claim 9 .
12. The pharmaceutical composition of claim 11 , wherein the dsRNA agent, or a salt thereof, is present in an unbuffered solution.
13. The pharmaceutical composition of claim 11 , wherein the dsRNA agent, or a salt thereof, is present in saline or water.
14. The pharmaceutical composition of claim 11 , wherein the dsRNA agent, or a salt thereof, is present in a buffer solution.
15. The pharmaceutical composition of claim 14 , wherein the buffer solution comprises acetate, citrate, prolamine, carbonate, or phosphate or any combination thereof.
16. The pharmaceutical composition of claim 14 , wherein the buffer solution is phosphate buffered saline (PBS).
17. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of cell death-inducing DFFA-like effector b (CIDEB) in a cell, or a salt thereof, comprising a sense strand and an antisense strand forming a double stranded region,
wherein the sense strand comprises the nucleotide sequence 5′-asgsuaucuaAfUfAfuaagcucggu-3′ of SEQ ID. NO: 1601 and the antisense strand comprises the nucleotide sequence 5′-asdCscgdAgdCuuaudAuUfagauacusgsa-3′ of SEQ ID. NO: 2049,
wherein
s is a phosphorothioate linkage;
a, c, g, and u are 2′-O-methyl (2′-OMe) A, C, G, and U, respectively;
dA is 2′-deoxyadenosine-3′-phosphate;
dC is 2′-deoxycytidine-3′-phosphate; and
Af and Uf are 2′-fluoro A and U, respectively.
18. The dsRNA agent, or a salt thereof, of claim 17 , further comprising a ligand.
19. The dsRNA agent, or a salt thereof, of claim 18 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA agent, or a salt thereof.
20. The dsRNA agent, or a salt thereof, of claim 18 , wherein the ligand comprises N-acetylgalactosamine (GalNAc).
21. The dsRNA agent, or a salt thereof, of claim 20 , wherein the ligand is
22. The dsRNA agent, or a salt thereof, of claim 21 , wherein the dsRNA agent, or a salt thereof, is conjugated to the ligand as shown in the following schematic
wherein X is O or S.
23. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of cell death-inducing DFFA-like effector b (CIDEB) in a cell, or a salt thereof, comprising a sense strand and an antisense strand forming a double stranded region,
wherein the sense strand comprises the nucleotide sequence 5′-asgsuaucuaAfUfAfuaagcucggu-3′ of SEQ ID. NO: 1601 and the antisense strand comprises the nucleotide sequence 5′-asdCscgdAgdCuuaudAuUfagauacusgsa-3′ of SEQ ID. NO: 2049,
wherein
s is a phosphorothioate linkage;
a, c, g, and u are 2′-O-methyl (2′-OMe) A, C, G, and U, respectively;
dA is 2′-deoxyadenosine-3′-phosphate;
dC is 2′-deoxycytidine-3′-phosphate; and
Af and Uf are 2′-fluoro A and U, respectively, and
wherein the 3′-end of the sense strand is conjugated to a ligand as shown in the following schematic
wherein X is O.