Ketohexokinase (KHK) iRNA compositions and methods of use thereof
The present invention relates to RNAi agents, e.g., dsRNA agents, targeting the ketohexokinase (KHK) gene. The invention also relates to methods of using such RNAi agents to inhibit expression of a KHK gene and to methods of treating or preventing a KHK-associated disorder in a subject.
1. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of ketohexokinase (KHK) in a cell, or a pharmaceutically acceptable salt thereof, comprising a sense strand and an antisense strand forming a double stranded region,
wherein the nucleotide sequence of the sense strand differs by no more than 4 bases from the nucleotide sequence 5′-gscsaggaagCfAfCfugagauucgu-3′ (SEQ ID NO: 1420) and the nucleotide sequence of the antisense strand differs by no more than 4 bases from the nucleotide sequence 5′-asdCsgadAudCucagdTgCfuuccugcsasc-3′ (SEQ ID NO:1532),
wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Cf and Af are 2′-fluoro (2′-F) C and A, respectively; dC, dA, and dT are 2′-deoxy C, A, and T, respectively; and s is a phosphorothioate linkage, and
wherein the sense strand of the dsRNA agent is conjugated to a ligand.
2. The dsRNA agent, or pharmaceutically acceptable salt thereof, of claim 1 ,
wherein the nucleotide sequence of the sense strand differs by no more than 3 bases from the nucleotide sequence 5′-gscsaggaagCfAfCfugagauucgu-3′ (SEQ ID NO:1420) and the nucleotide sequence of the antisense strand differs by no more than 3 bases from the nucleotide sequence 5′-asdCsgadAudCucagdTgCfuuccugcsasc-3′ (SEQ ID NO:1532).
3. The dsRNA agent, or pharmaceutically acceptable salt thereof, of claim 1 ,
wherein the nucleotide sequence of the sense strand differs by no more than 2 bases from the nucleotide sequence 5′-gscsaggaagCfAfCfugagauucgu-3′ (SEQ ID NO:1420) and the nucleotide sequence of the antisense strand differs by no more than 2 bases from the nucleotide sequence 5′-asdCsgadAudCucagdTgCfuuccugcsasc-3′(SEQ ID NO:1532).
4. The dsRNA agent, or pharmaceutically acceptable salt thereof, of claim 1 ,
wherein the nucleotide sequence of the sense strand differs by no more than 1 base from the nucleotide sequence 5′-gscsaggaagCfAfCfugagauucgu-3′ (SEQ ID NO:1420) and the nucleotide sequence of the antisense strand differs by no more than 1 base from the nucleotide sequence 5′-asdCsgadAudCucagdTgCfuuccugcsasc-3′ (SEQ ID NO:1532).
5. The dsRNA agent, or pharmaceutically acceptable salt thereof, of claim 1 ,
wherein the nucleotide sequence of the sense strand comprises the nucleotide sequence 5′-gscsaggaagCfAfCfugagauucgu-3′ (SEQ ID NO:1420) and the nucleotide sequence of the antisense strand comprises the nucleotide sequence 5′-asdCsgadAudCucagdTgCfuuccugcsasc-3′ (SEQ ID NO:1532).
6. The dsRNA agent, or pharmaceutically acceptable salt thereof, of claim 1 ,
wherein the nucleotide sequence of the sense strand consists of the nucleotide sequence 5′-gscsaggaagCfAfCfugagauucgu-3′ (SEQ ID NO:1420) and the nucleotide sequence of the antisense strand consists of the nucleotide sequence 5′-asdCsgadAudCucagdTgCfuuccugcsasc-3′ (SEQ ID NO:1532).
7. The dsRNA agent, or pharmaceutically acceptable salt thereof, of claim 1 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA agent.
8. The dsRNA agent, or pharmaceutically acceptable salt thereof, of claim 1 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.
9. The dsRNA agent, or pharmaceutically acceptable salt thereof, of claim 8 , wherein the ligand is one or more GalNAc derivatives attached through a monovalent, bivalent, or trivalent branched linker.
10. The dsRNA agent, or pharmaceutically acceptable salt thereof, of claim 8 , wherein the ligand is
11. The dsRNA agent, or pharmaceutically acceptable salt thereof, of claim 10 , wherein the dsRNA agent is conjugated to the ligand as shown in the following schematic
and, wherein X is O or S.
12. The dsRNA agent, or pharmaceutically acceptable salt thereof, of claim 11 , wherein X is O.
13. An isolated cell containing the dsRNA agent, or pharmaceutically acceptable salt thereof, of claim 1 .
14. A pharmaceutical composition for inhibiting expression of a gene encoding ketohexokinase (KHK) comprising the dsRNA agent, or pharmaceutically acceptable salt thereof, of claim 1 .
15. The pharmaceutical composition of claim 14 , wherein the dsRNA agent, or pharmaceutically acceptable salt thereof, is in an unbuffered solution.
16. The pharmaceutical composition of claim 15 , wherein the unbuffered solution is saline or water.
17. The pharmaceutical composition of claim 14 , wherein the dsRNA agent, or pharmaceutically acceptable salt thereof, is in a buffer solution.
18. The pharmaceutical composition of claim 17 , wherein the buffer solution comprises acetate, citrate, prolamine, carbonate, or phosphate or any combination thereof.
19. The pharmaceutical composition of claim 18 , wherein the buffer solution is phosphate buffered saline (PBS).
20. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of ketohexokinase (KHK) in a cell, or a pharmaceutically acceptable salt thereof, comprising a sense strand and an antisense strand,
wherein the sense strand comprises the nucleotide sequence 5′-gscsaggaagCfAfCfugagauucgu-3′ (SEQ ID NO:1420) and the antisense strand comprises the nucleotide sequence 5′-asdCsgadAudCucagdTgCfuuccugcsasc-3′ (SEQ ID NO:1532),
wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Cf and Af are 2′-fluoro (2′-F) C and A, respectively; dC, dA, and dT are 2′-deoxy C, A, and T, respectively; and s is a phosphorothioate linkage,
wherein a ligand conjugated to the 3′-end of the sense strand as shown in the following schematic
wherein X is O.
21. The dsRNA agent, or pharmaceutically acceptable salt thereof, of claim 20 , which is in a salt form.
22. An isolated cell containing the dsRNA agent, or pharmaceutically acceptable salt thereof, of claim 20 .
23. A pharmaceutical composition comprising the dsRNA agent, or pharmaceutically acceptable salt thereof, of claim 20 .
24. A composition, or a pharmaceutically acceptable salt thereof, comprising
5′-asdCsgadAudCucagdTgCfuuccugcsasc-3′ (SEQ ID NO:1532),
wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Cf is 2′-fluoro (2′-F) C; dC, dA, and dT are 2′-deoxy C, A, and T, respectively; and s is a phosphorothioate linkage.
25. The composition, or a pharmaceutically acceptable salt thereof, of claim 24 , which is in a salt form.
26. An isolated cell containing the composition, or pharmaceutically acceptable salt thereof, of claim 24 .
27. A pharmaceutical composition comprising the composition, or pharmaceutically acceptable salt thereof, of claim 24 .
28. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of ketohexokinase (KHK) in a cell, or a pharmaceutically acceptable salt thereof, comprising a sense strand and an antisense strand,
wherein the sense strand consists of the nucleotide sequence 5′-gscsaggaagCfAfCfugagauucgu-3′ (SEQ ID NO:1420) and the antisense strand consists of the nucleotide sequence 5′-asdCsgadAudCucagdTgCfuuccugcsasc-3′ (SEQ ID NO:1532),
wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Cf and Af are 2′-fluoro (2′-F) C and A, respectively; dC, dA, and dT are 2′-deoxy C, A, and T, respectively; and s is a phosphorothioate linkage,
wherein a ligand conjugated to the 3′-end of the sense strand as shown in the following schematic
wherein X is O.
29. The dsRNA agent, or pharmaceutically acceptable salt thereof, of claim 28 , which is in a salt form.
30. A pharmaceutical composition comprising the dsRNA agent, or pharmaceutically acceptable salt thereof, of claim 28 .