Ketohexokinase (KHK) iRNA compositions and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10370666-B2
Application number	US-201615224805-A
Country	US
Kind code	B2
Filing date	Aug 1, 2016
Priority date	Feb 11, 2014
Publication date	Aug 6, 2019
Grant date	Aug 6, 2019

Abstract

The present invention relates to RNAi agents, e.g., double-stranded RNAi agents, targeting the ketohexokinase (KHK) gene, and methods of using such RNAi agents to inhibit expression of KHK and methods of treating subjects having a KHK-associated disorder, e.g., liver disease (e.g., fatty liver, steatohepatitis), dyslipidemia (e.g., hyperlipidemia, high LDL cholesterol, low HDL cholesterol, hypertriglyceridemia, postprandial hypertriglyceridemia), disorders of glycemic control (e.g., insulin resistance, diabetes), cardiovascular disease (e.g., hypertension, endothelial cell dysfunction), kidney disease (e.g., acute kidney disorder, tubular dysfunction, proinflammatory changes to the proximal tubules), metabolic syndrome, adipocyte dysfunction, visceral adipose deposition, obesity, hyperuricemia, gout, eating disorders, and excessive sugar craving.

First claim

We claim:

1. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of a ketohexokinase (KHK) gene,
wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region,
wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of nucleotides 798-833 of SEQ ID NO:5, and the antisense strand comprises at least 15 contiguous nucleotides of the corresponding nucleotide sequence of SEQ ID NO:6;
wherein substantially all of the nucleotides of the sense strand and substantially all of the nucleotides of the antisense strand are modified nucleotides, and
wherein the sense strand is conjugated to a ligand attached at the 3′-terminus.

2. The dsRNA agent of claim 1 , wherein the double stranded region is 17-25 nucleotide pairs in length.

3. The dsRNA agent of claim 2 , wherein the double stranded region is 19-23 nucleotide pairs in length.

4. The dsRNA agent of claim 1 , wherein each of the sense strand and the antisense strand independently is 21 to 23 nucleotides in length.

5. The dsRNA agent of claim 1 , wherein the sense strand is 21 nucleotides in length and the antisense strand is 23 nucleotides in length.

6. The dsRNA agent of claim 1 , wherein the modifications on the nucleotides are 2′-O-methyl or 2′-fluoro modifications.

7. The dsRNA agent of claim 1 , wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker.

8. The dsRNA agent of claim 1 , wherein the antisense strand comprises a nucleotide sequence selected from the group consisting of

(SEQ ID NO: 212)

5′-AUCUUUGCUGACAAACACCACGU-3′,

(SEQ ID NO: 211)

5′-AUUUGCUGACAAACACCACGUCU-3′,

(SEQ ID NO: 208)

5′-AAACACCACGUCUCCGUAGCCAA-3′,

(SEQ ID NO: 209)

5′-UAAACACCACGUCUCCGUAGCCA-3′,

(SEQ ID NO: 214) 

5′-UACAUCUUUGCUGACAAACACCA-3′; and

(SEQ ID NO:213)

5′-ACAUCUUUGCUGACAAACACCAC-3′.

9. The dsRNA agent of claim 1 , wherein
(a) the sense strand comprises the nucleotide sequence

(SEQ ID NO: 162)

5′-GUGGUGUUUGUCAGCAAAGAU-3′

and the antisense strand comprises the nucleotide sequence

(SEQ ID NO: 212);

5′-AUCUUUGCUGACAAACACCACGU-3′

or
(b) the sense strand comprises the nucleotide sequence

(SEQ ID NO: 161)

5′-ACGUGGUGUUUGUCAGCAAAU-3′

and the antisense strand comprises the nucleotide sequence

(SEQ ID NO: 211);

5′-AUUUGCUGACAAACACCACGUCU-3′

or
(c) the sense strand comprises the nucleotide sequence

(SEQ ID NO: 158)

5′-GGCUACGGAGACGUGGUGUUU-3′

and the antisense strand comprises the nucleotide sequence

(SEQ ID NO: 208)

5′-AAACACCACGUCUCCGUAGCCAA-3′;

or
(d) the sense strand comprises the nucleotide sequence

(SEQ ID NO: 159)

5′-GCUACGGAGACGUGGUGUUUA-3′

and the antisense strand comprises the nucleotide sequence

(SEQ ID NO: 209)

5′-UAAACACCACGUCUCCGUAGCCA-3′;

or
(e) the sense strand comprises the nucleotide sequence

(SEQ ID NO: 164)

5′-GUGUUUGUCAGCAAAGAUGUA-3′

and the antisense strand comprises the nucleotide sequence

(SEQ ID NO: 214)

5′-UACAUCUUUGCUGACAAACACCA-3′;

Assignees

• Alnylam Pharmaceuticals Inc

Inventors

• Fitzgerald Kevin
• Bettencourt Brian
• Hinkle Gregory
• Willoughby Jennifer

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title