Modulation of diacylglycerol acyltransferase 2 expression

• US 7,732,590 B2
• Filed: 02/24/2005
• Issued: 06/08/2010
• Est. Priority Date: 08/18/2003
• Status: Expired due to Fees

• Current Assignee: ISIS Pharmaceuticals Incorporated
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Monia, Brett P., Dobie, Kenneth W., Bhanot, Sanjay, Yu, Xing-Xian
• Primary Examiner(s): Chong; Kimberly
• Application Number:
  US11/066,725
• Publication Number:
  US 20050272680A1
• Time in Patent Office: 1,930 Days
• Field of Search: None
• US Class Current: 536/24.5
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/48 of the pancreatic hormones
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07H 21/02 with ribosyl as saccharide radical
• CPC Class Codes: C12N 15/1137 against enzymes viral enzymes C12N15/1131; receptors C12N15/1138
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/14 interfering N.A.

Abstract

Compounds, compositions and methods are provided for modulating the expression of diacylglycerol acyltransferase 2. The compositions comprise oligonucleotides, targeted to nucleic acid encoding diacylglycerol acyltransferase 2. Methods of using these compounds for modulation of diacylglycerol acyltransferase 2 expression and for diagnosis and treatment of diseases and conditions associated with expression of diacylglycerol acyltransferase 2 are provided.

Claims

1. An antisense compound 13 to 40 nucleobases in length targeted to a target segment of a nucleic acid molecule encoding diacylglycerol acyltransferase 2 (SEQ ID NO:

4), the target segment consisting of nucleotides 222-269 and wherein said compound has at least 95% complementarity with said target segment and is a chimeric oligonucleotide comprising at least one phosphorothioate internucleotide linkage and at least one 2′

-O-methoxyethyl modified sugar moiety.

2. The antisense compound of claim 1 comprising 15 to 30 nucleobases in length.

3. The antisense compound of claim 1 having at least 99% complementarity with said target segment.

4. The antisense compound of claim 1, wherein the antisense compound is 20 nucleobases in length.

5. The antisense compound of claim 4, wherein all internucleotide linkages are phosphorothioates and at least one 2′

-O-methoxyethyl nucleotide is at each of the 3′ and

5′

termini of said antisense compound.

6. The antisense compound of claim 5, wherein nucleotides 1-5 are 2′

-O-methoxyethyl nucleotides, nucleotides 6-15 are 2′

-deoxynucleotides, and nucleotides 16-20 are 2′

-O-methoxyethyl nucleotides.

7. The antisense compound of claim 5, wherein nucleotides 1-2 are 2′

-O-methoxyethyl nucleotides, nucleotides 3-18 are 2′

-deoxynucleotides, and nucleotides 19-20 are 2′

-O-methoxyethyl nucleotides.

30. The antisense compound of claim 1, wherein said compound comprises a modified oligonucleotide consisting of 13-40 linked nucleosides having a nucleobase sequence having at least 95% complementarity within nucleotides 246-265 of a nucleic acid molecule encoding diacylglycerol acyltransferase 2 (SEQ ID NO:

4).

31. The antisense compound of claim 1, wherein said compound comprises a modified oligonucleotide consisting of 13-40 linked nucleosides and having a nucleobase sequence having at least 95% complementarity to a nucleic acid molecule encoding diacylglycerol acyltransferase 2 (SEQ ID NO:

4) and comprising at least 8 contiguous nucleobases of the nucleobase sequence recited in SEQ ID NO;

65.

8. An antisense compound 13 to 40 nucleobases in length targeted to at least an 8 nucleobase portion of nucleotides 222-269 of a nucleic acid molecule encoding diacylglycerol acyltransferase 2 (SEQ ID NO:

4), wherein said compound is a chimeric oligonucleotide comprising at least one phosphorothioate internucleotide linkage and at least one 2′

-O-methoxyethyl modified sugar moiety, wherein the nucleobase sequence of the modified oligonucleotide is at least 95% complementary to SEQ ID NO;

4.

9. A compound comprising a modified oligonucleotide consisting of 13-40 linked nucleosides having a nucleobase sequence comprising a portion having at least 8 contiguous nucleobases complementary within nucleotides 222-269 of a nucleic acid molecule encoding diacylglycerol acyltransferase 2 (SEQ ID NO:

4), wherein the nucleobase sequence of the modified oligonucleotide is at least 95% complementary to SEQ ID NO;

4.

10. The compound of claim 9, wherein the nucleobase sequence of the modified oligonucleotide is 100% complementary to SEQ ID NO:

4.

11. A compound comprising a modified oligonucleotide consisting of 13-40 linked nucleosides having a nucleobase sequence comprising a portion having at least 8 contiguous nucleobases complementary within nucleotides 222-241, 229-248, 232-251, 234-253, 237-256, 249-268 or 250-269 of a nucleic acid molecule encoding diacylglycerol acyltransferase 2 (SEQ ID NO:

4), wherein the nucleobase sequence of the modified oligonucleotide is at least 95% complementary to SEQ ID NO;

4.

15. The compound of claim 11, wherein the nucleobase sequence of the modified oligonucleotide is 100% complementary to SEQ ID NO:

4.

17. The compound of claim 11, wherein the nucleobases are complementary within nucleotides 222-241 of a nucleic acid molecule encoding diacylglycerol acyltransferase 2 (SEQ ID NO:

4).

18. The compound of claim 11, wherein the nucleobases complementary within nucleotides 229-248 of a nucleic acid molecule encoding diacylglycerol acyltransferase 2 (SEQ ID NO:

4).

19. The compound of claim 11, wherein the nucleobases complementary within nucleotides 232-251 of a nucleic acid molecule encoding diacylglycerol acyltransferase 2 (SEQ ID NO:

4).

20. The compound of claim 11, wherein the nucleobases complementary within nucleotides 234-253 of a nucleic acid molecule encoding diacylglycerol acyltransferase 2 (SEQ ID NO:

4).

21. The compound of claim 11, wherein the nucleobases complementary within nucleotides 237-256 of a nucleic acid molecule encoding diacylglycerol acyltransferase 2 (SEQ ID NO:

4).

22. The compound of claim 11, wherein the nucleobases complementary within nucleotides 249-268 of a nucleic acid molecule encoding diacylglycerol acyltransferase 2 (SEQ ID NO:

4).

12. A compound comprising a modified oligonucleotide consisting of 13-40 linked nucleosides having a nucleobase sequence comprising a portion having at least 8 contiguous nucleobases complementary within nucleotides 250-269 of a nucleic acid molecule encoding diacylglycerol acyltransferase 2 (SEQ ID NO:

4), wherein the nucleobase sequence of the modified oligonucleotide is at least 95% complementary to SEQ ID NO;

4.

16. The compound of claim 12, wherein the nucleobase sequence of the modified oligonucleotide is 100% complementary to SEQ ID NO:

4.

13. A compound comprising a modified oligonucleotide consisting of 13-40 linked nucleosides and having a nucleobase sequence having at least 95% complementarity to a nucleic acid molecule encoding diacylglycerol acyltransferase 2 (SEQ ID NO:

4) and comprising at least 8 contiguous nucleobases of a nucleobase sequence selected from among the nucleobase sequences recited in SEQ ID NOs;

64, 279, 280, 345, 346, 347, 425 and 426.

23. The compound of claim 13, wherein the nucleobase sequence is SEQ ID NO:

64.

24. The compound of claim 13, wherein the nucleobase sequence is SEQ ID NO:

279.

25. The compound of claim 13, wherein the nucleobase sequence is SEQ ID NO:

280.

26. The compound of claim 13, wherein the nucleobase sequence is SEQ ID NO:

345.

27. The compound of claim 13, wherein the nucleobase sequence is SEQ ID NO:

346.

28. The compound of claim 13, wherein the nucleobase sequence is SEQ ID NO:

347.

29. The compound of claim 13, wherein the nucleobase sequence is SEQ ID NO:

425.

14. A compound comprising a modified oligonucleotide consisting of 13-40 linked nucleo sides and having a nucleobase sequence having at least 95% complementarity to a nucleic acid molecule encoding diacylglycerol acyltransferase 2 (SEQ ID NO:

4) and comprising at least 8 contiguous nucleobases of a nucleobase sequence recited in SEQ ID NO;

426.