Modulation of diacylglycerol acyltransferase 2 expression

• US 8,258,289 B2
• Filed: 03/26/2010
• Issued: 09/04/2012
• Est. Priority Date: 08/18/2003
• Status: Active Grant

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Bhanot, Sanjay, Dobie, Kenneth W., Yu, Xing-Xian, Monia, Brett P.
• Primary Examiner(s): Chong, Kimberly
• Application Number:
  US12/748,281
• Publication Number:
  US 20100311810A1
• Time in Patent Office: 893 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. A compound comprising a modified oligonucleotide consisting of 13 to 40 linked nucleosides and comprising a nucleobase sequence comprising a portion of at least 8 contiguous nucleobases complementary to an equal length portion of nucleobases 654 to 698, nucleobases 654 to 713, nucleobases 1197 to 1226, nucleobases 1309 to 1338, nucleobases 1110-1144, nucleobases 1309 to 1468, nucleobases 1197 to 1468, nucleobases 1387-1433, nucleobases 1309-1338, nucleobases 1469-1493, nucleobases 1635-1666, nucleobases 1707 to 1743, nucleobases 1763 to 1821, nucleobases 1946 to 1988, nucleobases 1946-2008, nucleobases 2055-2107, nucleobases 2067 to 2169, nucleobases 2125-2169, nucleobases 2220-2288, nucleobases 2220 to 2261 of the nucleic acid molecule encoding diacylglycerol acyltransferase 2 in SEQ ID NO:

4 or an exon;

intron region, an intron;

exon region, or an intron of the nucleic acid molecule encoding diacylglycerol acyltransferase 2 in SEQ ID NO;

18, wherein the nucleobase sequence of the modified oligonucleotide is at least 95% complementary to SEQ ID NOS;

4 or 18 over the entire length of the modified oligonucleotide.

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

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

4. A method of lessening the severity of a condition of an animal, wherein the condition is obesity, diabetes, cholesterolemia, or liver steatosis, comprising contacting said animal with an effective amount of the compound of claim 1 thereby lessening the severity of said condition.

5. The method of claim 4 wherein the obesity is diet-induced.

6. The method of claim 4 wherein physical indicia of obesity is increased fat.

7. The method of claim 4 wherein the animal is a mammal.

8. The method of claim 4, wherein the liver steatosis is steatohepatitis, non-alcoholic fatty liver disease or non-alcoholic steatohepatitis (NASH).

9. The compound of claim 1 having at least 100% complementarity with said target segment.

10. The compound of claim 1 comprising an oligonucleotide.

11. The compound of claim 10 comprising an antisense oligonucleotide.

12. The compound of claim 10 comprising a DNA oligonucleotide.

13. The compound of claim 10 comprising a RNA oligonucleotide.

14. The compound of claim 10 comprising a chimeric oligonucleotide.

15. The compound of claim 10 wherein at least a portion of said compound hybridizes with RNA to form an oligonucleotide-RNA duplex.

16. The compound of claim 1 having at least one modified internucleoside linkage, sugar moiety, or nucleobase.

17. The compound of claim 1 having at least one 2′

-O-methoxyethyl sugar moiety.

18. The compound of claim 1 having at least one phosphorothioate internucleoside linkage.

19. The compound of claim 1 having at least one 5-methylcytosine.

20. A kit or assay device comprising the compound of claim 1.

21. The compound of claim 1, wherein said compound is 20 nucleobases in length.

22. The compound of claim 1, wherein said compound is an antisense oligonucleotide comprising:

a gap segment consisting of linked deoxynucleosides;

a 5′

wing segment consisting of linked nucleosides;

a 3′

wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5′

wing segment and the 3′

wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.

23. The compound of claim 22, wherein the antisense oligonucleotide comprises:

a gap segment consisting of ten linked deoxynucleosides;

a 5′

wing segment consisting of five linked nucleosides;

a 3′

wing segment consisting of five linked nucleosides;

wherein the gap segment is positioned between the 5′

wing segment and the 3′

wing segment, wherein each nucleoside of each wing segment comprises a 2′

-O-methoxyethyl sugar;

and wherein each internucleoside linkage is a phosphorothioate linkage.

24. A method of lowering DGAT-2 expression in a cell or tissue of an animal comprising administering to said animal the compound of claim 1, thereby lowering the expression of DGAT-2 in said cell or tissue.