Enhanced antisense oligonucleotides

1. A method of reducing expression of a target RNA in an animal, in need of reducing expression of said target RNA, comprising administering to said animal a gap-widened antisense oligonucleotide 18-24 nucleotides in length targeting a preselected RNA target in the liver, wherein said oligonucleotide comprises:

(a) a gap region having 12 to 18 contiguous 2′-deoxyribonucleotides;

(b) a first wing region having 2 to 4 contiguous nucleosides; and

(c) a second wing region having 2 to 4 contiguous nucleosides; wherein the gap region is located between said first wing region and said second wing region and, wherein each nucleoside of said first and second wing regions comprises a 2′-O-(2-methoxyethyl) modification;

thereby reducing expression of said preselected RNA target in the liver of said animal.

2. The method of claim 1 , wherein the target RNA is associated with a metabolic or a cardiovascular disease or condition.

3. The method of claim 1 , wherein the metabolic disease or condition is selected from metabolic syndrome, diabetes, obesity, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, Type 2 diabetes, diet-induced obesity, hyperglycemia, insulin resistance, hepatic steatosis, fatty liver disease, or non-alcoholic steatohepatitis.

4. The method of claim 1 , wherein the cardiovascular disease or condition is selected from familial hypercholesterolemia, nonfamilial hypercholesterolemia, mixed dyslipidemia, dysbetalipoproteinemia, atherosclerosis, coronary artery disease, myocardial infarction, hypertension, carotid artery disease, stroke, cerebrovascular disease, peripheral vascular disease, thrombosis, or arterial aneurism.

5. The method of claim 1 , wherein the gap-widened antisense oligonucleotide has at least one phosphorothioate internucleotide linkage.

6. The method of claim 5 , wherein the gap-widened antisense oligonucleotide has all phosphorothioate internucleotide linkages.

7. The method of claim 1 , wherein gap-widened antisense oligonucleotide has at least one 5-methylcytosine.

8. A method of modulating gene expression in an animal comprising the step of contacting said animal with a pharmaceutical composition comprising a gap-widened antisense oligonucleotide 18-24 nucleotides in length targeting a preselected RNA target in the liver in the manufacture of a medicament for the treatment of disorders and diseases related to said RNA, wherein the antisense oligonucleotide comprises:

(a) a gap region having 12 to 18 contiguous 2′-deoxyribonucleotides;

(b) a first wing region having 2 to 4 contiguous nucleosides; and

(c) a second wing region having 2 to 4 contiguous nucleosides; wherein the gap region is located between said first wing region and said second wing region and, wherein each nucleoside of said first and second wing regions comprises a 2′-O-(2-methoxyethyl) modification;

thereby modulating the expression of said preselected RNA target in the liver of said animal.

9. The method of claim 1 , wherein said wing-gap-wing motif is selected from 2-16-2, 3-14-3, 2-14-2, 3-12-3 and 4-12-4.

10. The method of claim 9 , wherein said wing-gap-wing motif is 2-16-2.

11. The method of claim 9 , wherein said wing-gap-wing motif is 3-14-3.

12. The method of claim 9 , wherein said wing-gap-wing motif is 2-14-2.

13. The method of claim 9 , wherein said wing-gap-wing motif is 3-12-3.

14. The method of claim 9 , wherein said wing-gap-wing motif is 4-12-4.

15. The method of claim 8 , wherein said wing-gap-wing motif is selected from 2-16-2, 3-14-3, 2-14-2, 3-12-3 and 4-12-4.

16. The method of claim 15 , wherein said wing-gap-wing motif is 2-16-2.

17. The method of claim 15 , wherein said wing-gap-wing motif is 3-14-3.

18. The method of claim 15 , wherein said wing-gap-wing motif is 2-14-2.

19. The method of claim 15 , wherein said wing-gap-wing motif is 3-12-3.

20. The method of claim 15 , wherein said wing-gap-wing motif is 4-12-4.