Modulation of angiopoietin-like 3 expression

1. A compound comprising a modified antisense oligonucleotide 10 to 30 linked nucleosides in length targeted to angiopoietin-like 3 (ANGPTL3), wherein

the modified antisense oligonucleotide is targeted to a target region consisting of nucleotides 1094 to 1264 of SEQ ID NO: 4.

2. The compound of claim 1 , wherein the modified antisense oligonucleotide has a nucleobase sequence comprising at least 8 contiguous nucleobases of a sequence recited in SEQ ID NO: 87 or SEQ ID NO: 90.

3. The compound of claim 1 , wherein at least one internucleoside linkage of said modified antisense oligonucleotide is a modified internucleoside linkage.

4. The compound of claim 3 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.

5. The compound of claim 1 , wherein at least one nucleoside of said modified antisense oligonucleotide comprises a modified nucleobase.

6. The compound of claim 5 , wherein the modified nucleobase is a 5-methylcytosine.

7. The compound of claim 1 , wherein the modified antisense oligonucleotide consists of 20 linked nucleosides.

8. The compound of claim 1 , wherein the modified antisense oligonucleotide comprises:

a) a gap segment consisting of linked deoxynucleosides;

b) a 5′ wing segment consisting of linked nucleosides;

c) 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.

9. The compound of claim 1 , which reduces ANGPTL3 expression in an animal and thereby:

a) reduces apoC-III expression levels;

b) reduces triglyceride levels;

c) reduces cholesterol levels;

d) reduces LDL levels;

e) reduces glucose levels;

f) improves insulin sensitivity;

g) ameliorates a metabolic and/or cardiovascular disease; and/or

h) reduces insulin resistance.

10. A kit for decreasing angiopoietin-like 3 (ANGPTL3), wherein the kit comprises:

(a) a compound comprising a modified antisense oligonucleotide 10 to 30 linked nucleosides in length targeted to ANGPTL3, wherein

the modified antisense oligonucleotide is targeted to a target region consisting of nucleotides 1094 to 1264 of SEQ ID NO: 4, and

(b) a label.

11. The kit of claim 10 , wherein the kit further comprises a second agent.

12. The kit of claim 11 , wherein the second agent is selected from among a glucose lowering agent, a lipid lowering agent and ascorbic acid.

13. The compound of claim 9 , wherein the metabolic and/or cardiovascular disease is selected from among obesity, diabetes, atherosclerosis, dyslipidemia, coronary heart disease, non-alcoholic fatty liver disease (NAFLD), hyperfattyacidemia and metabolic syndrome.

14. The compound of claim 1 , further comprising a conjugate.

15. The compound of claim 14 , wherein the conjugate is a carbohydrate group.

16. The compound of claim 1 , wherein:

at least one modified sugar comprises a (4′—CH(CH 3 )—O-2′) bridge, a (4′—CH 2 —O-2′) bridge, or a 4′ (CH 2 ) n —O-2′ bridge, and

n is 1 or 2.

17. The compound of claim 1 , wherein at least one nucleoside of the modified antisense oligonucleotide comprises a modified sugar.

18. The compound of claim 1 , wherein:

at least one modified sugar is a bicyclic sugar or comprises a substituent selected from the group consisting of 5′-methyl, 2′-fluoro, 2′-O—(CH 2 ) 2 OCH 3 and 2′-O—CH 2 —C(═O)—N(R m )(R n ), and

each R m and R n independently is hydrogen or substituted or unsubstituted C1-C10 alkyl.

19. The compound of claim 18 , wherein the at least one modified sugar is a bicyclic sugar.

20. The compound of claim 18 , wherein the at least one modified sugar comprises a 5′-methyl substituent.

21. The compound of claim 18 , wherein the at least one modified sugar comprises a 2′-fluoro substituent.

22. The compound of claim 18 , wherein the at least one modified sugar comprises a 2′-O—(CH 2 ) 2 OCH 3 substituent.

23. The compound of claim 18 , wherein the at least one modified sugar comprises a 2′-O—CH 2 —C(═O)—N(R m )(R n ) substituent, and wherein each R m and R n independently is hydrogen or substituted or unsubstituted C1-C10 alkyl.

24. The compound of claim 1 , which reduces expression of ANGPTL3 by at least 40%.

25. The kit of claim 10 , wherein at least one nucleoside of the modified antisense oligonucleotide comprises a modified sugar.

26. The kit of claim 25 , wherein:

at least one modified sugar is a bicyclic sugar or comprises a substituent selected from the group consisting of 5′-methyl, 2′-fluoro, 2′-O—(CH 2 ) 2 OCH 3 and 2′-O—CH 2 —C(═O)—N(R m )(R n ), and

each R m and R n independently is hydrogen or substituted or unsubstituted C1-C10 alkyl.

27. The kit of claim 10 , wherein the compound reduces expression of ANGPTL3 by at least 40%.

28. A compound comprising a modified antisense oligonucleotide consisting of 20 linked nucleosides and having a nucleobase sequence comprising at least 8 contiguous nucleobases targeted to angiopoietin-like 3 (ANGPTL3), wherein:

the modified antisense oligonucleotide is targeted to a target region consisting of nucleotides 1094 to 1264 of SEQ ID NO: 4;

the modified oligonucleotide comprises:

a gap segment consisting of ten linked deoxynucleosides,

a 5′ wing segment consisting of five linked nucleosides, and

a 3′ wing segment consisting of five linked nucleosides;

the gap segment is positioned between the 5′ wing segment and the 3′ wing segment;

each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar;

each internucleoside linkage is a phosphorothioate linkage; and

each cytosine residue is a 5-methylcytosine.

29. The compound of claim 28 , which reduces expression of ANGPTL3 by at least 40%.