MODULATION OF APOLIPOPROTEIN C-III EXPRESSION

• US 20110060030A1
• Filed: 05/17/2010
• Published: 03/10/2011
• Est. Priority Date: 04/16/2003
• Status: Active Grant

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Inventors: Lemonidis, Kristina M., Dobie, Kenneth W., Graham, Mark J., Crooke, Rosanne M.
• Granted Patent: US 8,530,439 B2
• Time in Patent Office: Days
• US Class Current: 514/44.A
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• 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: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/314 Phosphoramidates
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/322 2'-R Modification
• CPC Class Codes: C12N 2310/3341 5-Methylcytosine
• CPC Class Codes: C12N 2310/341 Gapmers, i.e. of the type ===---===
• CPC Class Codes: C12N 2310/346 having a combination of backbone and sugar modifications
• CPC Class Codes: C12N 2310/351 Conjugate
• CPC Class Codes: C12N 2310/3521 Methyl
• CPC Class Codes: C12N 2320/30 Special therapeutic applications
• CPC Class Codes: C12N 2330/31 Libraries, arrays

Abstract

Compounds, compositions and methods are provided for modulating the expression of apolipoprotein C-III. The compositions comprise oligonucleotides, targeted to nucleic acid encoding apolipoprotein C-III. Methods of using these compounds for modulation of apolipoprotein C-III expression and for diagnosis and treatment of disease associated with expression of apolipoprotein C-III are provided

Claims

1. A compound 8 to 80 nucleobases in length targeted to a nucleic acid molecule encoding apolipoprotein C-III, wherein said compound specifically hybridizes with said nucleic acid molecule encoding apolipoprotein C-III (SEQ ID NO:

4) and inhibits the expression of apolipoprotein C-III.

8. The compound of claim 1, comprising a chimeric oligonucleotide.

9. The compound according to claim 8, wherein said chimeric oligonucleotide is 20 nucleotides in length, comprising ten 2′

-deoxynucleotides, flanked on each side by five 2′

-methoxyethyl nucleotides, wherein the internucleoside linkages are phosphorothioate, and all cytosine residues are 5-methylcytosines.

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

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

-O-methoxyethyl sugar moiety.

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

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

19. A method of inhibiting the expression of apolipoprotein C-III in cells or tissues comprising contacting said cells or tissues with the compound of claim 1 so that expression of apolipoprotein C-III is inhibited.

24. A method of treating an animal having a disease or condition associated with apolipoprotein C-III comprising administering to said animal a therapeutically or prophylactically effective amount of the compound of claim 1 so that expression of apolipoprotein C-III is inhibited.

25. The method of claim 24, wherein the condition involves abnormal lipid metabolism, abnormal cholesterol metabolism, atherosclerosis, abnormal metabolic condition, hyperlipidemia, diabetes, Type 2 diabetes, obesity and/or cardiovascular disease.

34. A method of modulating glucose levels in an animal comprising administering to said animal the compound of claim 1.

39. A method of preventing or delaying the onset of a disease or condition associated with apolipoprotein C-III in an animal comprising administering to said animal a therapeutically or prophylactically effective amount of the compound of claim 1.

41. The method of claim 39, wherein the condition is an abnormal metabolic condition.

43. The method of claim 39, wherein the disease is diabetes.

45. The method of claim 39, wherein the condition is obesity.

54. A method of reducing serum glucose levels in an animal comprising contacting said animal with the compound of claim 1.

55. A method of decreasing fasted serum insulin levels in an animal comprising contacting said animal with the compound of claim 1.

56. The method of claim 24, wherein the compound comprises a modified oligonucleotide consisting of 12 to 30 linked nucleosides comprising an at least 8 consecutive nucleobases portion complementary to an equal number of nucleobases of nucleotides 3253-3558 of SEQ ID NO:

4, wherein said modified oligonucleotide is at least 90% complementary to SEQ ID NO;

4

57. The method of claim 24, wherein the compound comprises a modified oligonucleotide consisting of 12 to 30 linked nucleosides comprising an at least 8 consecutive nucleobases portion complementary to an equal number of nucleobases of nucleotides 3533-3552 of SEQ ID NO:

4, wherein said modified oligonucleotide is at least 90% complementary to SEQ ID NO;

4.

2-7. -7. (canceled)

10-14. -14. (canceled)

20. A method of screening for a modulator of apolipoprotein C-III, the method comprising the steps of:

a. contacting a preferred target segment of a nucleic acid molecule encoding apolipoprotein C-III with one or more candidate modulators of apolipoprotein C-III, and

b. identifying one or more modulators of apolipoprotein C-III expression which modulate the expression of apolipoprotein C-III.

21-23. -23. (canceled)

26-33. -33. (canceled)

35-38. -38. (canceled)

40. (canceled)

42. (canceled)

44. (canceled)

46-53. -53. (canceled)