MODULATION OF APOLIPOPROTEIN (A) EXPRESSION

• US 20110039910A1
• Filed: 03/17/2010
• Published: 02/17/2011
• Est. Priority Date: 06/02/2003
• Status: Active Grant

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Graham, Mark J., Crooke, Rosanne M.
• Granted Patent: US 8,673,632 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 3/06 Antihyperlipidemics
• 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 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-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 2310/3525 MOE, methoxyethoxy
• CPC Class Codes: C12N 2320/30 Special therapeutic applications

Abstract

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

Claims

1. A compound 8 to 80 nucleobases in length targeted to a nucleic acid molecule encoding apolipoprotein(a), wherein said compound is at least 70% complementary to said nucleic acid molecule encoding apolipoprotein(a), and wherein said compound inhibits the expression of apolipoprotein(a) mRNA by at least 10%.

2. The compound of claim 1 comprising 12 to 50 or 15 to 30 nucleobases in length or 20 nucleobases in length.

4. The compound of claim 1 comprising an oligonucleotide.

5. The compound of claim 4 comprising an antisense oligonucleotide.

8. The compound of claim 4 comprising a chimeric oligonucleotide.

9. The compound of claim 4 wherein at least a portion of said compound hybridizes with RNA to form an oligonucleotide-RNA duplex.

10. The compound of claim 1 having at least 80%, at least 90%, at least 95% or at least 99% complementarity with said nucleic acid molecule encoding apolipoprotein(a).

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

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

-O-methoxyethyl sugar moiety, phosphorothioate internucleoside linkage or 5-methylcytosine.

18. The compound of claim 1 that preferentially binds to a nucleic acid sequence of apolipoprotein(a) and does not bind, or binds weakly to a nucleic acid sequence encoding plasminogen.

19. The compound of claim 1, wherein said compound has a nucleobase sequence comprising at least 8 contiguous nucleobases of a nucleobase sequence selected from any one of SEQ ID NOs 11, 12, 14, 16, 17, 18, 19, 21, 23, 25, 30, 31, 32, 33, 34, 35, 36, 38, 39, 40, 41, 42, 43, 45, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95 or 96.

20. The compound of claim 1, wherein said compound comprises an antisense nucleic acid molecule that is specifically hybridizable with

(a) a 5′

-untranslated region (5′

UTR) of a nucleic acid molecule encoding apolipoprotein(a);

(b) a start region of a nucleic acid molecule encoding apolipoprotein(a);

(c) a coding region of a nucleic acid molecule encoding apolipoprotein(a);

(d) a stop region of a nucleic acid molecule encoding apolipoprotein(a);

or

(e) a 3′

-untranslated region (3′

UTR) of a nucleic acid molecule encoding apolipoprotein(a).

25. A method of inhibiting the expression of apolipoprotein(a) in a cell or tissue comprising contacting said cell or tissue with the compound of claim 1 so that expression of apolipoprotein(a) is inhibited.

29. A kit, pharmaceutical composition or assay device comprising the compound of claim 1.

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

32. The method of claim 30, wherein the disease or condition is a cardiovascular disorder, atherosclerosis, hypercholesterolimia, coronary artery disease or any combination thereof.

3. (canceled)

6-7. -7. (canceled)

11-13. -13. (canceled)

16-17. -17. (canceled)

21-24. -24. (canceled)

26-28. -28. (canceled)

31. (canceled)

33. A method of inhibiting the expression of apolipoprotein(a) comprising contacting a biological system expressing human apolipoprotein(a) with a synthetic antisense compound, wherein said synthetic antisense compound comprises from 15 to 30 nucleobases in length and has at least 3 mismatches to human plasminogen.

36. The method of claim 33, wherein said compound has a nucleobase sequence comprising a nucleobase sequence selected from any one of SEQ ID NOs:

11, 12, 14, 16-30, 32-40, and 43-44.

34-35. -35. (canceled)