METHODS AND COMPOSITIONS FOR THE TREATMENT AND DIAGNOSIS OF STATIN-INDUCED MYOPATHY

• US 20100310574A1
• Filed: 06/05/2008
• Published: 12/09/2010
• Est. Priority Date: 06/12/2007
• Status: Abandoned Application

• Current Assignee: BETH Israel Deaconess Medical Center (Caregroup Incorporated)
• Original Assignee: BETH Israel Deaconess Medical Center (Caregroup Incorporated)
• Inventors: Hanai, Junichi, Lecker, Stewart H., Sukhatme, Vikas P.
• Application Number:
  US12/663,423
• Publication Number:
  US 20100310574A1
• Time in Patent Office: Days
• US Class Current: 424/158.1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/22 of acyclic acids, e.g. pravastatin
• CPC Class Codes: A61K 31/366 having six-membered rings, e.g. delta-lactones
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 38/17 from animals; from humans enzyme inhibitors A61K38/005
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C12Q 1/25 involving enzymes not classifiable in groups C12Q1/26 - C12Q1/66
• CPC Class Codes: G01N 2333/9015 Ligases (6)
• CPC Class Codes: G01N 2500/10 involving cells
• CPC Class Codes: G01N 2800/10 Musculoskeletal or connective tissue disorders
• CPC Class Codes: G01N 2800/50 Determining the risk of developing a disease
• CPC Class Codes: G01N 2800/56 Staging of a disease; Further complications associated with the disease
• CPC Class Codes: G01N 33/573 for enzymes or isoenzymes
• CPC Class Codes: Y10T 436/143333 Saccharide [e.g., DNA, etc.]

Abstract

The invention provides compositions and kits containing an atrogin-1 inhibitor compound useful for the treatment of a statin-mediated myopathy. Kits for the diagnosis of a statin-mediated myopathy are also provided. The invention further features methods for treating or preventing a statin-mediated myopathy in a subject via administration of a therapeutically effective amount of an atrogin-1 inhibitor compound. The invention further provides methods of diagnosing a subject as having a propensity to develop a statin-induced myopathy and methods of monitoring a statin-induced myopathy or a propensity to develop a statin-mediated myopathy in a subject. The invention also features methods for identifying a compound for the treatment of a statin-mediated myopathy and methods of identifying a statin compound as having the propensity to induce a statin-mediated myopathy.

Claims

1. A method of treating or preventing a statin-mediated myopathy in a subject, said method comprising administering to said subject a therapeutically effective amount of an atrogin-1 inhibitor compound in an amount and for a time sufficient to treat or prevent said statin-mediated myopathy in said subject.

2. The method of claim 1, wherein said atrogin-1 inhibitor compound reduces or inhibits the expression levels or biological activity of an atrogin-1 protein or nucleic acid.

3. The method of claim 2, wherein said atrogin-1 inhibitor compound is PGC-1α

polypeptide or PGC-1α

polypeptide.

6. The method of claim 2, wherein said biological activity of said atrogin-1 polypeptide is ubiquitin ligase activity, substrate binding activity, or nuclear translocation.

8. The method of claim 1, wherein said atrogin-1 inhibitor compound specifically binds the ubiquitin ligase domain, the substrate-binding domain of atrogin-1, or the N- or C-terminal nuclear localization sequence of atrogin-1.

11. The method of claim 1, wherein said atrogin-1 inhibitor compound is an antibody or antigen-binding fragment thereof that specifically binds atrogin-1.

14. The method of claim 1, wherein said atrogin-1 inhibitor compound reduces or inhibits the expression levels of an atrogin-1 nucleic acid molecule.

17. The method of claim 14, wherein said atrogin-1 inhibitor compound is a morpholino oligomer that is complementary to at least a portion of an atrogin-1 nucleic acid molecule.

18. The method of claim 17, wherein said morpholino oligomer comprises a sequence substantially identical to SEQ ID NO:

8 or SEQ ID NO;

9.

19. The method of claim 14, wherein said atrogin-1 inhibitor compound is a small RNA having at least one strand that comprises a nucleic acid sequence substantially identical to at least a portion of an atrogin-1 nucleic acid molecule, or a complementary sequence thereof.

25. The method of claim 1, wherein said subject has been treated with a statin.

27. The method of claim 25, wherein said subject is still being treated with said statin.

32. The method of claim 1, wherein said subject will be treated with a statin compound and said atrogin-1 inhibitor compound is administered prior to administering said statin compound.

4-5. -5. (canceled)

7. (canceled)

9-10. -10. (canceled)

12-13. -13. (canceled)

15-16. -16. (canceled)

20-24. -24. (canceled)

26. (canceled)

28-31. -31. (canceled)

33. (canceled)

34. A composition comprising an atrogin-1 inhibitor compound that reduces or inhibits the expression or biological activity of atrogin-1, wherein said compound is formulated for the treatment or prevention of a statin-mediated myopathy.

47. The composition of claim 34, wherein said atrogin-1 inhibitor compound reduces or inhibits the expression levels of an atrogin-1 nucleic acid molecule.

50. The composition of claim 47, wherein said atrogin-1 inhibitor compound is a morpholino oligomer that is complementary to at least a portion of an atrogin-1 nucleic acid molecule.

51. The composition of claim 50, wherein said morpholino oligomer comprises a sequence substantially identical to SEQ ID NO:

8 or SEQ ID NO;

9.

52. The composition of claim 47, wherein said atrogin-1 inhibitor compound is a small RNA having at least one strand that comprises at least a portion of an atrogin-1 nucleic acid molecule, or a complementary sequence thereof.

35-46. -46. (canceled)

48-49. -49. (canceled)

53-54. -54. (canceled)

55. A kit comprising:

i) a statin;

ii) an atrogin-1 inhibitor compound; and

iii) instructions for administration of said statin and said atrogin-1 inhibitor compound for the treatment of a statin-induced myopathy.

56-57. -57. (canceled)

58. A method of diagnosing a subject as having or having a propensity to develop a statin-mediated myopathy, said method comprising measuring the level of an atrogin-1 polypeptide, atrogin-1 nucleic acid, or fragments thereof, in a sample from said subject relative to a reference sample or level, wherein an alteration in said subject levels relative to said reference sample or level is diagnostic of a statin-mediated myopathy or a propensity to develop a statin-mediated myopathy in said subject.

59. The method of claim 58, wherein said reference sample or level is a normal reference sample or level and said alteration is an increase.

60-61. -61. (canceled)

62. A method of diagnosing a subject as having or having a propensity to develop a statin-mediated myopathy, said method comprising measuring the level of an antibody, or a fragment thereof, that specifically binds atrogin-1 in a blood or serum sample from said subject relative to a reference level, wherein an alteration in said subject levels compared to said reference level is diagnostic of a statin-mediated myopathy or a propensity to develop a statin-mediated myopathy in said subject.

63. The method of claim 62, wherein said reference is a normal reference level and said alteration is an increase.

64. (canceled)

65. A method of monitoring a statin-mediated myopathy or a propensity to develop a statin-mediated myopathy in a subject, said method comprising measuring the level of an atrogin-1 polypeptide, nucleic acid, atrogin-1 specific antibody, or fragments thereof in a sample from said subject, and comparing said level to a reference sample or level, wherein an alteration in said level is an indicator of a change in the propensity to develop a statin-mediated myopathy, or a change in a statin-mediated myopathy of the subject.

66-85. -85. (canceled)

86. A method of treating a biological sample from a subject having a statin-induced myopathy or a propensity to develop a statin-induced myopathy comprising the steps of:

(i) obtaining a biological sample from a subject having a statin-induced myopathy or a propensity to develop a statin-induced myopathy; and

(ii) treating said biological sample ex vivo with a therapeutically effective amount of an atrogin-1 inhibitor compound.

87-89. -89. (canceled)