Methods for treating pompe disease

• US 20090117091A1
• Filed: 11/13/2007
• Published: 05/07/2009
• Est. Priority Date: 11/13/2006
• Status: Abandoned Application

• Current Assignee: Biomarin Pharmaceutical Incorporated (Amgen Inc.)
• Original Assignee: Biomarin Pharmaceutical Incorporated (Amgen Inc.)
• Inventors: LeBowitz, Jonathan, Maga, John
• Application Number:
  US11/985,360
• Publication Number:
  US 20090117091A1
• Time in Patent Office: Days
• US Class Current: 424/94.610
• CPC Class Codes: A61K 47/62 the modifying agent being a protein, peptide or polyamino acid
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention provides methods for treating Pompe disease in a subject by administering to the subject a therapeutically effective amount of a fusion protein which includes human acid alpha-glucosidase (GAA), or a fragment thereof, and a lysosomal targeting domain. The lysosomal targeting domain binds the human cation-independent mannose-6-phosphate receptor in a mannose-6-phosphate-independent manner.

Claims

1. A method for treating pompe disease in a subject comprising administering to the subject a therapeutically effective amount of a fusion protein comprising human acid alpha-glucosidase (GAA), or a fragment thereof, and a lysosomal targeting domain, wherein the lysosomal targeting domain binds the human cation-independent mannose-6-phosphate receptor in a mannose-6-phosphate-independent manner.

2. The method of claim 1, wherein the lysosomal targeting domain comprises mature human insulin-like growth factor II (IGF-II) or a fragment or sequence variant thereof.

3. The method of claim 2, wherein the lysosomal targeting domain comprises amino acids 1 and 8-67 of mature human IGF-II.

4. The method of claim 1, wherein the fusion protein comprises amino acids 70-952 of human GAA.

5. The method of claim 1, wherein the fusion protein has reduced mannose-6-phosphate (M6P) level thereon compared to wild-type human GAA.

6. The method of claim 1, wherein the fusion protein has no functional M6P level thereon.

7. The method of claim 1, wherein the therapeutically effective amount is in the range of 2.5-20 mg per kilogram of body weight of the subject.

8. The method of claim 1, wherein the fusion protein is administered intravenously.

9. The method of claim 1, wherein the fusion protein is administered bimonthly, monthly, triweekly, biweekly, weekly, daily, or at variable intervals.

10. A method for treating Pompe disease in a subject comprising administering to the subject a therapeutically effective amount of a fusion protein comprising amino acids 1 and 8-67 of mature human insulin-like growth factor II (IGF-II) and amino acids 70-952 of human acid alpha-glucosidase (GAA).

11. The method of claim 10, wherein the fusion protein further comprises a spacer sequence Gly-Ala-Pro between the amino acids of mature human IGF-II and the amino acids of human GAA.

12. The method of claim 10, wherein the fusion protein has reduced mannose-6-phosphate (M6P) level thereon compared to wild-type human GAA.

13. The method of claim 10, wherein the fusion protein has no functional M6P level thereon.

14. A method for reducing glycogen levels in vivo comprising administering to a subject suffering from Pompe disease an effective amount of a fusion protein comprising human acid alpha-glucosidase (GAA), or a fragment thereof, and a lysosomal targeting domain, wherein the lysosomal targeting domain binds the human cation-independent mannose-6-phosphate receptor in a mannose-6-phosphate-independent manner.

15. The method of claim 14, wherein the lysosomal targeting domain comprises mature human insulin-like growth factor II (IGF-II) or a fragment or sequence variant thereof.

16. The method of claim 15, wherein the lysosomal targeting domain comprises amino acids 1 and 8-67 of mature human IGF-II.

17. The method of claim 14, wherein the fusion protein comprises amino acids 70-952 of human GAA.

18. The method of claim 14, wherein the fusion protein has reduced mannose-6-phosphate (M6P) level thereon compared to wild-type human GAA.

19. The method of claim 14, wherein the fusion protein has no functional M6P level thereon.

20. The method of claim 14, wherein the therapeutically effective amount is in the range of 2.5-20 mg per kilogram of body weight of the subject.

21. The method of claim 14, wherein the fusion protein is administered intravenously.

22. The method of claim 14, wherein the fusion protein is administered bimonthly, monthly, triweekly, biweekly, weekly, daily, or at variable intervals.

23. A method for reducing glycogen levels in a mammalian lysosome comprising targeting to the lysosome an effective amount of a fusion protein comprising human acid alpha-glucosidase (GAA), or a fragment thereof, and a lysosomal targeting domain, wherein the lysosomal targeting domain binds the human cation-independent mannose-6-phosphate receptor in a mannose-6-phosphate-independent manner.

24. The method of claim 23, wherein the lysosomal targeting domain comprises mature human insulin-like growth factor II (IGF-II) or a fragment or sequence variant thereof.

25. The method of claim 23, wherein the lysosomal targeting domain comprises amino acids 1 and 8-67 of mature human IGF-II.

26. The method of claim 23, wherein the fusion protein comprises amino acids 70-952 of human GAA.

27. A method for reducing glycogen levels in a muscle tissue of a subject suffering from Pompe disease comprising delivering to the muscle tissue a therapeutically effective amount of a fusion protein comprising human acid alpha-glucosidase (GAA), or a fragment thereof, and a lysosomal targeting domain, wherein the lysosomal targeting domain binds the human cation-independent mannose-6-phosphate receptor in a mannose-6-phosphate-independent manner.

28. The method of claim 27, wherein the muscle tissue is skeletal muscle.

29. A method for treating cardiomyopathy associated with Pompe disease in a subject comprising administering to the subject a therapeutically effective amount of a fusion protein comprising human acid alpha-glucosidase (GAA), or a fragment thereof, and a lysosomal targeting domain, wherein the lysosomal targeting domain binds the human cation-independent mannose-6-phosphate receptor in a mannose-6-phosphate-independent manner.

30. A method for treating myopathy associated with Pompe disease in a subject comprising administering to the subject a therapeutically effective amount of a fusion protein comprising human acid alpha-glucosidase (GAA), or a fragment thereof, and a lysosomal targeting domain, wherein the lysosomal targeting domain binds the human cation-independent mannose-6-phosphate receptor in a mannose-6-phosphate-independent manner.

31. A method for increasing acid alpha-glucosidase (GAA) activity in a subject suffering from Pompe disease comprising administering to the subject a fusion protein comprising human acid alpha-glucosidase (GAA), or a fragment thereof, and a lysosomal targeting domain, wherein the lysosomal targeting domain binds the human cation-independent mannose-6-phosphate receptor in a mannose-6-phosphate-independent manner.

32. A pharmaceutical composition suitable for treatment of Pompe disease comprising a therapeutically effective amount of a fusion protein comprising human acid alpha-glucosidase (GAA), or a fragment thereof, and a lysosomal targeting domain, wherein the lysosomal targeting domain binds the human cation-independent mannose-6-phosphate receptor in a mannose-6-phosphate-independent manner.

33. The pharmaceutical composition of claim 32, wherein the lysosomal targeting domain comprises mature human insulin-like growth factor II (IGF-II) or a fragment or sequence variant thereof.

34. The pharmaceutical composition of claim 32, wherein the lysosomal targeting domain comprises amino acids 1 and 8-67 of mature human IGF-II.

35. The pharmaceutical composition of claim 32, wherein the fusion protein comprises amino acids 70-952 of human GAA.

36. The pharmaceutical composition of claim 32, wherein the fusion protein comprises amino acids 70-952 of human GAA and amino acids 1 and 8-67 of mature human IGF-II.

37. The pharmaceutical composition of claim 36, wherein the fusion protein further comprises a spacer sequence Gly-Ala-Pro between the amino acids of human GAA and the amino acids of mature human IGF-II.

38. The pharmaceutical composition of claim 32, wherein the fusion protein has reduced mannose-6-phosphate (M6P) level thereon compared to wild-type human GAA.

39. The pharmaceutical composition of claim 32, wherein the fusion protein has no functional M6P level thereon.

40. The pharmaceutical composition of claim 32, wherein the pharmaceutical composition further comprises a pharmaceutical carrier.