USE OF HMGB1 FOR PROTECTION AGAINST ISCHEMIA REPERFUSION INJURY

• US 20080004207A1
• Filed: 02/06/2007
• Published: 01/03/2008
• Est. Priority Date: 02/06/2006
• Status: Active Grant

• Current Assignee: The Feinstein Institutes For Medical Research, University of Pittsburgh of The Commonwealth System of Higher Education
• Original Assignee: The Feinstein Institute for Medical Research (Northwell Health, Inc.), University of Pittsburgh of The Commonwealth System of Higher Education
• Inventors: Billiar, Timothy, Fink, Mitchell, Tracey, Kevin, Tsung, Allan
• Granted Patent: US 7,829,097 B2
• Time in Patent Office: Days
• US Class Current: 514/2
• CPC Class Codes: A01N 1/02 Preservation of living parts
• CPC Class Codes: A01N 1/0226 Physiologically active agents, i.e. substances affecting physiological processes of cells and tissue to be preserved, e.g. anti-oxidants or nutrients
• CPC Class Codes: A61K 38/17 from animals; from humans enzyme inhibitors A61K38/005
• CPC Class Codes: A61P 37/02 Immunomodulators
• 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

Abstract

Methods and compositions are disclosed for protecting an organ or tissue from inflammation and organ injury following ischemia, reperfusion, and trauma through the administration of an HMGB1 protein within a time period sufficient to protect the organ or tissue from injury.

Claims

1. A method of protecting an organ or tissue from ischemic injury comprising administering administration of a High Mobility Group Box 1 (HMGB1) protein to the organ or tissue, wherein the HMGB1 protein is administered in an amount effective to protect the organ or tissue from injury, and wherein the HMGB1 protein is administered within a time period sufficient to protect the organ or tissue from injury.

6. The method of claim 1, comprising administration of an HMGB1 protein.

7. The method of claim 6, wherein the HMGB1 protein comprises a polypeptide having an amino acid sequence at least 80% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:

1, SEQ ID NO;

2, SEQ ID NO;

3, SEQ ID NO;

18, SEQ ID NO;

19, SEQ ID NO;

24, and SEQ ID NOS;

27-38.

8. The method of claim 7, wherein the HMGB1 protein comprises a polypeptide having the amino acid sequence of SEQ ID NO:

2.

9. The method of claim 7, wherein the HMGB1 protein consists of a polypeptide having the amino acid sequence of SEQ ID NO:

2.

10. The method of claim 1, comprising administration of a biologically active fragment of an HMGB1 protein.

11. The method of claim 10, wherein the biologically active fragment has an amino acid sequence at least 80% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:

4, SEQ ID NO;

5, SEQ ID NO;

16, SEQ ID NO;

17, SEQ ID NOS;

20-23, and SEQ ID NOS;

25-26.

12. The method of claim 10, wherein the biologically active fragment comprises a polypeptide having the amino acid sequence of SEQ ID NO:

26.

13. The method of claim 10, wherein the biologically active fragment consists of a polypeptide having the amino acid sequence of SEQ ID NO:

26.

14. The method of claim 1, wherein the HMGB1 protein is administered prior to one hour after injury.

15. The method of claim 14, wherein the HMGB1 protein is administered prior to 45 minutes after injury.

16. The method of claim 14, wherein the HMGB1 protein is administered prior to 30 minutes after injury.

17. The method of claim 14, wherein the HMGB1 protein is administered prior to 15 minutes after injury.

18. The method of claim 14, wherein the HMGB1 protein is administered prior to 10 minutes after injury.

19. The method of claim 14, wherein the HMGB1 protein is administered prior to 5 minutes after injury.

27. The method of claim 1, wherein the organ or tissue is in a host.

28. The method of claim 1, wherein the organ or tissue is in vitro.

29. The method of claim 27, wherein the host is a human.

30. The method of claim 27, wherein the host is a non-human mammal.

31. The method of claim 27, wherein the HMGB1 protein is administered systemically to the host.

32. The method of claim 27, wherein the HMGB1 protein is administered by a route selected from the group consisting of intravenous, intramuscular, intraperitoneal, percutaneous, subcutaneous, topical, transmucosal, or oral.

33. The method of claim 1, wherein the HMGB1 protein is administered locally to the organ or tissue.

34. The method of claim 1, wherein the HMGB1 protein is administered in a dosage of about 5 μ

g to about 35 mg.

35. The method of claim 34, wherein the HMGB1 protein is administered in a dosage of about 5 μ

g to about 20 μ

g.

36. The method of claim 34, wherein the HMGB1 protein is administered in a dosage of about 20 μ

g to about 1 mg.

37. The method of claim 34, wherein the HMGB1 protein is administered in a dosage of about 1 mg to about 10 mg.

38. The method of claim 34, wherein the HMGB1 protein is administered in a dosage of about 10 mg to about 35 mg.

43. The method of claim 1, wherein the organ or tissue is selected from the group consisting of a brain, a heart, a liver, a portion of a liver, a lung, a portion of a lung, a kidney, an intestine, a portion of an intestine, a pancreas, an eye, a muscle, a portion of a muscle, a bone, a portion of a bone, a nerve tissue, a vascular tissue, or an epithelial tissue.

44. The method of claim 43, wherein the organ or tissue is a heart.

45. The method of claim 43, wherein the organ or tissue is a brain.

46. The method of claim 43, wherein the organ or tissue is a liver or a portion of a liver.

47. The method of claim 43, wherein the organ or tissue is a bone or a portion of a bone.

2. A method of protecting an organ or tissue from injury resulting from ischemia and reperfusion comprising administration of an HMGB1 protein to the organ or tissue prior to completion of reperfusion, wherein the HMGB1 protein is administered in an amount effective to protect the organ or tissue from injury.

3. The method of claim 2 wherein the ischemia and reperfusion is controlled.

4. The method of claim 2 wherein the ischemia and reperfusion is uncontrolled.

20. The method of claim 3, wherein the HMGB1 protein is administered prior to the injury.

21. The method of claim 20, wherein the HMGB1 protein is administered about one hour prior to the injury.

22. The method of claim 20, wherein the HMGB1 protein is administered about 45 minutes prior to the injury.

23. The method of claim 20, wherein the HMGB1 protein is administered about 30 minutes prior to the injury.

24. The method of claim 20, wherein the HMGB1 protein is administered about 15 minutes prior to the injury.

25. The method of claim 20, wherein the HMGB1 protein is administered about 10 minutes prior to the injury.

26. The method of claim 20, wherein the HMGB1 protein is administered about 5 minutes prior to the injury.

39. The method of claim 2, wherein the ischemia and reperfusion occur during transplantation of the organ from a donor to a recipient.

40. The method of claim 39, wherein the HMGB1 protein is administered to the donor prior to ischemia.

41. The method of claim 39, wherein the HMGB1 protein is administered to the recipient prior to reperfusion.

42. The method of claim 2, wherein the ischemia and reperfusion occur during a surgical procedure.

5. A method of protecting an organ or tissue from traumatic injury comprising administration of an HMGB1 protein to the organ or tissue, wherein the HMGB1 protein is administered in an amount effective to protect the organ or tissue from injury, and wherein the HMGB1 protein is administered within a time period sufficient to protect the organ or tissue from injury.

48. A method of preparing an organ or tissue for transplantation from a donor into a recipient comprising administration of an HMGB1 protein to the donor, wherein the organ or tissue is within the donor.

49. The method of claim 48, wherein the donor is a cadaver donor.

50. The method of claim 48, wherein the donor is a human.

51. The method of claim 48, wherein the donor is a non-human mammal.

52. The method of claim 48, wherein the HMGB1 protein is administered systemically to the donor.

53. The method of claim 48, wherein the HMGB1 protein is administered locally to the organ.

54. The method of claim 48, wherein the HMGB1 protein is administered by a route selected from the group consisting of intravenous, intramuscular, intraperitoneal, percutaneous, subcutaneous, transmucosal, topical, or oral.

55. A method of preparing an organ or tissue for implantation into a recipient comprising administration of an HMGB1 protein to the organ or tissue ex vivo.

56. The method of claim 55 wherein the recipient is a human.

57. The method of claim 55, wherein the recipient is a non-human mammal.

58. A composition for the prevention of injury to an organ following ischemia and reperfusion, comprising an HMGB1 protein and a pharmaceutically acceptable carrier.

59. The composition of claim 58, wherein the composition is formulated for administration by a route selected from the group consisting of intravenous, intramuscular, intraperitoneal, percutaneous, subcutaneous, transmucosal, topical, or oral.

60. The composition of claim 58, further comprising one or more components selected from the group consisting of diluents, adjuvants, excipients, or pH adjusting agents.

61. A kit comprising a composition for the prevention of injury to an organ following isehemia and reperfusion and suitable instructions for administration, and optionally comprising a means for administration of the composition, wherein the composition comprises an HMGB1 protein and a pharmaceutically acceptable carrier.

62. Use of an HMGB1 protein in preparation of a medicament for use in protecting an organ from injury caused by an event selected from the group consisting of ischemia, reperfusion, and trauma.

63. The use of claim 62, wherein the organ or tissue is selected from the group consisting of a brain, a heart, a liver, a portion of a liver, a lung, a portion of a lung, a kidney, an intestine, a portion of an intestine, a pancreas, an eye, a muscle, a portion of a muscle, a bone, a portion of a bone, a nerve tissue, a vascular tissue, or an epithelial tissue.

64. The method of claim 63, wherein the organ or tissue is a heart.

65. The method of claim 63, wherein the organ or tissue is a brain.

66. The method of claim 63, wherein the organ or tissue is a liver or a portion of a liver.

67. The method of claim 63, wherein the organ or tissue is a bone or a portion of a bone.

68. The use of claim 62, wherein the medicament is formulated for administration by a route selected from the group consisting of intravenous, intramuscular, intraperitoneal, percutaneous, subcutaneous, transmucosal, topical, or oral.