Patent EA-005157-B1 (EA)
Title: Techniques and compositions for treating heart failure and ventricular remodeling by in vivo delivery of angiogenic transgenes
Inventor: HAMMOND H KIRK
IPC: A61K35/76
Filed: 1998-04-30
Abstract: 1. A method for treating a patient suffering from congestive heart failure, comprising delivering a vector to the heart of said patient, said vector comprising a gene encoding an angiogenic protein or peptide operably linked to a promoter for expression of the gene. 2. The method of claim 1, wherein the congestive heart failure is associated with severe coronary artery disease and myocardial ischemia. 3. The method of claim 1, wherein the congestive heart failure is associated with a dilated cardiomyopathy. 4. The method of claim 1, wherein the vector is delivered to a blood vessel supplying blood to the myocardium of the heart. 5. The method of claim 4, wherein said blood vessel supplying blood to the myocardium is a coronary artery, a saphenous vein graft, or an internal mammary artery graft. 6. The method of claim 4, wherein the vector is delivered by intracoronary injection directly into the left and/or right coronary arteries. 7. The method of claim 6, wherein said intracoronary injection is conducted about 1 cm into the lumens of the left and/or right coronary arteries. 8. The method of claim 1, wherein the angiogenic protein or peptide is a member of the fibroblast growth factor (FGF) family. 9. The method of claim 8, wherein the angiogenic protein or peptide is an FGF-4, FGF-5, FGF-6, FGF-1 or FGF-2. 10. The method of claim 9, wherein the angiogenic protein is an FGF-4. 11. The method of claim 9, wherein the angiogenic protein is an FGF-5. 12. The method of claim 9, wherein the angiogenic protein is an FGF-1. 13. The method of claim 9, wherein the angiogenic protein is an FGF-2. 14. The method of claim 1, wherein the angiogenic protein comprises a secretion signal sequence. 15. The method of claim 14, wherein the angiogenic protein is an FGF-2 modified by inclusion of a heterologous secretion signal sequence. 16. The method of claim 1, wherein the angiogenic protein or peptide is a member of the vascular endothelial growth factor (VEGF) family. 17. The method of claim 16, wherein the angiogenic protein or peptide is a VEGF-121, VEGF-145, VEGF-165, VEGF-189, VEGF-206, VEGF-167, VEGF-186 or a VEGF-C. 18. The method of claim 1, wherein the angiogenic protein or peptide is a member of the platelet-derived growth factor (PDGF) family. 19. The method of claim 18, wherein the angiogenic protein or peptide is a PDGF-A or a PDGF-B. 20. The method of claim 1, wherein the angiogenic protein or peptide is a member of the insulin-like growth factor (IGF) family. 21. The method of claim 1, wherein said promoter is a CMV promoter. 22. The method of claim 1, wherein said promoter is tissue-specific for cardiac myocytes. 23. The method of claim 22, wherein said tissue-specific promoter is a ventricular myocyte-specific promoter. 24. The method of claim 23, wherein said ventricular myocyte-specific promoter is a ventricular myosin light chain-2 promoter or a ventricular myosin heavy chain promoter. 25. The method of claim 1, wherein the vector is a viral vector or a lipid-based vector. 26. The method of claim 25, wherein the vector is a viral particle. 27. The method of claim 26, wherein the viral particle is a replication-defective adenovirus (Ad). 28. The method of claim 26, wherein the viral particle is a replication-defective adeno-associated virus (AAV). 29. The method of claim 26, wherein about 10<6>-10<14> virus vector particles are delivered in the injection. 30. The method of claim 27, wherein about 10<8>-10<12> adenovirus vector particles are delivered in the injection. 31. A method for preventing or alleviating ventricular remodeling in a patient who has suffered a myocardial infarction, comprising delivering a vector to the heart of said patient, said vector comprising a gene encoding an angiogenic protein or peptide operably linked to a promoter for expression of the gene, thereby increasing myocardial blood flow and alleviating deleterious ventricular remodeling. 32. The method of claim 31, wherein the vector is delivered to a blood vessel supplying blood to the myocardium of the heart. 33. The method of claim 32, wherein said blood vessel supplying blood to the myocardium is a coronary artery, a saphenous vein graft, or an internal mammary artery graft. 34. The method of claim 32, wherein the vector is delivered by intracoronary injection directly into the left and/or right coronary arteries. 35. The method of claim 34, wherein said intracoronary injection is conducted about 1 cm into the lumens of the left and/or right coronary arteries. 36. The method of claim 31, wherein the angiogenic protein or peptide is a member of the fibroblast growth factor (FGF) family. 37. The method of claim 36, wherein the angiogenic protein or peptide is an FGF-4, FGF-5, FGF-6, FGF-1 or FGF-2. 38. The method of claim 37, wherein the angiogenic protein is an FGF-4. 39. The method of claim 37, wherein the angiogenic protein is an FGF-5. 40. The method of claim 39, wherein the angiogenic protein is an FGF-1. 41. The method of claim 39, wherein the angiogenic protein is an FGF-2. 42. The method of claim 31, wherein the angiogenic protein comprises a secretion signal sequence. 43. The method of claim 42, wherein the angiogenic protein is an FGF-2 modified by inclusion of a heterologous secretion signal sequence. 44. The method of claim 31, wherein the angiogenic protein or peptide is a member of the vascular endothelial growth factor (VEGF) family. 45. The method of claim 44, wherein the angiogenic protein or peptide is a VEGF-121, VEGF-145, VEGF-165, VEGF-189, VEGF-206, VEGF-167, VEGF-186 or a VEGF-C. 46. The method of claim 31, wherein the angiogenic protein or peptide is a member of the platelet-derived growth factor (PDGF) family. 47. The method of claim 46, wherein the angiogenic protein or peptide is a PDGF-A or a PDGF-B. 48. The method of claim 31, wherein the angiogenic protein or peptide is a member of the insulin-like growth factor (IGF) family. 49. The method of claim 31, wherein said promoter is a CMV promoter. 50. The method of claim 31, wherein said promoter is tissue-specific for cardiac myocytes. 51. The method of claim 50, wherein said tissue-specific promoter is a ventricular myocyte-specific promoter. 52. The method of claim 51, wherein said ventricular myocyte-specific promoter is a ventricular myosin light chain-2 promoter or a ventricular myosin heavy chain promoter. 53. The method of claim 31, wherein the vector is a viral vector or a lipid-based vector. 54. The method of claim 53, wherein the vector is a viral particle. 55. The method of claim 54, wherein the viral particle is a replication-defective adenovirus (Ad). 56. The method of claim 54, wherein the viral particle is a replication-defective adeno-associated virus (AAV). 57. The method of claim 54, wherein about 10<6>-10<14> virus vector particles are delivered in the injection. 58. The method of claim 55, wherein about 10<8>-10<12> adenovirus vector particles are delivered in the injection.