Claims
- 1. A method for increasing contractile function in the heart of a patient, comprising delivering a transgene encoding an angiogenic protein or peptide to the myocardium of the patient by introducing a vector comprising the transgene into at least one coronary artery, wherein the transgene is delivered to the myocardium and expressed, and contractile function in the heart is increased.
- 2. The method of claim 1, wherein the vector is introduced from a catheter conducted into the lumen of one or more coronary arteries.
- 3. The method of claim 2, wherein the vector is injected from the tip of said catheter.
- 4. The method of claim 1, wherein the introduction of vector comprises injecting the vector into the lumen of at least two coronary arteries supplying blood to the myocardium.
- 5. The method of claim 4, wherein the vector is introduced into at least one right coronary artery and at least one left coronary artery.
- 6. The method of claim 3, wherein the vector is introduced by injection from a catheter conducted at least about 1 cm into the lumen of said arteries.
- 7. The method of claim 6, wherein the vector is introduced into at least one right coronary artery and at least one left coronary artery.
- 8. The method of claim 1, wherein the vector is also introduced into a saphenous vein graft and/or an internal mammary artery graft supplying blood to the myocardium.
- 9. The method of claim 1, wherein the vector is introduced by retrograde perfusion from a catheter placed into a conduit receiving blood from the myocardium.
- 10. The method of claim 1, wherein said vector is a viral vector.
- 11. The method of claim 10, wherein said vector is a replication-deficient viral vector.
- 12. The method of claim 10, wherein said vector is an adenovirus vector.
- 13. The method of claim 12, wherein said vector is a replication-deficient adenovirus vector.
- 14. The method of claim 12, wherein about 107 to about 1013 adenovirus vector particles are delivered in vivo.
- 15. The method of claim 14, wherein about 109 to about 1012 adenovirus vector particles are delivered in vivo.
- 16. The method of claim 1, wherein expression of said transgene is driven by a CMV promoter which is contained in the vector.
- 17. The method of claim 1, wherein expression of said transgene is driven by a tissue-specific promoter which is contained in the vector.
- 18. The method of claim 17, wherein expression of said transgene is driven by a cardiomyocyte-specific promoter which is contained in the vector.
- 19. The method of claim 18, wherein said cardiomyocyte-specific promoter is selected from the group consisting of a cardiomyocyte-specific myosin light chain promoter and a cardiomyocyte-specific myosin heavy chain promoter.
- 20. The method of claim 1, wherein said angiogenic protein or peptide is selected from the group consisting of a fibroblast growth factor, a vascular endothelial growth factor, a platelet-derived growth factor and an insulin-like growth factor.
- 21. The method of claim 1, wherein said angiogenic protein or peptide is a fibroblast growth factor.
- 22. The method of claim 21, wherein said angiogenic protein or peptide is a fibroblast growth factor selected from the group consisting of aFGF, bFGF, FGF-4, FGF-5 and FGF-6.
- 23. The method of claim 1, wherein said angiogenic protein is a vascular endothelial growth factor.
- 24. The method of claim 23, wherein said vascular endothelial growth factor is selected from the group consisting of a VEGF-A, a VEGF-B and a VEGF-C.
- 25. The method of claim 1, wherein said angiogenic protein or peptide is an insulin-like growth factor.
- 26. The method of claim 25, wherein said angiogenic protein or peptide is insulin-like growth factor 1.
- 27. The method of claim 1, wherein said angiogenic protein or peptide comprises a signal peptide.
- 28. The method of claim 1, wherein said angiogenic protein or peptide is an angiogenic polypeptide regulator.
- 29. The method of claim 1, wherein said vector further comprises a second transgene encoding an angiogenic protein or peptide.
- 30. The method of claim 1, wherein said vector comprises a transgene or transgenes encoding at least two angiogenic proteins or peptides.
- 31. The method of claim 30, wherein said angiogenic proteins or peptides are each independently selected from the group consisting of a fibroblast growth factor, a vascular endothelial growth factor, a platelet-derived growth factor and an insulin-like growth factor.
- 32. The method of claim 30, wherein said angiogenic proteins or peptides are each independently selected from the group consisting of a fibroblast growth factor, a vascular endothelial growth factor, a platelet-derived growth factor, an insulin-like growth factor, a hypoxia-inducible factor and an angiogenic polypeptide regulator.
- 33. The method of claim 30, wherein the first of said angiogenic proteins or peptides is selected from the group consisting of a fibroblast growth factor, a vascular endothelial growth factor, a platelet-derived growth factor, a hypoxia-inducible factor, an insulin-like growth factor and an angiogenic polypeptide regulator and wherein the second of said angiogenic proteins or peptides is selected from another member of said group.
- 34. The method of claim 30, wherein the first of said angiogenic proteins or peptides is a fibroblast growth factor and the second of said angiogenic proteins or peptides is a vascular endothelial growth factor.
- 35. The method of claim 30, wherein the first of said angiogenic proteins or peptides is a fibroblast growth factor or a vascular endothelial growth factor and the second of said angiogenic proteins or peptides is an insulin-like growth factor.
- 36. The method of claim 30, wherein said vector comprises a transgene or transgenes encoding a fibroblast growth factor, a vascular endothelial growth factor and an insulin-like growth factor.
- 37. The method of claim 1, wherein said vector further comprises a transgene encoding a cardiac enhancing protein or peptide.
- 38. The method of claim 37, wherein said cardiac enhancing protein or peptide is a beta-adrenergic signaling protein or peptide (beta-ASP).
- 39. The method of claim 37, wherein said cardiac enhancing protein or peptide induces the growth or function of myocytes, thereby enhancing contractile function in the heart.
- 40. The method of claim 1, wherein said angiogenic protein or peptide stimulates collateral vessel development in the heart, thereby enhancing blood flow in the heart.
- 41. The method of claim 1, wherein delivery of the transgene using said vector is predominantly localized to the heart.
- 42. The method of claim 1, wherein said vector predominantly transfects cardiac cells.
- 43. The method of claim 1, wherein expression of said transgene occurs predominantly within the myocardium.
- 44. The method of claim 43, wherein expression of said transgene occurs predominantly within cardiac myocytes.
- 45. The method of claim 1, wherein percent wall thickening in the heart is increased.
- 46. A method according to one of claims 1 to 45, wherein the step of introducing a vector into at least one coronary artery is performed coincident with or following infusion of the artery with a vasoactive agent.
- 47. The method of claim 46, wherein said vasoactive agent is infused into the artery at least about 2 minutes prior to the injection of said vector
- 48. The method of claim 46, wherein the vasoactive agent is histamine or a histamine agonist or a vascular endothelial growth factor (VEGF) protein.
- 49. The method of claim 48, wherein the vasoactive agent is histamine or a histamine agonist.
- 50. The method of claim 49, wherein the vasoactive agent is histamine at a concentration of about 1 to 75 micrograms/ml.
- 51. The method of claim 50, wherein the vasoactive agent is histamine at a concentration of about 25 micrograms/ml infused into the artery at a rate of approximately 1 ml/min for about 3 minutes prior to the injection of said vector.
- 52. The method of claim 1, wherein said patient has cardiovascular disease.
- 53. The method of claim 52, wherein said patient has atherosclerosis.
- 54. The method of claim 52, wherein said patient has myocardial ischemia.
- 55. A method according to one of claims 1 to 45 or 52 to 54, wherein said patient is a human.
- 56. The method of claim 55, wherein blood flow within the heart is increased.
- 57. A method for increasing blood flow in an ischemic tissue of a patient, comprising delivering a transgene encoding an angiogenic protein or peptide to an ischemic region of said tissue by introducing a vector comprising the transgene to said tissue, whereby the transgene is expressed in the tissue, and blood flow in the tissue is increased.
- 58. The method of claim 57, wherein the vector is introduced into a tissue by anterograde perfusion from a catheter placed into a conduit delivering blood to the tissue.
- 59. The method of claim 57, wherein the vector is introduced into a tissue by retrograde perfusion from a catheter placed into a conduit receiving blood from the tissue.
- 60. The method of claim 57, wherein the ischemic tissue comprises muscle cells and wherein increasing blood flow within the ischemic tissue results in increased contractile function.
- 61. The method of claim 60, wherein the muscle cells are cardiac myocytes.
- 62. The method of claim 62, wherein the blood vessel is selected from the group consisting of a coronary artery and a femoral artery.
- 63. The method of claim 57, wherein the vector is introduced by injecting a solution comprising the vector into skeletal muscle, wherein the angiogenic protein or peptide causes an increase in blood flow and a decrease in ischemia in the tissue.
- 64. The method of claim 63, wherein said solution comprises at least about one ml.
- 65. The method of claim 57, wherein the patient has cardiovascular disease.
- 66. The method of claim 65, wherein the patient has peripheral vascular disease.
- 67. The method of claim 57, wherein the vector is introduced from a catheter conducted into the lumen of one or more coronary arteries.
- 68. The method of claim 57, wherein the introduction of vector comprises injecting the vector into the lumen of at least two coronary arteries supplying blood to the myocardium.
- 69. The method of claim 68, wherein the vector is introduced into at least one right coronary artery and at least one left coronary artery.
- 70. The method of claim 68, wherein the vector is introduced by injection from a catheter conducted at least about 1 cm into the lumen of said arteries.
- 71. The method of claim 70, wherein the vector is introduced into at least one right coronary artery and at least one left coronary artery.
- 72. The method of claim 66, wherein the vector is also introduced into a saphenous vein graft and/or an internal mammary artery graft supplying blood to the myocardium.
- 73. The method of claim 57, wherein the vector is introduced by retrograde perfusion from a catheter placed into a conduit receiving blood from the myocardium.
- 74. The method of claim 57, wherein said vector is a viral vector.
- 75. The method of claim 74, wherein said vector is a replication-deficient viral vector.
- 76. The method of claim 74, wherein said vector is an adenovirus vector.
- 77. The method of claim 76, wherein said vector is a replication-deficient adenovirus vector.
- 78. The method of claim 76, wherein about 107 to about 1013 adenovirus vector particles are delivered in vivo.
- 79. The method of claim 78, wherein about 109 to about 1012 adenovirus vector particles are delivered in vivo.
- 80. The method of claim 57, wherein expression of said transgene is driven by a CMV promoter which is contained in the vector.
- 81. The method of claim 57, wherein expression of said transgene is driven by a tissue-specific promoter which is contained in the vector.
- 82. The method of claim 81, wherein expression of said transgene is driven by a cardiomyocyte-specific promoter which is contained in the vector.
- 83. The method of claim 82, wherein said cardiomyocyte-specific promoter is selected from the group consisting of a cardiomyocyte-specific myosin light chain promoter and a cardiomyocyte-specific myosin heavy chain promoter.
- 84. The method of claim 57, wherein said angiogenic protein or peptide is selected from the group consisting of a fibroblast growth factor, a vascular endothelial growth factor, a platelet-derived growth factor and an insulin-like growth factor.
- 85. The method of claim 57, wherein said angiogenic protein or peptide is a fibroblast growth factor.
- 86. The method of claim 85, wherein said angiogenic protein or peptide is a fibroblast growth factor selected from the group consisting of aFGF, bFGF, FGF-4, FGF-5 and FGF-6.
- 87. The method of claim 57, wherein said angiogenic protein is a vascular endothelial growth factor.
- 88. The method of claim 87, wherein said vascular endothelial growth factor is selected from the group consisting of a VEGF-A, a VEGF-B and a VEGF-C.
- 89. The method of claim 57, wherein said angiogenic protein or peptide is an insulin-like growth factor.
- 90. The method of claim 89, wherein said angiogenic protein or peptide is insulin-like growth factor 1.
- 91. The method of claim 57, wherein said angiogenic protein or peptide comprises a signal peptide.
- 92. The method of claim 57, wherein said angiogenic protein or peptide is an angiogenic polypeptide regulator.
- 93. The method of claim 57, wherein said vector further comprises a second transgene encoding an angiogenic protein or peptide.
- 94. The method of claim 57, wherein said vector comprises a transgene or transgenes encoding at least two angiogenic proteins or peptides.
- 95. The method of claim 94, wherein said angiogenic proteins or peptides are each independently selected from the group consisting of a fibroblast growth factor, a vascular endothelial growth factor, a platelet-derived growth factor and an insulin-like growth factor.
- 96. The method of claim 94, wherein said angiogenic proteins or peptides are each independently selected from the group consisting of a fibroblast growth factor, a vascular endothelial growth factor, a platelet-derived growth factor, an insulin-like growth factor, a hypoxia-inducible factor and an angiogenic polypeptide regulator.
- 97. The method of claim 94, wherein the first of said angiogenic proteins or peptides is selected from the group consisting of a fibroblast growth factor, a vascular endothelial growth factor, a platelet-derived growth factor, a hypoxia-inducible factor, an insulin-like growth factor and an angiogenic polypeptide regulator and wherein the second of said angiogenic proteins or peptides is selected from another member of said group.
- 98. The method of claim 94, wherein the first of said angiogenic proteins or peptides is a fibroblast growth factor and the second of said angiogenic proteins or peptides is a vascular endothelial growth factor.
- 99. The method of claim 94, wherein the first of said angiogenic proteins or peptides is a fibroblast growth factor or a vascular endothelial growth factor and the second of said angiogenic proteins or peptides is an insulin-like growth factor.
- 100. The method of claim 94, wherein said vector comprises a transgene or transgenes encoding a fibroblast growth factor, a vascular endothelial growth factor and an insulin-like growth factor.
- 101. The method of claim 57, wherein said vector further comprises a transgene encoding a cardiac enhancing protein or peptide.
- 102. The method of claim 101, wherein said cardiac enhancing protein or peptide is a beta-adrenergic signaling protein or peptide (beta-ASP).
- 103. The method of claim 101, wherein said cardiac enhancing protein or peptide induces the growth or function of myocytes, thereby enhancing contractile function in the heart.
- 104. The method of claim 57, wherein said angiogenic protein or peptide stimulates collateral vessel development in the heart, thereby enhancing blood flow in the heart.
- 105. The method of claim 57, wherein delivery of the transgene using said vector is predominantly localized to the heart.
- 106. The method of claim 57, wherein said vector predominantly transfects cardiac cells.
- 107. The method of claim 57, wherein expression of said transgene occurs predominantly within the myocardium.
- 108. The method of claim 107, wherein expression of said transgene occurs predominantly within cardiac myocytes.
- 109. The method of claim 57, wherein percent wall thickening in the heart is increased.
- 110. A method according to one of claims 52 to 54 or 57 to 109, wherein the step of introducing a vector into at least one coronary artery is performed coincident with or following infusion of the artery with a vasoactive agent.
- 111. The method of claim 110, wherein said vasoactive agent is infused into the artery at least about 2 minutes prior to the injection of said vector.
- 112. The method of claim 110, wherein the vasoactive agent is histamine or a histamine agonist or a vascular endothelial growth factor (VEGF) protein.
- 113. The method of claim 112, wherein the vasoactive agent is histamine or a histamine agonist.
- 114. The method of claim 113, wherein the vasoactive agent is histamine at a concentration of about 1 to 75 micrograms/ml.
- 115. The method of claim 114, wherein the vasoactive agent is histamine at a concentration of about 25 micrograms/ml infused into the artery at a rate of approximately 1 ml/min for about 3 minutes prior to the injection of said vector.
- 116. The method of claim 57, wherein the patient has cardiovascular disease.
- 117. The method of claim 116, wherein said patient has atherosclerosis.
- 118. The method of claim 116, wherein said patient has myocardial ischemia.
- 119. A method according to one of claims 57 to 109 or 116 to 118, wherein said patient is a human.
- 120. The method of claim 119, wherein contractile function within the tissue is increased.
- 121. A gene therapy composition comprising a vector containing a transgene encoding an angiogenic protein or peptide.
- 122. The composition of claim 121, wherein said vector is a viral vector.
- 123. The composition of claim 122, wherein said vector is a replication-deficient viral vector.
- 124. The composition of claim 122, wherein said vector is an adenovirus vector.
- 125. The composition of claim 124, wherein said vector is a replication-deficient adenovirus vector.
- 126. The composition of claim 124, comprising about 107 to about 1013 adenovirus vector particles.
- 127. The composition of claim 126, comprising about 109 to about 1012 adenovirus vector particles.
- 128. The composition of claim 121, wherein expression of said transgene is driven by a CMV promoter which is contained in the vector.
- 129. The composition of claim 121, wherein expression of said transgene is driven by a tissue-specific promoter which is contained in the vector.
- 130. The composition of claim 129, wherein expression of said transgene is driven by a cardiomyocyte-specific promoter which is contained in the vector.
- 131. The composition of claim 130, wherein said cardiomyocyte-specific promoter is selected from the group consisting of a cardiomyocyte-specific myosin light chain promoter and myosin heavy chain promoter.
- 132. The composition of claim 121, wherein said angiogenic protein or peptide is selected from the group consisting of a fibroblast growth factor, a vascular endothelial growth factor, a platelet-derived growth factor and an insulin-like growth factor.
- 133. The composition of claim 121, wherein said angiogenic protein or peptide is a fibroblast growth factor.
- 134. The composition of claim 133, wherein said angiogenic protein or peptide is a fibroblast growth factor selected from the group consisting of aFGF, bFGF, FGF-4, FGF-5 and FGF-6.
- 135. The composition of claim 121, wherein said angiogenic protein is a vascular endothelial growth factor.
- 136. The composition of claim 135, wherein said vascular endothelial growth factor is selected from the group consisting of a VEGF-A, a VEGF-B and a VEGF-C.
- 137. The composition of claim 121, wherein said angiogenic protein or peptide is an insulin-like growth factor.
- 138. The composition of claim 137, wherein said angiogenic protein or peptide is insulin-like growth factor 1.
- 139. The composition of claim 121, wherein said angiogenic protein or peptide comprises a signal peptide.
- 140. The composition of claim 121, wherein said angiogenic protein or peptide is angiogenic polypeptide regulator.
- 141. The composition of claim 121, wherein said vector further comprises a second transgene encoding an angiogenic protein or peptide.
- 142. The composition of claim 121, wherein said vector comprises a transgene or transgenes encoding at least two angiogenic proteins or peptides.
- 143. The composition of claim 142, wherein said angiogenic proteins or peptides are each independently selected from the group consisting of a fibroblast growth factor, a vascular endothelial growth factor, a platelet-derived growth factor and an insulin-like growth factor.
- 144. The composition of claim 142, wherein said angiogenic proteins or peptides are each independently selected from the group consisting of a fibroblast growth factor, a vascular endothelial growth factor, a platelet-derived growth factor, an insulin-like growth factor, a hypoxia-inducible factor and an angiogenic polypeptide regulator.
- 145. The composition of claim 142, wherein the first of said angiogenic proteins or peptides is selected from the group consisting of a fibroblast growth factor, a vascular endothelial growth factor, a platelet-derived growth factor, a hypoxia-inducible factor, an insulin-like growth factor and an angiogenic polypeptide regulator and wherein the second of said angiogenic proteins or peptides is selected from another member of said group.
- 146. The composition of claim 142, wherein the first of said angiogenic proteins or peptides is a fibroblast growth factor and the second of said angiogenic proteins or peptides is a vascular endothelial growth factor.
- 147. The composition of claim 142, wherein the first of said angiogenic proteins or peptides is a fibroblast growth factor or a vascular endothelial growth factor and the second of said angiogenic proteins or peptides is an insulin-like growth factor.
- 148. The composition of claim 142, wherein said vector comprises a transgene or transgenes encoding a fibroblast growth factor, a vascular endothelial growth factor and an insulin-like growth factor.
- 149. The composition of claim 121, wherein said vector further comprises a transgene encoding a cardiac enhancing protein or peptide.
- 150. The composition of claim 149, wherein said cardiac enhancing protein or peptide is a beta-adrenergic signaling protein or peptide (beta-ASP).
- 151. The composition of claim 121, further comprising a pharmaceutical excipient.
- 152. A kit comprising a gene therapy composition according to one of claims 121 to 151.
- 153. A kit of claim 152, further comprising a device for introducing the composition into a blood vessel or tissue in vivo.
- 154. A kit of claim 153, wherein the device is a catheter.
- 155. A kit of claim 152, further comprising a vasoactive agent.
- 156. A kit of claim 155, wherein the vasoactive agent is histamine.
CROSS REFERENCE TO RELATED CASES
[0001] This application is a continuation-in-part of U.S. application Ser. No. 09/609,080, filed Jun. 30, 2000, which is a continuation-in-part of U.S. application Ser. No. 09/435,156, filed Nov. 5, 1999, which is a continuation-in-part of U.S. application Ser. No. 08/722,27 1, filed Feb. 27, 1996 (now proceeding to issuance), which is a continuation-in-part of U.S. application Ser. No. 08/485,472, filed Jun. 7, 1995 (now issued as U.S. Pat. No. 5,792,453), which was a continuation-in-part of U.S. application Ser. No. 08/396,207, filed Feb. 28, 1995; and this application is a continuation-in-part of international application PCT/US00/30345, filed Nov. 3, 2000; and this application is a continuation-in-part of international application PCT/US99/02702 filed Feb. 9, 1999, which is a continuation-in-part of U.S. application Ser. No. 09/021,773, filed Feb. 11, 1998, which is a continuation-in-part of U.S. application Ser. No. 08/485,472, filed Jun. 7, 1995 (now issued as U.S. Pat. No. 5,792,453); and this application is a continuation-in-part of U.S. application Ser. No. 09/068,102, filed Apr. 30, 1998, which is a continuation of U.S. A pplication Ser. No. 08/852,779, filed May 6, 1997 and is a continuation-in-part of U.S. application Ser. No. 09/132,167, filed Aug. 10, 1998. All of the above patent applications are incorporated by reference herein.
STATEMENT REGARDING GOVERNMENT-SPONSORED RESEARCH
[0002] Certain of the work described herein was supported in part by grants from the United States Government under Grant Nos. VA-HL0281201, HL1768218 and IP50HL53773.01 awarded by the National Institutes of Health. The U.S. Government may have certain rights in this invention.
Continuations (2)
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Continuation in Parts (10)
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