Methods and compositions for the repair and/or regeneration of damaged myocardium

• US 20020061587A1
• Filed: 07/31/2001
• Published: 05/23/2002
• Est. Priority Date: 07/31/2000
• Status: Abandoned Application

• Current Assignee: New York Medical College (Touro College & University System)
• Original Assignee: New York Medical College (Touro College & University System)
• Inventors: Anversa, Piero
• Application Number:
  US09/919,732
• Publication Number:
  US 20020061587A1
• Time in Patent Office: Days
• US Class Current: 435/366
• CPC Class Codes: A01K 67/0271 Chimeric vertebrates, e.g. comprising exogenous cells
• CPC Class Codes: A61K 2035/124 the cells being hematopoietic, bone marrow derived or blood cells
• 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 35/28 Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
• CPC Class Codes: A61K 35/34 Muscles; Smooth muscle cells; Heart; Cardiac stem cells; Myoblasts; Myocytes; Cardiomyocytes vascular smooth muscle A61K35/44
• CPC Class Codes: A61K 38/18 Growth factors; Growth regulators
• CPC Class Codes: A61K 38/193 Colony stimulating factors [CSF]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C12N 2501/12 Hepatocyte growth factor [HGF]
• CPC Class Codes: C12N 5/0647 Haematopoietic stem cells; Uncommitted or multipotent progenitors

Abstract

Methods, compositions, and kits for repairing damaged myocardium and/or myocardial cells including the administration of stem cells, such as adult stem cells, optionally with cytokines are disclosed and claimed.

Claims

1. A method for repairing and/or generating and/or regenerating myocardium and/or myocardial cells comprising the administration of somatic stem cells.

2. The method of claim 1, wherein the administered somatic stem cells are adult stem cells.

3. The method of claim 1, wherein the administered somatic stem cells are cardiac stem cells.

4. The method of claim 1, wherein the administered somatic stem cells are adult cardiac stem cells.

5. The method of claim 1, wherein the administered somatic stem cells are cardiac stem cells and stem cells of another type other than cardiac stem cells.

6. The method of claim 1, wherein the administered somatic stem cells are adult cardiac stem cells and stem cells of another type other than adult cardiac stem cells.

7. The method of claim 1, wherein the administered somatic stem cells are cardiac and hematopoietic stem cells.

8. The method of claim 1, wherein the administered somatic stem cells are adult cardiac and adult hematopoietic stem cells.

9. The method of claim 1, wherein the somatic stem cells are lineage negative.

10. The method of claim 9, wherein the lineage negative somatic stem cells are c-kit^POS.

11. The method of claim 1, wherein a therapeutically effective dose of somatic stem cells are delivered to the heart.

12. The method of claim 11, wherein the therapeutically effective dose of the somatic stem cells is 2×

10⁴−

1×

10⁵ cells.

13. The method of claim 11, wherein the therapeutically effective dose is delivered to the border area of the damaged myocardium.

14. The method of claim 11, wherein the therapeutically effective dose is administered by injection.

15. The method of claim 13, wherein the therapeutically effective dose is injected intramyocardially.

16. The method of claim 15, wherein the therapeutically effective dose is injected trans-epicardially or transendocardially.

17. The method of claim 16, wherein with the trans-endocardial approach a catheter-based approach is used.

18. The method of claim 13, wherein the administered somatic stem cells migrate into the damaged myocardium.

19. The method of claim 18, wherein the delivered somatic stem cells differentiate into one or more of the following types of cells selected from the group consisting of:

a. myocyctes;

b. smooth muscle cells; and

c. endothelial cells.

20. The method of claim 19, wherein the differentiated somatic stem cells proliferate.

21. The method of claim 19, wherein the differentiated somatic stem cells assemble into myocardium and/or myocardial cells.

22. The method of claim 19, wherein the differentiated somatic stem cells assemble into a coronary artery.

23. The method of claim 19, wherein the differentiated somatic stem cells assemble into an arteriole.

24. The method of claim 19, wherein the differentiated somatic stem cells assemble into a capillary.

25. The method of claim 19, wherein the differentiated somatic stem cells at least partially restore structural and functional integrity to the damaged myocardium and/or myocardial cells.

27. The method of claim 26, wherein the cytokine comprises a cytokine selected from the group consisting of:

a. a stem cell factor;

b. a granulocyte-colony stimulating factor;

c. a stromal cell-derived factor-1;

d. an interleukin-3;

e. a granulocyte-macrophage colony stimulating factor;

f. a macrophage colony stimulating factor;

g. a steel factor;

h. a vascular endothelial growth factor;

and combinations thereof.

28. The method of claim 27, wherein a therapeutically effective dose of a cytokine is administered.

29. The method of claim 28, wherein the therapeutically effective dose of the cytokine is 50-500 μ

g/kg per day.

30. The method of claim 28, wherein the therapeutically effective dose is injected.

31. The method of claim 30, wherein the therapeutically effective dose is injected subcutaneously.

32. The method of claim 30, wherein the therapeutically effective dose is injected intravenously.

33. The method of claim 28, wherein the therapeutically effective dose stimulates the patient'"'"'s own somatic stem cells.

34. The method of claim 33, wherein the stimulated somatic stem cells are adult stem cells.

35. The method of claim 33, wherein the stimulated somatic stem cells are hematopoietic stem cells.

36. The method of claim 33, wherein the stimulated somatic stem cells are adult hematopoietic stem cells.

37. The method of claim 33, wherein the stimulated somatic stem cells are cardiac stem cells.

38. The method of claim 33, wherein the stimulated somatic stem cells are adult cardiac stem cells.

39. The method of claim 33, wherein the stimulated somatic stem cells are cardiac stem cells and stem cells of another type of stem cell other than cardiac stem cells.

40. The method of claim 33, wherein the stimulated somatic stem cells are adult cardiac stem cells and stem cells of another type of stem cell other than adult cardiac stem cells.

41. The method of claim 33, wherein the stimulated somatic stem cells are cardiac and hematopoietic stem cells.

42. The method of claim 33, wherein the stimulated somatic stem cells are adult cardiac and adult hematopoietic stem cells.

43. The method of claim 33, wherein the stimulated somatic stem cells become mobilized.

44. The method of claim 43, wherein the mobilized somatic stem cells home to the damaged myocardium and/or myocardial cells.

45. The method of claim 43, wherein the mobilized somatic stem cells migrate into the damaged myocardium and/or myocardial cells.

46. The method of claim 44, wherein the somatic stem cells differentiate into one or more of the following types of cells selected from the group consisting of:

a. myocyctes;

b. smooth muscle cells; and

c. endothelial cells.

47. The method of claim 46, wherein the differentiated somatic stem cells proliferate.

48. The method of claim 46 wherein the differentiated somatic stem cells assemble into myocardium and/or myocardial cells.

49. The method of claim 46, wherein the differentiated somatic stem cells assemble into a coronary artery.

50. The method of claim 46, wherein the differentiated somatic stem cells assemble into an arteriole.

51. The method of claim 46, wherein the differentiated somatic stem cells assemble into a capillary.

52. The method of claim 46, wherein the differentiated somatic stem cells at least partially restore function to the damaged myocardium and/or myocardial cells.

26. A method of repairing and/or generating and/or regenerating recently damaged myocardium and/or myocardial cells comprising the administration of a cytokine.

53. A method of repairing and/or generating and/or regenerating recently damaged myocardium and/or myocardial cells comprising the administration of somatic stem cells and a cytokine.

54. The method of claim 53, wherein the administered somatic stem cells are adult stem cells.

55. The method of claim 53, wherein the administered somatic stem cells are hematopoietic stem cells.

56. The method of claim 53, wherein the administered somatic stem cells are adult hematopoietic stem cells.

57. The method of claim 53, wherein the administered somatic stem cells are cardic stem cells.

58. The method of claim 53, wherein the administered somatic stem cells are adult cardiac stem cells.

59. The method of claim 53, wherein the administered somatic stem cells are cardiac stem cells and stem cells of another type of stem cell other than cardiac stem cells.

60. The method of claim 53, wherein the administered somatic stem cells are adult cardiac stem cells and stem cells of another type of stem cell other than adult cardiac stem cells.

61. The method of claim 53, wherein the administered somatic stem cells are cardiac and hematopoietic stem cells.

62. The method of claim 53, wherein the administered somatic stem cells are adult cardiac and adult hematopoietic stem cells.

63. The method of claim 53, wherein the administered somatic stem cells are lineage negative.

64. The method of claim 63, wherein the administered lineage negative somatic stem cells are c-kit^POS.

65. The method of claim 53, wherein a therapeutically effective dose of somatic stem cells is delivered to the heart.

66. The method of claim 65, wherein the therapeutically effective dose of the somatic stem cells is 2×

10⁴−

1×

10⁵ cells.

67. The method of claim 65, wherein the therapeutically effective dose is administered by injection.

68. The method of claim 67, wherein the therapeutically effective dose is injected mintramyocardially.

69. The method of claim 67, wherein the therapeutically effective dose is injected trans-epicardially or transendocardially.

70. The method of claim 69, wherein with the trans-endocardial approach a catheter-based approach is used.

71. The method of claim 53, where in the cytokine comprises a cytokine selected from the group consisting of:

a. a stem cell factor;

b. a granulocyte-colony stimulating factor;

C. a stromal cell-derived factor-1;

d. an interleukin-3;

e. a granulocyte-macrophage colony stimulating factor;

f. a macrophage colony stimulating factor;

g. a steel factor;

h. a vascular endothelial growth factor;

and combinations thereof.

72. The method of claim 71, wherein a therapeutically effective dose of a cytokine is administered.

73. The method of claim 72, wherein the therapeutically effective dose of the cytokine is 50-500 μ

g/kg per day.

74. The method of claim 72, wherein the therapeutically effective dose is injected.

75. The method of claim 74, wherein the therapeutically effective dose is injected subcutaneously.

76. The method of claim 74, wherein the therapeutically effective dose is injected intravenously.

77. The method of claim 74, wherein the therapeutically effective dose stimulates the patient'"'"'s somatic stem cells.

78. The method of claim 77, wherein the stimulated somatic stem cells are mobilized.

79. The method of claim 77, wherein the stimulated somatic stem cells home to the damaged myocardium and/or myocardial cells.

80. The method of claim 79, wherein the somatic stem cells migrate into the damaged myocardium and/or myocardial cells.

81. The method of claim 80, wherein the somatic stem cells differentiate into one or more of the following types of cells selected from the group consisting of:

a. myocytes;

b. smooth muscle cells; and

C. endothelial cells.

82. The method of claim 81, wherein the differentiated somatic stem cells proliferate.

83. The method of claim 82, wherein the differentiated somatic stem cells assemble into myocardium and/or myocardial cells.

84. The method of claim 82, wherein the differentiated somatic stem cells assemble into a coronary artery.

85. The method of claim 82, wherein the differentiated somatic stem cells assemble into an arteriole.

86. The method of claim 82, wherein the differentiated somatic stem cells assemble into a capillary.

87. The method of claim 82, wherein the differentiated somatic stem cells at least partially restore structural and functional integrity to the damaged myocardium and/or myocardial cells.

88. A pharmaceutical composition comprising a therapeutically effective amount of somatic stem cells.

89. The pharmaceutical composition of claim 88, wherein the administered somatic stem cells are adult stem cells.

90. The pharmaceutical composition of claim 88, wherein the administered somatic stem cells are hematopoietic stem cells.

91. The pharmaceutical composition of claim 88, wherein the administered somatic stem cells are adult hematopoietic stem cells.

92. The pharmaceutical composition of claim 88, wherein the administered somatic stem cells are cardiac stem cells.

93. The pharmaceutical composition of claim 88, wherein the administered somatic stem cells are adult cardiac stem cells.

94. The pharmaceutical composition of claim 88, wherein the administered somatic stem cells are cardiac stem cells and stem cells of another type of stem cell other than cardiac stem cells.

95. The pharmaceutical composition of claim 88, wherein the administered somatic stem cells are adult cardiac stem cells and stem cells of another type of stem cell other than adult cardiac stem cells.

96. The pharmaceutical composition of claim 88, wherein the administered somatic stem cells are cardiac and hematopoietic stem cells.

97. The pharmaceutical composition of claim 88, wherein the administered somatic stem cells are adult cardiac and adult hematopoietic stem cells.

98. The pharmaceutical composition of claim 88, wherein the therapeutically effective dose of the somatic stem cells is 2×

10⁴−

1×

10⁵ cells.

147. A kit comprising a pharmaceutical composition of claims 88 or 99 for use in the treatment, therapy or prevention of cardiovascular disease or related complaint.

148. A kit comprising a pharmaceutical composition of claims 88 or 99 for use in repairing and/or generating and/or regenerating recently damaged myocardium and/or myocardial cells.

150. A kit for preparing pharmaceutical compositions of claims 88 or 99.

151. A method of making pharmaceutical compositions of claims 88 or 99.

99. A pharmaceutical composition comprising a therapeutically effective amount of somatic stem cells and a cytokine comprising a cytokine selected from the group consisting of:

a. a stem cell factor;

b. a granulocyte-colony stimulating factor;

c. a stromal cell-derived factor-1;

d. an interleukin-3;

e. a granulocyte-macrophage colony stimulating factor;

f. a macrophage colony stimulating factor;

g. a steel factor;

h. vascular endothelial growth factor;

and combinations thereof.

100. The pharmaceutical composition of claim 99 wherein the therapeutically effective dose of the cytokine is 50-500 μ

g/kg per day.

101. A composition comprising a therapeutically effective amount of somatic stem cells.

102. The composition of claim 101, wherein the administered somatic stem cells are adult stem cells.

103. The composition of claim 101, wherein the administered somatic stem cells are hematopoietic stem cells.

104. The composition of claim 101, wherein the administered somatic stem cells are adult hematopoietic stem cells.

105. The composition of claim 101, wherein the administered somatic stem cells are cardiac stem cells.

106. The composition of claim 101, wherein the administered somatic stem cells are adult cardiac stem cells.

107. The composition of claim 101, wherein the administered somatic stem cells are cardiac stem cells and stem cells of another type of stem cell other than cardiac stem cells.

108. The composition of claim 101, wherein the administered somatic stem cells are adult cardiac stem cells and stem cells of another type of stem cell other than adult cardiac stem cells.

109. The composition of claim 101, wherein the administered somatic stem cells are cardiac and hematopoietic stem cells.

141. The composition of claim 101, wherein the administered somatic stem cells are adult cardiac and adult hematopoietic stem cells.

142. The composition of claim 101, wherein the therapeutically effective dose of the somatic stem cells is 2×

10⁴−

1×

10⁵ cells.

152. A method of making compositions of claim 101 or 112.

110. A method of implanting or depositing cells or causing the implantation or depositing of somatic stem cells in cardiac or blood vessel tissue comprising administration of somatic stem cells.

111. The method of claim 110, wherein the administered somatic stem cells are adult stem cells.

112. The method of claim 110, wherein the administered somatic stem cells are hematopoietic stem cells.

113. The method of claim 110, wherein the administered somatic stem cells are adult hematopoietic stem cells.

114. The method of claim 110, wherein the administered somatic stem cells are cardiac stem cells.

115. The method of claim 110, wherein the administered somatic stem cells are adult cardiac stem cells.

116. The method of claim 110, wherein the administered somatic stem cells are cardiac stem cells and stem cells of another type other than cardiac stem cells.

117. The method of claim 110, wherein the administered somatic stem cells are adult cardiac stem cells and stem cells of another type other than adult cardiac stem cells.

118. The method of claim 110, wherein the administered somatic stem cells are cardiac and hematopoietic stem cells.

119. The method of claim 110, wherein the administered somatic stem cells are adult cardiac and adult hematopoietic stem cells.

120. The method of claim 110, wherein the somatic stem cells are lineage negative.

121. The method of claim 120, wherein the lineage negative somatic stem cells are c-kit^POS.

122. The method of claim 110, wherein a therapeutically effective dose of somatic stem cells are delivered to the heart.

123. The method of claim 110, wherein the therapeutically effective dose of the somatic stem cells is 2×

10⁴ −

1×

10⁵ cells.

125. The method of claim 124, wherein the cytokine comprises a cytokine selected from the group consisting of:

i. a stem cell factor;

j. a granulocyte-colony stimulating factor;

k. a stromal cell-derived factor-1;

l. an interleukin-3;

m. a granulocyte-macrophage colony stimulating factor;

n. a macrophage colony stimulating factor;

O. a steel factor;

p. a vascular endothelial growth factor;

and combinations thereof.

126. The method of claim 124, wherein a therapeutically effective dose of a cytokine is administered.

127. The method of claim 126, wherein the therapeutically effective dose of the cytokine is 50-500 μ

g/kg per day.

128. The method of claim 126, wherein the therapeutically effective dose stimulates the patient'"'"'s own somatic stem cells.

129. The method of claim 128, wherein the stimulated somatic stem cells are adult stem cells.

130. The method of claim 128, wherein the stimulated somatic stem cells are hematopoietic stem cells.

131. The method of claim 128, wherein the stimulated somatic stem cells are adult hematopoietic stem cells.

132. The method of claim 128, wherein the stimulated somatic stem cells are cardiac stem cells.

133. The method of claim 128, wherein the stimulated somatic stem cells are adult cardiac stem cells.

134. The method of claim 128, wherein the stimulated somatic stem cells are cardiac stem cells and stem cells of another type of stem cell other than cardiac stem cells.

135. The method of claim 128, wherein the stimulated somatic stem cells are adult cardiac stem cells and stem cells of another type of stem cell other than adult cardiac stem cells.

136. The method of claim 128, wherein the stimulated somatic stem cells are cardiac and hematopoietic stem cells.

137. The method of claim 128, wherein the stimulated somatic stem cells are adult cardiac and adult hematopoietic stem cells.

138. The method of claim 128, wherein the stimulated somatic stem cells become mobilized.

139. The method of claim 138, wherein the mobilized somatic stem cells home to the damaged myocardium and/or myocardial cells.

140. The method of claim 138, wherein the mobilized somatic stem cells migrate into the damaged myocardium and/or myocardial cells.

144. The composition of claim 112 wherein the therapeutically effective dose of the cytokine is 50-500 μ

g/kg per day.

124. A method of implanting or depositing cells or causing the implantation or depositing of somatic stem cells in cardiac or blood vessel tissue comprising administration of a cytokine.

143. A composition comprising a therapeutically effective amount of somatic stem cells and a cytokine comprising a cytokine selected from the group of:

i. a stem cell factor;

j. a granulocyte-colony stimulating factor;

k. a stromal cell-derived factor-1;

l. an interleukin-3;

m. a granulocyte-macrophage colony stimulating factor;

n. a macrophage colony stimulating factor;

o. a steel factor;

p. vascular endothelial growth factor;

and combinations thereof.

145. A pharmaceutical composition for use in the treatment, therapy or prevention of cardiovascular disease or related complaint.

146. A pharmaceutical composition for use in repairing and/or generating and/or regenerating recently damaged myocardium and/or myocardial cells.

149. A kit comprising somatic stem cells and optionally a cytokine for the treatment, therapy or prevention of cardiovascular disease or related complaint.

153. A method of treating damaged myocardium and/or myocardial cells comprising the steps of:

a. harvesting somatic stem cells;

b. in vitro culturing of the harvested somatic stem cells in conjunction with heart tissue, optionally in the presence of a cytokine;

c. in vitro differentiation of the somatic stem cells into myocytes, smooth muscle cells and endothelial cells;

d. in vitro proliferation of differentiated cells and formation of tissue;

e. in vitro assemply of differentiated cells and/or tissue into cardiac structures, including coronary arteries, arterioles, capillaries, and myocardium.

f. implanting the cultured somatic stem cells, tissue, or cardiac structures into the heart.