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

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.

I claim:  
     
         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 2×10 4 −1×10 5  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.  
     
     
         26 . A method of repairing and/or generating and/or regenerating recently damaged myocardium and/or myocardial cells comprising the administration of a cytokine.  
     
     
         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 μg/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.  
     
     
         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 2×10 4 −1×10 5  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 μg/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 2×10 4 −1×10 5  cells.  
     
     
         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 μg/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.  
     
     
         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 2×10 4  −1×10 5  cells.  
     
     
         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.  
     
     
         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 μg/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.  
     
     
         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 2×10 4 −1×10 5  cells.  
     
     
         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.    
     
     
         144 . The composition of  claim 112  wherein the therapeutically effective dose of the cytokine is 50-500 μg/kg per day.  
     
     
         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.  
     
     
         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.  
     
     
         149 . A kit comprising somatic stem cells and optionally a cytokine for the treatment, therapy or prevention of cardiovascular disease or related complaint.  
     
     
         150 . A kit for preparing pharmaceutical compositions of claims  88  or  99 .  
     
     
         151 . A method of making pharmaceutical compositions of claims  88  or  99 .  
     
     
         152 . A method of making compositions of  claim 101  or  112 .  
     
     
         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.