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

a technology of myocardium and composition, applied in the field of methods, can solve the problems of ischemia, lack of oxygen supply in organ tissues, and major health risks of cardiac disease, and achieve the effect of restoring the structural and functional integrity of the infar

Inactive Publication Date: 2002-07-25
UNITED STATES OF AMERICA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0036] It has surprisingly been found that the implantation of hematopoietic stem cells into the myocardium surrounding an infarct following a myocardial infarction, migrate into the damaged area, where they differentiate into myocytes, endothelial cells and smooth muscle cells and then proliferate and form structures including myocardium, coronary arteries, arterioles, and capillaries, restoring the structural and functional integrity of the infarct.

Problems solved by technology

Cardiovascular disease is a major health risk throughout the industrialized world.
Ischemia is a condition characterized by a lack of oxygen supply in tissues of organs due to inadequate perfusion.
Many medical interventions, such as the interruption of the flow of blood during bypass surgery, for example, also lead to ischemia.
Ischemia may occur in any organ, however, that is suffering a lack of oxygen supply.
Without adequate blood supply, the tissue becomes ischemic, leading to the death of myocytes and vascular structures.
These treatments may succeed in reestablishing the blood supply, however tissue damage that occurred before the reperfusion treatment began has been thought to be irreversible.
While the cells may survive after transplantation, they fail to reconstitute healthy myocardium and coronary vessels that are both functionally and structurally sound.
Once the cells have reached the blastula stage, the potential of the cells has lessened, with the cells still able to develop into any cell within the body, however they are unable to develop into the support tissues needed for development of an embryo.
Due to the regenerative properties of stem cells, they have been considered an untapped resource for potential engineering of tissues and organs.
Furthermore, at least certain of these patent documents fail to teach or suggest the present invention for additional reasons.
The source of the stem cells of interest is limited to the known precursors of the type of tissue for which regeneration is required.
Obtaining and purifying these specific cells can be extremely difficult, as there are often very few stem cells in a given tissue.
And, other of these patent documents utilize stem cells as the source of various chemical compositions, without utilizing their proliferative capabilities, and thereby fail to teach or suggest the invention.
Despite their relevance in other areas, these earlier studies do not describe any cellular transplantation technology that can be successfully applied to the heart, where the ability to replace damaged myocardium would have obvious clinical relevance.

Method used

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

Examples

Experimental program
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Effect test

example 1

[0123] Hematopoietic Stem Cell (HSC) Repair of Infarcted Myocardium

[0124] A. Harvesting of Hematopoietic Stem Cells

[0125] Bone marrow was harvested from the femurs and tibias of male transgenic mice expressing enhanced green fluorescent protein (EGFP). After surgical removal of the femurs and tibias, the muscle was dissected and the upper and lower surface of the bone was cut on the surface to allow the collecting buffer to infiltrate the bone marrow. The fluid containing buffer and cells was collected in tubes such as 1.5 ml Epindorf tubes. Bone marrow cells were suspended in PBS containing 5% fetal calf serum (FCS) and incubated on ice with rat anti-mouse monoclonal antibodies specific for the following hematopoietic lineages: CD4 and CD8 (T-lymphocytes), B-220 (B-lymphocytes), Mac-1 (macrophages), GR-1 (granulocytes) (Caltag Laboratories) and TER-119 (erythrocytes) (Pharmingen). Cells were then rinsed in PBS and incubated for 30 minutes with magnetic beads coated with goat anti-r...

example 2

[0141] Mobilization of Bone Marrow Cells to Repair Infarcted Myocardium

[0142] A. Myocardial Infarction and Cytokines.

[0143] Fifteen C57BL / 6 male mice at 2 months of age were splenectomized and 2 weeks later were injected subcutaneously with recombinant rat stem cell factor (SCF), 200 .mu.g / kg / day, and recombinant human granulocyte colony stimulating factor (G-CSF), 50 .mu.g / kg / day (Amgen), once a day for 5 days (Bodine et al., 1994; Orlic et al., 1993). Under ether anesthesia, the left ventricle (LV) was exposed and the coronary artery was ligated (Orlic et al., 2001; Li et al., 1997; Li et al., 1999). SCF and G-CSF were given for 3 more days. Controls consisted of splenectomized infarcted and sham-operated (SO) mice injected with saline. BrdU, 50 mg / kg body weight, was given once a day, for 13 days, before sacrifice; mice were killed at 27 days. Protocols were approved by New York Medical College. Results are mean.+-.SD. Significance was determined by the Student's t test and Bonfe...

example 3

[0161] Migration of Primitive Cardiac Cells in the Adult Mouse Heart

[0162] To determine whether a population of primitive cells was present in the adult ventricular myocardium and whether these cells possessed the ability to migrate, three major growth factors were utilized as chemoattractants: hepatocyte growth factor (HGF), stem cell factor (SCF) and granulocyte monocyte colony stimulating factor (GM-CSF). SCF and GMCSF were selected because they have been shown to promote translocation of herriatopoietic stem cells. Although HGF induces migration of hematopoietic stem cells, this growth factor is largely implicated in mitosis, differentiation and migration of cardiac cell precursors during early cardiogenesis. On this basis, enzymatically dissociated cells from the mouse heart were separated according to their size. Methods for dissociating cardiac cells from heart tissue are well-known to those skilled in the art and therefore would not involve undue experimentation (CfU.S Pat. ...

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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.

Description

[0003] The present invention relates generally to the field of cardiology, and more particularly relates to methods and cellular compositions for treatment of a patient suffering from a cardiovascular disease, including, but not limited to, atherosclerosis, ischemia, hypertension, restenosis, angina pectoris, rheumatic heart disease, congenital cardiovascular defects and arterial inflammation and other disease of the arteries, arterioles and capillaries.[0004] Moreover, the present invention relates to any one or more of:[0005] Methods and / or pharmaceutical composition comprising a therapeutically effective amount of somatic stem cells alone or in combination with a cytokine such as a cytokine selected from the group consisting of stem cell factor (SCF), granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), stromal cell-derived factor-1, steel factor, vascular endothelial growth factor, macrophage colony stimulating factor, granulo...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A01K67/027A61K35/12A61K35/28A61K35/34A61K38/19C12N5/077C12N5/0789
CPCA01K67/0271A61K2035/124C12N5/0647C12N2501/12A61K38/18A61K38/193A61K35/28A61K35/34A61K2300/00A61P43/00
Inventor ANVERSA, PIEROORLIC, DONALD
Owner UNITED STATES OF AMERICA
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