Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Genetically modified micro-organism – cell – or virus
Reexamination Certificate
2000-09-05
2003-03-18
Crouch, Deborah (Department: 1632)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Genetically modified micro-organism, cell, or virus
C435S325000, C435S373000, C435S377000
Reexamination Certificate
active
06534052
ABSTRACT:
FIELD OF THE INVENTION
The present invention is concerned generally with myocardial infarctions of the heart and the damage caused to the heart of a living mammalian subject by such infarctions; and is particularly directed to methods and means for improving cardiac function and the potential repair of infarcted areas of the heart after the occurence of a myocardial infarction.
BACKGROUND OF THE INVENTION
Myocardial infarction (MI) is a life-threatening event that may cause cardiac sudden death and heart failure. Despite considerable advances in the diagnosis and treatment of heart disease, cardiac dysfunction after MI is still the major worldwide cardiovascular disorder that is increasing in incidence, prevalence, and overall mortality
1
. After acute myocardial infarction, the damaged cardiomyocytes are gradually replaced by fibrotic non-contractile tissue. The developing ventricular dysfunction is primarily due to a massive loss of cardiomyocytes. It is widely accepted that adult cardiomyocytes have little regenerative capability. Therefore, the loss of cardiac myocytes after MI is irreversible. Finding new effective approaches to improve cardiac dysfunction after MI remains a major therapeutic challenge.
Cell transplantation has emerged as a potentially new approach of repairing damaged myocardium for recent several years. Transplanted cardiomyocytes have been shown to survive, proliferate, and connect with the host myocardium in murine models
2
. Li and his coworkers
3,4
demonstrated that transplanted fetal cardiomyocytes could form new cardiac tissue within the myocardial scar induced by cryoinjury and improve heart function, but the transplanted allogenic cells survived for only a short period in the recipient heart due to immunorejection
5
. Bishop et al.
6
reported that the embryonic myocardium of rats can be implanted and cultured in oculo and demonstrated that the engrafted embryonic cardiomyocytes proliferated and differentiated in a recent review, Heschler et al.
7
pointed out that pluripotent embryonic stem (ES) cells cultivated within embryonic bodies reproduce highly specialized phenotypes of the cardiac tissue. Most of the biological and pharmacological process of cardiac-specific ion currents are expressed in cardiomyocytes developed in vitro from pluripotent ES cells, which were similar to those previously described in adult cardiomyocytes or neonatal mammalian heart cells
7,8
However the significance of ES cell transplantation in postinfarcted failing hearts remains to be examined.
Several studies have demonstrated the feasibility of engrafting exogenously supplied cells into host myocardium, including fetal cardiomyocytes
2
derived from artial tumor (ATI)
15
, satellite cells
16
, or bone marrow cells
17
. These engrafted cells have been histologically identified in normal myocardium up to 4 months after transplantation
15
Gap junctions have been found between the engrafted fetal cardiomyocytes and the host myocardium
2
, thereby raising the possibility of electrical-contraction coupling between transplanted cells and the host tissue. Recently, myocyte transplantation has been extended into ischemically damaged myocardium with coronary artery occlusion in rats
0.8
, or with cryoinjury in rats
3,4
and dogs
16
.
Nevertheless, despite all these research efforts and reported investigations, very little progress has been made to date in methods and cellular materials which might directly or markedly improve cardiac function in the living host after the occurrence of a myocardial infarction; or might serve as a cell transplantation therapeutic technique for effecting at least a partial repair of the infarcted area of the myocardium; or might offer a potential long-term improvement of the damaged heat tissue in the afflicted host subject. Were such an effective methodology to be generated and empirically demonstrated, such a development would be regarded as a major advance and unforeseen event by physicians and surgeons working in the field of cardiology.
SUMMARY OF THE INVENTION
The present invention provides a method for improving cardiac function in a living mammalian subject after the occurrence of a myocardial infarct within the heart tissue, said method comprising the steps of:
obtaining a plurality of undifferentiated mammalian embryonic stem cells then maintained in a culture media suitable for subsequent initiation of cell differentiation;
introducing said cultured mammalian embryonic stem cells to at least a portion of the previously infarcted area of the heart tissue in the living subject; and
allowing said introduced mammalian embryonic stem cells to differentiate in-situ as viable cells situated within the previously infarcted area of the heart tissue, whereby the cardiac function of the heart in the living subject becomes markedly improved.
REFERENCES:
patent: 5639618 (1997-06-01), Gay
patent: 5843780 (1998-12-01), Thomson
patent: 6146888 (2000-11-01), Smith et al.
patent: 6200806 (2001-03-01), Thomson
patent: 6280718 (2001-08-01), Kaufman et al.
Klug. M.G. et al. Genetically Selected Cardiomyocytes from Differentiating Embryonic Stem Cells For Stable Intracardiac Grafts. Journal of Clinical Investigation. vol. 98, No. 1, Jul. 1996, pp. 216-224.*
Odorico et al., Stem Cells 19:193-204 (2001).
Schuldiner et al., PNAS 97:11307-11312 (2000).
Pera et al., Human embryonic stem cells, 2000, Journal of Cell Science, vol. 113, pp. 5-10.*
“Stem Cells: A Primer”, National Institutes of health, May 2000.
Chapter 3, “The Human Embryoic Stem Cell and The Human Embryonic Germ Cell”, in Stem Cells, National Institutes of Health, 2000.
Appendix C:“Human Embryonic Stem Cells And Human Embryonic Germ Cells”, in Stem Cells, National Institute of Health, 2000.
“NIH Human Embryonic Stem Cell Registry”, National Institutes of Health, 2001.
Morgan James P.
Xiao Yong-Fu
Crouch Deborah
Prashker David
Ton Thai-an N.
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