Surgery: light – thermal – and electrical application – Light – thermal – and electrical application – Electrical therapeutic systems
Reexamination Certificate
2000-11-03
2003-12-30
Wolfe, Willis R. (Department: 3747)
Surgery: light, thermal, and electrical application
Light, thermal, and electrical application
Electrical therapeutic systems
C607S003000
Reexamination Certificate
active
06671558
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods and implantable systems to reverse damage to heart muscle following myocardial infarction and more generally in and /or near damaged or diseased myocardial tissue. Specifically, this involves the repopulation of the damaged or diseased myocardium with undifferentiated or differentiated contractile cells, which additionally may be formed in situ through the use of genetic engineering techniques, and augmentation with electrical stimulation.
BACKGROUND OF THE INVENTION
Coronary Artery Disease (CAD) affects 1.5 million people in the USA annually. About 10% of these patients die with in the first year and about 900,000 suffer from acute myocardial infarction. During CAD, formation of plaques under the endothelial tissue narrows the lumen of the coronary artery and increases its resistance to blood flow, thereby reducing the O
2
supply. Injury to the myocardium (i.e., the middle and thickest layer of the heart wall, composed of cardiac muscle) fed by the coronary artery begins to become irreversible within 0.5-1.5 hours and is complete after 6-12 hours, resulting in a condition called acute myocardial infarction (AMI) or simply myocardial infarction (MI).
Myocardial infarction is a condition of irreversible necrosis of heart muscle that results from prolonged ischemia. Damaged or diseased regions of the myocardium are infiltrated with noncontracting scavenger cells and ultimately are replaced with scar tissue. This fibrous scar does not significantly contribute to the contraction of the heart and can, in fact, create electrical abnormalities.
Those who survive AMI have a 4-6 times higher risk of developing heart failure. Current and proposed treatments for those who survive AMI focus on pharmacological approaches and surgical intervention. For example, angioplasty, with and without stents, is a well known technique for reducing stenosis. Most treatments are designed to achieve reperfusion and minimize ventricular damage. However, none of the current or proposed therapies address myocardial necrosis (i.e., degradation and death of the cells of the heart muscle). Because cardiac cells do not divide to repopulate the damaged or diseased region, this region will fill with connective tissue produced by invading fibroblasts. Fibroblasts produce extracellular matrix components of which collagen is the most abundant. Neither the fibroblasts themselves nor the connective tissue they form are contractile. Thus, molecular and cellular cardiomyoplasty research has evolved to directly address myocardial necrosis.
Cellular cardiomyoplasty involves transplanting cells, rather than organs, into the damaged or diseased myocardium with the goal of restoring its contractile function. Research in the area of cellular cardiomyoplasty is reviewed in
Cellular Cardiomyoplasty: Myocardial Repair with Cell Implantation
, ed. Kao and Chiu, Landes Bioscience (1997), particularly Chapters 5 and 8. For example, Koh et al.,
J. Clinical Invest
., 96, 2034-2042 (1995), grafted cells from AT-1 cardiac tumor cell line to canines, but found uncontrolled growth. Robinson et al.,
Cell Transplantation
, 5, 77-91 (1996), grafted cells from C
2
C
12
skeletal muscle cell line to mouse ventricles. Although these approaches produced intriguing research studies, cells from established cell lines are typically rejected from the human recipient. Li et al.,
Annals of Thoracic Surgery
, 62, 654-661 (1996), delivered fetal cardiomyocytes to adult mouse hearts. They found improved systolic pressures and noticed that the presence of these cells prevented remodeling after the infarction. Although their results showed the efficacy of transplanted cell technology, this approach would not likely be effective in clinical medicine since the syngeneic fetal cardiac tissue will not be available for human patients. Chiu et al.,
Ann. Thorac. Surg
., 60, 12-18 (1995) performed direct injection of cultured skeletal myoblasts to canine ventricles and found that well developed muscle tissue could be seen. This method, however, is highly invasive, which compromises its feasibility on human MI patients.
Molecular cardiomyoplasty has developed because fibroblasts can be genetically manipulated. That is, because fibroblasts, which are not terminally differentiated, arise from the same embryonic cell type as skeletal muscle, their phenotype can be modified, and possibly converted into skeletal muscle satellite cells. This can be done by turning on members of a gene family (myogenic determination genes or “MDGS”) specific for skeletal muscle. A genetically engineered adeno-virus carrying the myogenin gene can be delivered to the MI zone by direct injection. The virus penetrates the cell membrane and uses the cell's own machinery to produce the myogenin protein. Introduction of the myogenin protein into a cell turns on the expression of the myogenin gene, which is a skeletal muscle gene, and which, in turn, switches on the other members of the MDGS and can transform the fibroblast into a skeletal myoblast. To achieve this gene cascade in a fibroblast, replication deficient adenovirus carrying the myogenin gene can be used to deliver the exogenous gene into the host cells. Once the virus infects the fibroblast, the myogenin protein produced from the viral genes turns on the endogenous genes, starting the cascade effect, and converting the fibroblast into a myoblast. Without a nuclear envelope, the virus gets degraded, but the cell's own genes maintain the cell's phenotype as a skeletal muscle cell.
This concept has been well-developed in vitro. For example, Tam et al.,
J. Thoracic and Cardiovascular Surgery
, 918-924 (1995), used MyoD expressing retrovirus in vitro for fibroblast to myoblast conversion. However, its viability has not been demonstrated in vivo. For example, Klug et al.,
J. Amer. Physiol. Society
, 1913-1921 (1995), used SV40 in vivo and succeeded in replicating the nucleus and DNA, but not the cardiomyocytes themselves. Also, Leor et al.,
J. Molecular and Cellular Cardiology
, 28, 2057-2067 (1996), reported the in situ generation of new contractile tissue using gene delivery techniques.
Thus, there is a need for an effective system and the method for less invasive delivery of a source of repopulating agents, such as cells or vectors, to the location of the infarct zone of the myocardium and more generally in and/or near damaged or diseased myocardial tissue.
Many of the following lists of patents and nonpatent documents disclose information related to molecular and cellular cardiomyoplasty techniques. Others are directed to background information on myocardial infarction, for example.
TABLE 1a
Patents
Patent No.
Inventor(s)
4,379,459
Stein
4,411,268
Cox
4,476,868
Thompson
4,556,063
Thompson et al.
4,821,723
Baker et al.
5,030,204
Badger et al.
5,060,660
Gambale et al.
5,069,680
Grandjean
5,104,393
Isner et al.
5,131,388
Pless
5,144,949
Olson
5,158,078
Bennett et al.
5,205,810
Guiraudon et al.
5,207,218
Carpentier et al.
5,312,453
Shelton et al.
5,314,430
Bardy
5,354,316
Keimel
5,510,077
(Dinh et al.)
5,545,186
Olson et al.
5,658,237
Francishelli
5,697,884
Francishelli et al.
TABLE 1b
Foreign Patent Documents
Document No.
Applicant
Publication Date
WO 93/04724
Rissman et al.
03/15/93
WO 94/11506
Leiden et al.
05/26/94
WO 95/05781
Mulier et al.
03/02/95
WO 97/09088
Elsberry et al.
03/13/97
TABLE 1c
Nonpatent Documents
Acsadi et al, The New Biol., 3, 71-81 (1991).
Barr et al., Gene Ther., 1, 51-58 (1994).
Cellular Cardiomyoplasty: Myocardial Repair with Cell Implantation, ed.
Kao and Chiu, Landes Bioscience (1997)
Chiu et al., “Cellular Cardiomyoplasty: Myocardiol Regeneration With
Satellite Cell Implantation”, Ann. Thorac. Surg., 60, 12-18 (1995).
Fletcher et al., “Acute Myocardiol Infarction”, Pathophysiology of Heart
Disease,
French et al., Circulation, 90, 2414-2424 (1994).
Gal et al., Lab. Invest., 68, 18-25 (1993).
Innis et al. Eds. PCR Strategies, 1995, Academic Press, New York, New
York.
Johns, J. Clin. Invest., 96, 1152-1158 (1995).
Klug et al.
Donovan Maura G.
Soykan Orhan
Collier Ken
Latham Daniel
Wolfe Willis R.
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