Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Animal or plant cell
Reexamination Certificate
2001-09-30
2004-10-19
Saucier, Sandra E. (Department: 1651)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Animal or plant cell
C604S508000, C604S509000, C604S510000, C604S522000
Reexamination Certificate
active
06805860
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates generally to transluminal application of myogenic cells for tissue repair, such as myocardial repair, and more particularly to balloon catheter protected transluminal application of myogenic cells for repair of a failing body organ such as heart, brain, liver, kidney or pancreas. It is a principal aim of the invention to provide a novel method to repair failing tissue.
In principle, the human body has three types of cells. One type constitutes cells that continuously undergo replication and reproduction, such as dermal cells and epithelial cells of the intestine, for example. These cells, which have a life as short as ten days, are replaced by the same cell type which is replicating continuously. A second type of cell is differentiated in the adult state, but has the potential to undergo replication and the ability to reenter the cell cycle under certain conditions, an example being liver cells. The liver has the capacity to regrow and repair itself even if a tumor is excised and a major portion of the liver is removed. The third cell type comprises those cells that stop dividing after they have reached their adult stage, such as neuro cells and myocardial cells.
For the latter type or group of cells, the number of cells in the body is determined shortly after birth. For example, myocardial cells stop dividing at about day ten after delivery, and for the rest of its life the human body has a fixed number of myocardial cells. Changes in myocardial function occur not by division and new cell growth, but only as a result of hypertrophy of the cells.
Although the absence of cell division in myocardial cells is beneficial to prevent the occurrence of tumors—which practically never occur in the heart—it is detrimental with regard to local repair capacities. During the individual's lifetime, myocardial cells are subjected to various causes of damage, that irreversibly lead to cell necrosis or apoptosis.
The primary reason for cell death in the myocardium is ischemic heart disease—in which the blood supply to the constantly beating heart is compromised through either arteriosclerotic build-up or acute occlusion of a vessel following a thrombus formation, generally characterized as myocardial infarction (MI). The ischemic tolerance of myocardial cells following the shut-off of the blood supply is in a range of three to six hours. After this time the overwhelming majority of cells undergo cell death and are replaced by scar tissue.
Myocardial ischemia or infarction leads to irreversible loss of functional cardiac tissue with possible deterioration of pump function and death of the individual. It remains the leading cause of death in civilized countries. Occlusion of a coronary vessel leads to interruption of the blood supply of the dependent capillary system. After some 3 to 6 hours without nutrition and oxygen, cardiomyocytes die and undergo necrosis. An inflammation of the surrounding tissue occurs with invasion of inflammatory cells and phagocytosis of cell debris. A fibrotic scarring occurs, and the former contribution of this part of the heart to the contractile force is lost. The only way for the cardiac muscle to compensate for this kind of tissue loss is hypertrophy of the remaining cardiomyocytes (accumulation of cellular protein and contractile elements inside the cell), since the ability to replace dead heart tissue by means of hyperplasia (cell division of cardiomyocytes with formation of new cells) is lost shortly after the birth of mammals.
Other means of myocardial cell alteration are the so-called cardiomyopathies, which represent various different influences of damage to myocardial cells. Endocrine, metabolic (alcohol) or infectious (virus myocarditis) agents lead to cell death, with a consequently reduced myocardial function. The group of patients that suffer myocardial damage following cytostatic treatment for cancers such as breast or gastrointestinal or bone marrow cancers is increasing as well, attributable to cell necrosis and apoptosis from the cytostatic agents.
Heretofore, the only means for repair has been to provide an optimal perfusion through the coronary arteries using either interventional cardiology—such as PTCA (percutaneous transluminal coronary angioplasty), balloon angioplasty or stent implantation—or surgical revascularization with bypass operation. Stunned and hibernating myocardial cells, i.e., cells that survive on a low energy level but are not contributing to the myocardial pumping function, may recover. But for those cells which are already dead, no recovery has been achieved.
The current state of interventional cardiology is one of high standard. Progress in balloon material guide wires, guiding catheters and the interventional cardiologist's experience as well as the use of concomitant medication such as inhibition of platelet function, has greatly improved the everyday practice of cardiology. Nevertheless, an acute myocardial infarction remains an event that, even with optimal treatment today, leads to a loss of from 25 to 100% of the area at risk—i.e., the myocardium dependent on blood supply via the vessel that is blocked by an acute thrombus formation; A complete re-canalization by interventional means is feasible, but the ischemic tolerance of the myocardium is the limiting factor.
A recent article published in the New England Journal of Medicine (Schömig A. et al., “Coronary stenting plus platelet glycoprotein IIb/IIIa blockade compared with tissue plasminogen activator in acute myocardial infarction,”
N Engl J Med
2000; 343:385-391), for which the applicant herein was the primary clinical investigator, reports on a study of the myocardial salvage following re-canalization in patients with an acute myocardial infarction.
The average time until admission to the hospital in these patients was 2.5 hours and complete re-canalization was feasible after 215 minutes, roughly 3.5 hours. Nevertheless, only 57% of the myocardium at risk could be salvaged by re-canalization through interventional cardiology by means of a balloon and stent. When the group of patients was randomized to the classical thrombolytic therapy, which is the worldwide standard (with no interventional means), only 26% of the myocardium at risk could be salvaged. This means that even under optimal circumstances more than 40% of the myocardial cells are irreversibly lost.
With the knowledge that many patients arrive at a hospital at from 6 to 72 hours after the acute symptoms of vessel blockage by a thrombus, one can assume that the average loss of affected myocardial tissue is in a range of from 75 to 90% following an acute MI.
As noted above, cells can survive on a lower energy level, referred to as hibernating and stunning myocardium. As the collateral blood flow increases or re-canalization provides new blood supply they can recover their contractile function. The principle of myocardial re-perfusion, limitation of infarct size, reduction of left ventricular dysfunction and their effect on survival were described by Braunwald (Braunwald E. et al., “Myocardial reperfusion, limitation of infarct size, reduction of left ventricular dysfunction, and improved survival: should the paradigm be expanded?,”
Circulation
1989; 79:441-4).
Annually, about five million Americans survive an acute myocardial infarction. Clearly then, loss of affected myocardial tissue is a problem of major clinical importance. Currently, repair is limited to hypertrophy of the remaining myocardium, and optimal medical treatment by a reduction in pre- and after-load as well as the optimal treatment of the ischemic balance by &bgr;-blockers, nitrates, calcium antagonist, and ACE inhibitors.
If it were feasible to replace the dead myocardium (scar tissue) by regrowing cells, such a technique would have a profound impact on the quality of life of affected patients.
As noted earlier herein, in addition to ischemic heart disease other reasons exist for the reduction of myocardial cells that contribute to the pumping function of the
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