Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Genetically modified micro-organism – cell – or virus
Reexamination Certificate
2001-06-27
2003-09-23
Tate, Christopher R. (Department: 1651)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Genetically modified micro-organism, cell, or virus
C424S093100, C424S520000, C424S572000, C435S325000
Reexamination Certificate
active
06623733
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention involves a method of treating vascular disease through administration of an autologous angiogenic solution, and methods and devices for preparing such a solution.
2. Description of the Background
Localized hypoxia of tissue due to obstruction of the inflow of arterial blood (a form of vascular disease known as ischemia) leads to the secretion of chemicals from this tissue. These chemicals are often referred to as angiogenic factors. The secretion of angiogenic factors causes normally quiescent endothelial cells that line the blood vessels to become activated. The activated endothelial cells then release enzymes that degrade extracellular matrix barriers. Through proliferation and migration, the cells then form new vessels. The formation of new capillary blood vessels from a pre-existing vessel is known as “angiogenesis.”
In patients afflicted with diminished coronary blood flow, ischemia in the area of the heart known as the myocardium is called “myocardial ischemia.” Current research efforts for treating myocardial ischemia include injecting substances that promote angiogenesis into the myocardium of the patient. The therapeutic substances being investigated for such procedures include vascular endothelial cell growth factor (VEGF) and fibroblast growth factor (FGF). VEGF and/or FGF may be delivered to the myocardium by means of a catheter to the coronary arteries. Alternatively, the VEGF and/or FGF may be introduced through an open chest procedure.
Scientific literature available includes many articles that show the presence of VEGF and FGF promote angiogenesis. Recent review articles surveying the literature include: Ferrara, N., “Role of Vascular Endothelial Growth Factor in the Regulation of Angiogenesis” Kidney Int. 1999 September; 56(3) 794-814; Isner, J M “Vascular Endothelial Growth Factor: Gene Therapy and Therapeutic Angiogenesis” Am. J. Cardiol. 1998 November 19; 82(10A):63S-64S; Vlodavsky et al., “Extracellular Matrix-resident Basic Fibroblast Growth Factor; Implication For The Control of Angiogenesis”, J. Cell Biochem. 1991 February; 45(2): 167-176; Klein et al., “Fibroblast Growth Factors As Angiogenesis Factors: New Insights Into Their Mechanism of Action”, EXS. 1997; 79:159-192; Wilzenbichler B. et al., “Vascular Endothelial Growth Factor-C (VEGF-C/VEGF-2) Promotes Angiogenesis in the Setting of Tissue Ischemia” AM Pathol. 153: 381-394, 1998 (VEGF induces endothelial cell proliferation (EC50=1-10 ng/ml) and migration (EC=0.1-1.0 ng/ml) in culture; Lopez J J et al., “VEGF Administration in Chronic Myocardial Ischemia in Pigs” Cardiovasc Res 40: 272-281, 1998 (In pigs, administration of 20 micrograms of VEGF delivered to the heart via intracoronary injection or epicardial implantation significantly increased myocardial blood flow and vasodilatory reserve compared to saline); Hendel R C et al., “Effect of Intracoronary Recombinant Human Vascular Endothelial Growth Factor on Myocardial Perfusion. Evidence for a Dose-Dependent Response” Circulation 101: 118-121, 2000 (In humans, single intracoronary injections of recombinanat human VEGF at concentrations of 0.005-0.167 micrograms/kg have been used in an attempt to induce myocardial angiogenesis); Kawasuji M. et al., “Therapuetic Angiogenesis with Intramyocardial Administration of Basic Fibroblast Growth Factor” Ann Thorac Surg 69: 115-1161, 2000 (In dogs, 100 micrograms of human recombinant bFGF injected into the myocardium at the time of LAD coronary artery ligation significantly increased capillary density and blood flow to the myocardium compared to the injection of saline); Laham R J. “Intrapericardial Delivery of Fibroblast Growth Factor-2 Induces Neovascularization in a Porcine Model of Chronic Myocardial Ischemia” J Pharmacol Exper Therap 292: 795-802, 2000 (In pigs with ameroid induced myocardial ischemia, a single intrapercardial injection of 200 micrograms bFGF increased angiographic collaterals and myocardial perfusion and function); and Unger EF et al. “Effects of a Single Intracoronary Injection of Basic Fibroblast Growth Factor in Stable Angina Pectoris” Am J Cardiol 85: 1414-1419, 2000 (In humans, single injections into the left main coronary artery of bFGF in doses ranging from 3 to 30 ug/kg were well tolerated).
Under a current treatment method, the VEGF and/or FGF are obtained from a xenogenic source (i.e., derived from a non-human animal, such as a pig or rabbit), or an allogenic source (i.e., derived from a human, but not the patient being treated). Insufficiently purified VEGF or FGF may result in an adverse patient reaction (e.g., infections, or immune system rejection) which destroys the “foreign” substance, as well as decreased potency of the VEGF or FGF. When administered directly to the myocardium (which is not well protected.by the immune system), insufficiently purified VEGF or FGF may result in myocardial cell necrosis due to the recruitment of neutrophils to the area, which can release potent free radicals and enzymes that can kill cells. Accordingly, many steps are required to complete separation of the VEGF or FGF from other proteins in the xenogenic or allogenic cells, and the potential for contamination must be dealt with at each step. Consequently, the process of purifying the VEGF or FGF from a xenogenic or allergenic source is very expensive. Moreover, there is a high probability of disease transfection to the patient, despite best efforts to limit contamination, since every animal and human carries a bacterial and viral population that is at least slightly different than that carried by the patient to be treated.
In accordance with another current treatment method, the VEGF or FGF is obtained from a genetically engineered source and then administered to the patient. For example, a bacterial culture may be stimulated to secrete VEGF or FGF by inserting porcine DNA fragments coding for VEGF or FGF into the DNA of the bacteria. As the bacteria reproduce, more VEGF and FGF can be produced. While this method may be less expensive than obtaining VEGF or FGF from xenogenic or allergenic sources, and may have a lower risk of disease transfection, the VEGF or FGF produced must still be separated from other compounds produced by the bacteria.
In accordance with yet another current method, gene therapy is used to cause the patient's own cells to produce VEGF or FGF. Gene therapy involves the injection of genetic material, known as deoxyribonucleic acid (DNA), into the patient. The DNA may be used directly, or packaged in an inactive virus, or in a liposome. The DNA so injected enters the nucleus of target cells (e.g., myocardial cells if treating myocardial ischemia) and causes the target cells to produce the protein dictated by the DNA sequence (in this case the DNA for VEGF or FGF). Angiogenesis will occur in those areas where the VEGF or FGF are found in a high enough concentration to elicit an effect and where the local cells are responsive to the stimulus (assuming VEGF or FGF are the only proteins required for angiogenesis).
However, the use of gene therapy to induce angiogenesis in a patient also has drawbacks. First, placing the DNA in the target cells is difficult. While conventional drugs work outside cell walls, the DNA must penetrate not only the cell wall, but also the nucleus within the cell. The fraction of cells that actually take up and express the new DNA is quite low, typically a few percent, and at best 10-20%. Secondly, the DNA that actually enters the cell nuclei may be attacked by the patient's immune system. When the immune system is activated in this manner, the immune system may also harm healthy genes in the target cells and in other nearby cells.
Thus, there is a clear need for a method of treating ischemia and other disorders associated with diminished blood flow that does not suffer from the disadvantages described above associated with non-autologous sources, genetic engineering, and gene therapy.
SUMMARY OF THE INVENTION
The present invention provides method
Consigny Paul M.
Hossainy Syed F. A.
Steward Jeffrey A.
Advanced Cardiovascular Systems Inc.
Tate Christopher R.
Winston Randall
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