Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-07-19
2003-02-11
Wilson, Michael C. (Department: 1632)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C424S093100, C424S093200, C435S455000
Reexamination Certificate
active
06518255
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a method for enhancing the level of perfusion of blood to a target tissue, a method for treating a target tissue suffering from or at risk of suffering from ischemic damage, and a method of inducing angiogenesis in a target tissue.
BACKGROUND OF THE INVENTION
Angiogenesis, the growth of new blood vessels, is a complex process involving the disruption of vascular basement membranes, migration and proliferation of endothelial cells, and subsequent blood vessel formation and maturation. Several mediators are known to elicit angiogenic responses, and administration of these mediators promotes revascularization of ischemic tissues. Vascular endothelial growth factor (VEGF protein) is one of the most specific of the known angiogenic mediators due to localization of its receptors almost exclusively on endothelial cells. Receptors for VEGF are upregulated under ischemic conditions, and the administration of recombinant VEGF augments the development of collateral vessels and improves function in peripheral and myocardial ischemic tissue.
However, delivery of VEGF protein remains a significant challenge. The half-life of VEGF protein is very short; the administration of high doses of VEGF protein is associated with hypotension, and systemic administration of VEGF protein can cause promiscuous induction of angiogenesis in tissues other than that which has been targeted. Promiscuous induction of angiogenesis can cause blindness, increase the aggressiveness of tumor cells, and lead to a multitude of other negative side-effects. Furthermore, the quantity of VEGF protein delivered is important. If too little VEGF protein is delivered, angiogenesis will not be induced, and a significant therapeutic benefit will not be achieved. If too much VEGF protein is delivered, the formation of disorganized vasculature beds, loss of function in the affected tissue, and promiscuous angiogenesis can result.
Additionally, induction of angiogenesis via administration of liposomes and/or “naked” DNA comprising a DNA encoding an angiogenic peptide also suffer from numerous disadvantages. Specifically, both liposomal and “naked” DNA forms of delivery are less efficient than viruses at transferring genes to cells, are inefficient at integrating genes into the host genome, and are difficult to target to specific tissues.
In view of the foregoing, there exists a need for an effective method of inducing angiogenesis in a target tissue. The present invention provides such a method. These and other advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.
BRIEF SUMMARY OF THE INVENTION
The present invention provides a method for enhancing the level of perfusion of blood to a target tissue comprising administering, via multiple applications to the target tissue, a dose of a pharmaceutical composition comprising (a) a pharmaceutically acceptable carrier and (b) an adenoviral vector comprising a DNA encoding an angiogenic peptide, such that the level of perfusion of blood to the target tissue is enhanced. Also provided is a method for treating a target tissue suffering from or at risk of suffering from ischemic damage comprising administering, via multiple applications to the target tissue, a dose of a pharmaceutical composition comprising (a) a pharmaceutically acceptable carrier and (b) an adenoviral vector comprising a DNA encoding an angiogenic peptide, such that the dose has a therapeutic or prophylactic effect on the target tissue. Further provided is a method for inducing angiogenesis in a target tissue comprising administering, via multiple applications to the target tissue, a dose of a pharmaceutical composition comprising (a) a pharmaceutically acceptable carrier and (b) an adenoviral vector comprising a DNA encoding an angiogenic peptide, such that angiogenesis is induced in the target tissue. Additionally provided is a method for inducing collateral blood vessel formation in a target tissue affected by or at risk of being affected by a vascular occlusion comprising administering to the target tissue a dose of a pharmaceutical composition comprising (a) a pharmaceutically acceptable carrier and (b) an adenoviral vector comprising a DNA encoding an angiogenic peptide, such that the adenoviral vector contacts a region including the source, the terminus, and an area therebetween for the collateral blood vessel formation, and collateral blood vessel formation is induced.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The invention may best be understood with reference to the following detailed description of the preferred embodiments. The present invention provides a method for enhancing the level of perfusion of blood to a target tissue, a method for treating a target tissue suffering from or at risk of suffering from ischemic damage, a method for inducing angiogenesis in a target tissue, and/or a method for inducing collateral blood vessel formation in a target tissue affected by or at risk of being affected by a vascular occlusion. Each of these methods involves administering, via multiple applications to the target tissue, a dose of a pharmaceutical composition comprising (a) a pharmaceutically acceptable carrier and (b) an adenoviral vector comprising a DNA encoding an angiogenic peptide, such that the level of perfusion of blood to the target tissue is enhanced, the dose has a therapeutic or prophylactic effect on the target tissue, angiogenesis is induced in the target tissue, and/or the adenoviral vector contacts a region including the source, the terminus, and an area therebetween for collateral blood vessel formation, and collateral blood vessel formation is induced.
Induction of Angiogenesis
By the term “inducing angiogenesis,” it is meant that angiogenesis is either initiated or enhanced. Therefore, for example, when the target tissue is not already undergoing angiogenesis, the present method provides for the initiation of angiogenesis in the target tissue. However, when the target tissue is already undergoing angiogenesis, the present method provides a means by which the level of angiogenesis is enhanced or heightened.
Target Tissue
Any suitable tissue can be subject to administration within the context of the present invention. Preferably, the target tissue comprises receptors capable of binding the angiogenic peptide encoded by the DNA; more preferably, the target tissue comprises VEGF receptors. Most preferably, the target tissue comprises endothelial cells. Generally, the target tissue will be a part of or form a discrete organ, e.g., a muscle, such as the heart.
Typically, the target tissue will be suffering from or be at risk of suffering from ischemic damage which results when the tissue is deprived of an adequate supply of oxygenated blood. The interruption of the supply of oxygenated blood is often caused by a vascular occlusion. Such vascular occlusion can be caused by arteriosclerosis, trauma, surgical procedures, disease, and/or other indications. There are many ways to determine if a tissue is at risk of suffering ischemic damage from undesirable vascular occlusion. Such methods are well known to physicians who treat such conditions. For example, in myocardial disease these methods include a variety of imaging techniques (e.g., radiotracer methodologies such as
99m
Tc-sestamibi scanning, x-ray, and MRI scanning) and physiological tests. Therefore, induction of angiogenesis in tissue affected by or at risk of being affected by a vascular occlusion is an effective means of preventing and/or attenuating ischemia in such tissue. As a result, although any suitable tissue can be targeted for the induction of angiogenesis, the target tissue is preferably one which is affected by or at risk of being affected by a vascular occlusion.
For example, the blood supply to discrete organs such as the brain, heart, pancreas, entire limbs, or generalized areas of the body, such as a foot, can be attenuated by disease, trauma, surgery, or other events. T
Crystal Ronald G.
Rosengart Todd K.
Cornell Research Foundation Inc.
Leydig , Voit & Mayer, Ltd.
Wilson Michael C.
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