Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-12-09
2002-07-16
Ketter, James (Department: 1632)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C424S093100, C424S093210, C435S440000, C435S455000, C435S475000, C435S476000, C435S320100, C536S023100
Reexamination Certificate
active
06420345
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to the inhibition of angiogenesis, particularly the inhibition of angiogenesis in angiogenesis-associated conditions including, without limitation, neoplasia, rheumatoid arthritis, endometriosis, psoriasis, and vascular retinopathies.
2. Summary of the Related Art
The process of angiogenesis results in the formation of new blood vessels. During the process of angiogenesis, endothelial cells which exist in a quiescent state as part of an existing blood vessel grow and enter a migratory, proliferative state. This migratory, proliferative state of endothelial cells undergoing angiogenesis is eventually resolved when the cells return to the quiescent state as part of a functional new blood vessel. The process of angiogenesis is orchestrated by a complex network of multiple macromolecular interactions. Some essential angiogenic factors include fibroblast growth factor-basic (bFGF), vascular endothelial growth factor (VEGF), the Angiopoietins (Ang −½/3/4), cytokines, extracellular matrix (ECM) proteins, and matrix metalloproteases (MMP). These factors are produced locally by stromal cells (e.g., smooth muscle cells, pericytes, fibroblasts) and by activated leukocytes that are recruited to the area (Risau, W. (1997)
Nature
386(6626):671-674; Risau and Flamme (1995)
Ann. Rev. Cell Dev. Biol.
11:73-91).
The interplay of growth factors (e.g., VEGF and Ang-2) and surface protein-ECM interactions (e.g., &agr;v&bgr;3/5 interactions with both collagen and matrix metalloprotease-2) drive the process of angiogenesis through a predictable sequence of events. Activation of endothelial cells by pro-angiogenic stimuli results in vasodilation, hyperpermeability, and local release of proteases which degrade the basement membrane and ECM. This allows the formation of a provisional fibrin matrix, which provides a primary scaffold for the assembly of early microvessels. Motogenic endothelial cells sprout into the matrix and migrate with controlled matrix degradation at the tip. Proliferation occurs proximal to migration with formation of a primitive tube. Extensive remodeling ensues until the new capillary matures and anastomoses (i.e., fuses and joins) with other sprouts (Risau, W. (1997)
Nature
386(6626):671-674; Risau and Flamme (1995)
Ann. Rev. Cell Dev. Biol.
11:73-91).
Angiogenesis is stimulated and harnessed by some neoplasms (e.g., tumors) to increase nutrient uptake. However, in contrast to normal angiogenesis, which leads to anastomoses and capillary maturation, angiogenesis associated with neoplasia is a continuous process. Endothelial cells are activated by nearby neoplastic cells to secrete not only VEGF which stimulates angiogenesis, but also matrix metalloproteases (MMP) which degrade the surrounding extracellular matrix. The endothelial cells then invade the extracellular matrix where they proliferate, migrate, and organize to form new blood vessels, which support neoplasm growth and survival.
The newly vascularized neoplasm continues to grow, leading to further nutrient deprivation and chronic pro-angiogenic signaling. The vasculature of neoplasms is characterized by the presence of lacunae and a low rate of anastomosis. This partially dysfunctional vasculature fuels the permanent requirement for angiogenesis. Additionally, this incomplete vasculature allows the shedding of neoplastic cells into the systemic circulation. Hence, the angiogenic potential of a neoplasm correlates with metastatic potential (Weidner et al. (1991)
N. Engl. J. Med.
324(1):1-8; Folkman and Shing (1992)
J. Biol. Chem.
267(16):10931-10934). As a significant proportion of neoplasms are dependent on continued angiogenesis, inhibition of angiogenesis blocks neoplasm growth which often leads to complete necrosis of the neoplasm. (Weidner et al. (1991)
N. Engl. J. Med.
324(1):1-8; Folkman and Shing (1992)
J. Biol. Chem.
267(16):10931-10934). Thus, methods or reagents for inhibiting angiogenesis associated with neoplasia could represent a viable anti-neoplasia therapy.
Other disease conditions are characterized by aberrant levels of angiogenesis. For example, rheumatoid arthritis (RA) is an inflammatory disease associated with intense angiogenesis (see, e.g., Jackson et al. (1988)
Ann. Rheum. Dis.
57(3):158-161). Another angiogenesis-associated condition is psoriasis, a chronic skin disorder that affects one in fifty people world wide and over five million people in the United States. The most common form of the disease is called plaque psoriasis or psoriasis vulgaris. Other forms are pustular, guttate, inverse, and erythrodermic psoriasis.
Yet another angiogenesis-associated condition is vascular retinopathy, which includes diabetic retinopathy, retinal vein occlusion, retinopathy of prematurity (ROP), exudative age-related macular degeneration, sickle cell retinopathy, and radiation retinopathy (see, e.g., Aiello, L. P. (1997)
Curr. Opin. Ophthalmol.
8(3):19-31; Pierce et al. (1994)
Int. Ophth. Clinics
34:121-148). An additional angiogenesis-associated condition is endometriosis (see, e.g., Abulafia and Sherer (1999)
Obstet. Gynecol.
94(1):148-153; Healy (1998)
Hum. Reprod. Update
4(5):736-740). Thus, there exists a need to control angiogenesis as a means for treating and/or alleviating the symptoms of angiogenesis-associated conditions.
There are a number of known reagents that inhibit angiogenesis that have been used for various conditions associated with angiogenesis. For example, O'Reilly et al. teach that isolated endostatin protein is allegedly an inhibitor of endothelial cell proliferation and angiogenesis (O'Reilly et al., U.S. Pat. No. 5,854,205). Another compound with alleged anti-angiogenesis activity is heparin or heparin fragments (Folkman et al., U.S. Pat. No. 4,994,443). O'Reilly et al. also teach that angiostatin can allegedly reversibly inhibit proliferation of endothelial cells (O'Reilly et al., U.S. Pat. No. 5,733,876). However, many of the known anti-angiogenesis reagents and therapies have limitations. For example, for ROP, a common cause of blindness in children, two therapeutic methods, cryotherapy and laser therapy, are not completely effective and themselves cause damage to the eye, resulting in a reduction of vision (Pierce et al. (1994)
Int. Ophth. Clinics
34:121-148).
Therefore, there still exists a need for improved reagents that reduce angiogenesis while overcoming the shortcomings of known reagents for inhibiting angiogenesis. Such novel reagents and methods for using them are useful for treating conditions associated with angiogenesis including, without limitation, neoplasia, rheumatoid arthritis, endometriosis, psoriasis, and vascular retinopathies.
BRIEF SUMMARY OF THE INVENTION
The invention provides methods and reagents for inhibiting angiogenesis and allows for the treatment of various angiogenesis-associated conditions.
It has been discovered that cyclin dependent kinase inhibitors (CDKi's) can inhibit angiogenesis. This discovery has been exploited to develop the present invention which includes methods and compositions for inhibiting angiogenesis.
In a first aspect, the invention provides a method for inhibiting angiogenesis comprising introducing into a target endothelial cell an effective amount of a recombinant virus that comprises a transgene encoding a cyclin dependent kinase inhibitor (CDKi), wherein proliferation and/or migration of the endothelial cell is inhibited. In a certain preferred embodiment, the cyclin dependent kinase inhibitor is derived from a mammal (e.g., a human). In a certain embodiment, the cyclin dependent kinase inhibitor is a protein from the CIP/KIP family or an active fragment thereof, such as an active fragment selected from the group consisting of amino acids 25-93 of human p27 protein (SEQ ID NO:26) and amino acids 12-178 of human p27 protein. In a certain embodiment, the cyclin dependent kinase inhibitor is a protein from the INK4 family or an active fragment thereof, such as human p1116 protein (SEQ
Gyuris Jeno
McArthur James
Patel Salil
Cell Genesys Inc.
Ketter James
Li Q. Janice
Roylance Abrams Berdo & Goodman L.L.P.
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