Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-10-26
2003-03-18
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S008100, C514S912000, C514S913000
Reexamination Certificate
active
06534475
ABSTRACT:
BACKGROUND OF THE INVENTION
There has been a great deal of interest in matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) over the past several years particularly related to the role of these molecules in cancer biology. MMPs are responsible for the invasion of tumors into normal tissue, tumor angiogenesis, and metastasis. There is a large body of research directed at finding MMP antagonists for the treatment of cancer (see e.g. Wojtowicz-Praga, et al., “Matrix metalloproteinase inhibitors,”
Invest New Drugs,
Vol. 15(1):61-75, 1997).
TIMP-3 is a member of a family of natural proteins which inhibit the activities of MMPs. There are at least 15 distinct MMPs with differing, but often overlapping, specificities which are responsible for degrading extracellular matrix molecules and breaking down (turning-over) the extracellular matrix of tissues and cells. TIMPs help to regulate the activity of MMPs and thereby control the extracellular matrix environment.
There are a variety of diseases and conditions that cause neovascularization in the eye which results in the loss of vision. One rate limiting step in the neovascular process is the breakdown of the basement membrane enclosing vascular endothelial cells which allows the vascular endothelial cells to migrate towards the angiogenic signal, proliferate, and form new capillaries. MMPs are responsible for this initial step in neovascularization, and a therapy directed towards inhibiting these MMPs would be angiostatic. TIMP-3 is a “natural” angiostatic agent which is made by retinal pigment epithelial cells (Della, et al., “Localization of TIMP-3 mRNA Expression to the Retinal Pigment Epithelium,”
Invest. Ophthal.
&
Visual Science,
Vol. 37(9):1921-22, August, 1996; Ruiz, et al., “TIMP-3 is Expressed in the Human Retinal Pigment Epithelium,”
Biochemical and Biophysical Res. Comm.,
Vol. 226(2):467-474, 1996) and resides in Bruch's membrane between the choroid and retinal pigment epithelium (Vranka, et al., “Discrete Expression and Distribution Pattern of TIMP-3 in the Human Retina and Choroid,”
Current Eye Research,
pg. 102-109, 1996; Fariss, et al., “Tissue Inhibitor of Metalloproteinases-3 Is a Component of Bruch's Membrane of the Eye,”
American Journal of Pathology,
Vol. 150(1):323-326, January, 1997) effectively providing an angiostatic barrier to the choroid. TIMP-3 has been shown to have angiostatic activity in vitro (Anand-Apte, et al., “Inhibition of Angiogenesis by Tissue Inhibitor of Metalloproteinase-3,”
Invest. Ophthal.
&
Visual Science,
Vol. 38(5):817-821, April, 1997). Mutations in TIMP-3 are responsible for an inherited condition, Sorsby's fundus dystrophy (Weber, et al., “Mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) in patients with Sorsby's fundus dystrophy,”
Nature Genetics,
Vol. 8:352-356, 1994; Felbor, et al., “Evaluation of the Gene Encoding the Tissue Inhibitor of Metalloproteinases-3 in Various Maculopathies,”
Invest. Ophthal.
&
Visual Science,
Vol. 38(6):1054-1059, May, 1997), which is characterized by subretinal neovascularization and hemorrhage and is clinically similar to the wet form of age-related macular degeneration (ARMD).
Diabetic retinopathy is currently treated with panretinal photocoagulation which destroys healthy retinal tissue to inhibit further neovascularization. Sub-foveal and juxtafoveal neovascular membranes in ARMD are treated with laser photocoagulation which causes an immediate vision loss in attempt to prevent further growth of the neovascular membrane. There are currently no effective therapies which inhibit ocular neovascularization without also causing the destruction of healthy tissue. The proposed invention would provide a method of inhibiting the neovascular disease process at an initial step in the neovascularization pathway.
SUMMARY OF THE INVENTION
The present invention is directed do compositions and methods for treating conditions associated with ocular neovascularization, specifically, corneal neovascularization, rubeosis iridis, neovascular glaucoma, age-related macular degeneration, diabetic retinopathy, ischemic retinopathy, and retinopathy of prematurity.
REFERENCES:
Wojtowicz-Praga, et al., “Matrix metalloproteinase inhibitors,”Invest New Drugs, vol. 15(1):61-75, 1997.
Della, et al., “Localization of TIMP-3 mRNA Expression to the Retinal Pigment Epithelium,”Invest. Ophthal.&Visual Science, vol. 37(9):1921-22, Aug., 1996.
Ruiz, et al., “TIMP-3 is Expressed in the Human Retinal Pigment Epithelium,”Biochemical and Biophysical Res. Comm., vol. 226(2):467-474, 1996.
Vranka, et al., “Discrete Expression and Distribution Pattern of TIMP-3 in the Human Retina and Choroid,”Current Eye Research, p. 102-109, 1996.
Fariss, et al., “Tissue Inhibitor of Metalloproteinases-3 Is a Component of Bruch's Membrane of the Eye,”American Journal of Pathology, vol. 150(1):323-326, Jan., 1997.
Anand-Apte, et al., “Inhibition of Angiogenesis by Tissue Inhibitor of Metalloproteinase-3,”Invest. Ophthal.&Visual Science, vol. 38(5):817-821, Apr., 1997.
Weber, et al., “Mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) in patients with Sorsby's fundus dystrophy,”Nature Genetics, vol. 8:352-356, 1994.
Felbor, et al., “Evaluation of the Gene Encoding the Tissue Inhibitor of Metalloproteinases-3 in Various Maculopathies,”Invest. Ophthal.&Visual Science, vol. 38(6):1054-1059, May, 1997.
Alcon Inc.
Fay Zohreh
Yeager Sally
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