Drug – bio-affecting and body treating compositions – Enzyme or coenzyme containing – Hydrolases
Patent
1989-04-14
1993-11-09
Stone, Jacqueline
Drug, bio-affecting and body treating compositions
Enzyme or coenzyme containing
Hydrolases
435226, 514913, A61K 3754, C12N 964
Patent
active
052600599
DESCRIPTION:
BRIEF SUMMARY
ion. The method comprises providing to the optic cup (retina, and retinal pigmented epithelium) or tissue in direct fluid communication therewith (e.g., choroid, posterior vitreous), by site specific delivery means (e.g., microinjection), an extracellular matrix metalloproteinase/tissue inhibitor (MMP/TIMP) ratio modulating substance in an effective amount to ameliorate the retinal disease.
In this embodiment of the invention, it is preferred that the modulating substance decrease the MMP/TIMP ratio, and be selected from the group; TIMP (natural or recombinant) retinoic acid, Razoxane, Dexamethasone, EDTA, EGTA, 1,10-phenanthroline, and combinations thereof.
DETAILED DESCRIPTION OF THE INVENTION
It has been discovered that certain ocular diseases can be treated by providing to the diseased tissue, or tissue in fluid communication therewith, a matrix metalloproteinase/tissue inhibitor (MMP/TIMP) ratio modulating substance. The MMP/TIMP ratio modulating substance is selected to adjust the MMP/TIMP ratio in a particular direction depending on the ocular disease to be treated. It has been found that by increasing the MMP/TIMP ratio in the trabecular meshwork, intraocular pressure can be reduced, ameliorating the symptoms of open-angle glaucoma. Conversely, decreasing the MMP/TIMP ratio in the retina is effective in treating retinal degeneration or detachment, and diabetic retinopathy and the attendant ocular neovascularization. Accordingly, since the direction of modulation will be different depending on the ocular disease, it is important to provide or direct the selected MMP/TIMP ratio modulating substance directly to the diseased tissue instead of systemically.
GLAUCOMA AND INTRAOCULAR PRESSURE
The intraocular pressure in the normal human aqueous and vitreous is about 15 to 16 mmHg, with a diurnal variation of about 5 mmHg or more. Many people have intraocular pressures greater than the accepted safe range, but without significant angle closure or optic cup changes which would contra-indicate therapeutic intervention. At higher pressures, i.e., 25-40 mmHg, the risk of vision loss makes treatment an over-riding necessity regardless of anatomical considerations. Consequently, there are certain intraocular pressures either alone or in combination with angle closure which would indicate treatment to avoid visual loss. Since neither the pathological or target intraocular pressure can be determined with precision, due to individual variations in sensitivity, initiation and cessation of treatment or therapy in accordance with the present invention is carried out at the discretion of the opthamologist.
Three basic causes of increased intraocular pressure are: (1) stenosis or blockage of the aqueous outflow channels through the trabecular meshwork and canal of Schlemm; (2) increased venous pressure in the head region, causing secondary ocular hypertension; and, (3) increased production of aqueous in the ciliary processes. The incidence of (1), where no clear anatomical variance is detectable is much higher than (2) or (3) and therefore, is of primary interest. Various prior art treatments have been directed at (2) and (3) above. The instant invention is directed at alleviating blockage or clogging of the trabecular meshwork by increasing the rate of remodeling and repair of the extracellular trabecular matrix. It has been discovered that the rate of remodeling and repair is controlled by the trabecular cells, and that these cells exert their control by secreting a family of matrix metalloproteinases including MMP-1, MMP-2, MMP-3, and transin, as well as their glycoprotein tissue inhibitor, TIMP.
Briefly, it has been discovered that human trabecular explants and human and fetal calf trabecular cells in culture secrete four major gelatinases at approximate Mr.apprxeq.110, 67, 60, and 224 kDa, in order from highest to lowest activity toward their substrate, gelatin. Minor gelatinases are observed in SDS-PAGE gels at 170, 215, 92, 47, and 270 kDa. Caseinases of approximate Mr.apprxeq.67, 61, 110, and 73 kDa are al
REFERENCES:
patent: 3267006 (1966-08-01), Hakim et al.
patent: 3677900 (1972-07-01), Merkel
patent: 3869548 (1975-05-01), Dabis
patent: 4174389 (1979-11-01), Cope
Clinical Research, vol. 35, No. 1 (1987), Gard et al., p. 196A.
Sanchez-Lopez, R. et al., Structure-Function Relationships in the Collagenase Family Member Transin, J. Biol. Chem. 263, 11892-11899 (Aug. 25, 1988).
Matrisian, L. M. et al., Isolation of the Oncogene and Epidermal Growth Factor-Induced Transin Gene: Complex Control in Rat Fibroblasts, Mol. Cell. Biol. 6, 1679-1686 (May, 1986).
Acott, T. S. et al., Human Trabecular Meshwork Organ Culture: Morphology and Glycosaminoglycan Synthesis, Investigative Ophthalmology & Visual Science, 29, 90-100 (Jan., 1988).
Acott, T. S. et al., Trabecular Meshwork Glycosaminoglycans in Human and Cynomolgus Monkey Eye, Investigative Ophthalomology & Visual Science, 26, 1320-1329 (Oct., 1985).
Stetler-Stevenson, W. G. et al., The Activation of Human Type IV Collagenase Proenzyme, J. Biol. Chem. 264, 1353-1356 (Jan. 25, 1989).
Mainardi, C. L. et al., Degradation of Type IV (Basement Membrane) Collagen by a Proteinase Isolated from Human Polymorphonuclear Leukocyte Granules, J. Biol. Chem. 255, 5435-5541 (Jun. 10, 1980).
Collier, I. E., H-ras Oncogene-transformed Human Bronchial Epithelial Cells (TBE-1) Secrete a Single Metalloprotease Capable of Degrading Basement Membrane Collagen, J. Biol. Chem. 263, 6579-6597 (May 15, 1988).
Murphy, G. et al., Metalloproteinases from rabbit bone culture medium degrade types IV and V collagens, laminin and fibronectin, Biochem J. 199, 807-811 (1981).
Liotta, L. A. et al., Partial Purification and Characterization of a Neutral Protease Which Cleaves Type IV Collagen, Biochem., (published 1981 by American Chemical Society).
Hibbs, M. S. et al., Biochemical and Immunological Characterization of the Secreted Forms of Human Neutrophil Gelatinase, J. Biol. Chem. 260, 2493-2500 (Feb. 25, 1985).
Chin, J. R. et al., Stromelysin, a Connective Tissue-degrading Metalloendopeptidase Secreted by Stimulated Rabbit Synovial Fibroblasts in Parallel with Collagenase, J. Biol. Chem. 260, 12367-12376 (Oct. 5, 1985).
Wilhelm, S. M. et al., Human skin fibroblast stromelysin: Structure, glycosylation, substrate specificity, and differential expression in normal and tumorigenic cells, Proc. Natl. Acad. Sci. USA, 84, 6725-6729 (Oct., 1987).
Okada, Y. et al., A Metalloproteinase from Human Rheumatoid Synovial Fibroblasts that Digests Connectiver Tissue Matrix Components, J. Biol. Chem. 261, 14245-14255 (Oct. 25, 1986).
Whitham, S. E. et al., Comparison of human stromelysin and collagenase bycloning and sequence analysis, Biochem. J. (1986) 240, 913-916 (U.K.).
Herron, G. S. et al., Secretion of Metalloproteinases by Stimulated Capillary Endothelial Cells, J. Biol. Chem. 261, 2810-2813 (Feb. 25, 1986).
Frisch, S. M. et al., Coordinate regulation of stromelysin and collagenase genes determined with cDNA probes, Proc. Natl. Sci. USA, 84, 2600-2604 (May, 1987).
Stricklin, G. P. et al., Human Skin Fibroblast Procollagenase: Mechanisms of Activation by Organomercurials and Trypsin, Biochem., 22, 61-68 (1983).
Gordon, J. M. et al., Collagenase in Human Cornea, Arch. Ophthalmol., 98, 341-345 (Feb., 1980).
Stricklin, G. P., Human Skin Fibroclas
Acott Ted S.
Alexander J. Preston
Bradley John M. B.
Stone Jacqueline
The State of Oregon Acting by and through the State Board of Hig
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