US 20080187572A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0187572 A1 West-Mays (43) Pub. Date: Aug. 7, 2008 (54) MATRX METALLOPROTEINASE Related U.S. Application Data INHIBITORS OF TGFB-INDUCED SUBCAPSULAR CATARACT FORMATION (60) Provisional application No. 60/675,443, filed on Apr. 28, 2005. (75) Inventor: Judith West-Mays, Oakville (CA) Correspondence Address: Publication Classification OCCHIUTI ROHLICEK & TSAO, LLP (51) Int. Cl. 10 FAWCETT STREET A6IR 9/00 (2006.01) CAMBRIDGE, MA 02138 A 6LX 3L/95 (2006.01) A61 P27/12 (2006.01) (73) Assignee: McMaster University, Hamilton.Ontario (CA) (52) U.S. Cl. ......................................... 424/429: 514/563 (21) Appl. No.: 11/912,729 (57) ABSTRACT PCT Fled: Apr. 28, 2006 (22) The present invention provides novel methods and composi (86) PCT NO.: PCTACA2OO6/OOO661 tions for the treatment and/or prevention of cataracts. A com position that inhibits destabilization of E-cadherin is admin S371 (c)(1), istered. Preferably the composition comprises a matrix (2), (4) Date: Mar. 11, 2008 metalloproteinase inhibitor. Patent Application Publication Aug. 7, 2008 Sheet 1 of 7 US 2008/0187572 A1 FIG. 1A FIG. 1B t ta o anX c s ana pm s : a a a Al O d E O 9 r pass SS ow 2 WS .2 g 3 8 I I 1 Back Vertex Distance (mm) Back Vertex Distance (mm) Patent Application Publication Aug. 7, 2008 Sheet 2 of 7 US 2008/0187572 A1 FIG. 2 0.18 0.16 0.14 0.12 0.1 0.08 0.06 (). 0.02 O 2 4 6 Days. After Treatment rr Couture (n-3) --TGF-2 (2ng ml)+GM6001 (n-3) -A-TGFp.2 (2ngin) (nas) --TGF-2 (ing inly (n=4) ---TGF-2 (insin}+GM6001 (n=4) Patent Application Publication Aug. 7, 2008 Sheet 3 of 7 US 2008/0187572 A1 FIG. 3 (), 8 ().7 (),6 (). 5 - ().3.4. O 2 0. O Control 25uMT rvel control r TGF-8 TGF-B Patent Application Publication Aug. 7, 2008 Sheet 4 of 7 US 2008/0187572 A1 FIG. 4 TGFB TGFB Control TGFB GM6001 MMP2/9 striars Patent Application Publication Aug. 7, 2008 Sheet 5 of 7 US 2008/O187572 A1 FIG. 5 A Day 6 T rzig MP9 -- 9.2 kDa MMP-2 -- 72 kDa - 6.5kDa B Day 2 Day 4 Day 6 C T TH29 C T T- T2s T -- T-29 MP9 sea sailies a see sess -- a-- - sists - siski, MP2 -b- ne e C MMP-9 ; *Feas NES E Non Significant Patent Application Publication Aug. 7, 2008 Sheet 6 of 7 US 2008/O187572 A1 FIG. 6 C T T-I T-279 E-cadherin- gas 3000 o S 2000 Am g 1000 O C T T+ T+29 Paco,05 B E-cadherin mRNA RT-QPCR 2 Ark C () S 1 ". t L O C T T+ "Paolo.1 * “Paoloc1 OSMA mRNA RT-QPCR 0.2 ? A. 5 0.1 S V) & 0.0 - *Pago, NS - not significant Patent Application Publication Aug. 7, 2008 Sheet 7 of 7 US 2008/O187572 A1 FIG. 7 Hematoxylin and Eosin staining A WT AdTGF|| Het - AdTGFBl MMP-9 KO + AdTGF|| i strowth weavese s 6 US 2008/O 187572 A1 Aug. 7, 2008 MATRIX METALLOPROTEINASE 0008 U.S. Pat. No. 5,925,617 discloses a prophylactic/ INHIBITORS OF TGFB-INDUCED therapeutic composition for secondary cataract. The method SUBCAPSULAR CATARACT FORMATION comprises administering a composition comprising a polypeptide that inhibits cell adhesion and a lactic acid/gly FIELD OF INVENTION colic acid polymer. 0009 U.S. Pat. No. 5,876,438 discloses a device for the 0001. The present invention relates to methods, composi intraocular delivery of immunotoxins for the prevention of tions and devices for the prevention or treatment of cataracts. secondary cataract. The immunotoxins inhibit the prolifera tion of lens epithelial cells. BACKGROUND OF THE INVENTION 0010 U.S. Pat. No. 5,874,455 discloses a method for the treatment of cataract that comprises administering an effec 0002 Cataract is a refractory ocular disease leads to lower tive amount of a radical scavenger Such as a thiol derivative or vision and, in Some cases, to blindness. As the crystalline lens a disulfide derivative. loses its normal transparency, less light passes through the (0011 U.S. Pat. No. 5,827,862 discloses an agent for the lens. The degree to which vision is lost depends on the degree prophylaxis or treatment of cataract comprising a carboStyril of opacification of the lens. compound. 0003. Many different factors can lead to cataract forma (0012 U.S. Pat. No. 5,698,585 discloses that 3(2H)—fura tion. These include aging, congenital lesions or trauma, some none derivatives or their salts can be used to prevent or treat medicines such as steroids and glaucoma medications, ciga Cataract. rettes, and alcohol. Inborn metabolic errors such as galac 0013. In U.S. Pat. No. 5,696,091, the intraocular use of tosemia and diseases like diabetes, atopic dermatitis and combinations of lens epithelia) cell growth stimulators (e.g., retinitis pigmentosa are also associated with cataract forma TGF-beta.) and antimetabolites (e.g., mitomycin C) is tion. described. The combination is applied to the capsular bag to 0004. The lens is a relatively simple tissue composed of prevent or retard the formation of secondary cataracts follow two cell types, epithelial cells and fiber cells. In adults, lens ing cataract Surgery. The lens epithelial cell stimulators acti proliferation and differentiation occurs near the lens equator. vate DNA synthesis in dormant lens epithelial cells, and However, in a pathological situation, the anterior lens epithe thereby make those cells, susceptible to the anti-metabolites. lial cells (LECs) can be triggered to proliferate and multilayer This enables the antimetabolites to suppress the proliferation beneath the lens capsule. This can trigger further changes that of lens epithelial cells to a much greater extent, relative to the lead to the development of cataracts. Fibrous anterior subcap proliferation observed ken the metabolites alone are utilized. Sular cataract (ASC) plaques are formed that develop into The Increased suppression of the growth of lens epithelial distinct opacities in the lens. cells results in a significant improvement in the ability to 0005 Cataracts are a major problem in the aging popula prevent or retard the formation of opacities on the lens cap tion. It is estimated that about 60-70% of people in their Sule (i.e., secondary cataracts). sixties and nearly 100% of people over eighty have some 0014 U.S. Pat. No. 5,686,487 discloses a method for treat degree of cataract and cataract excision is the most common ment of a cataract that comprises administering, to a subject type of operation in the aged population. While cataract Sur in need of Such treatment, a ketoprostaglandin compound in gery is highly effective, the incidence of secondary cataract an amount effective in treatment of cataract. after Surgery is a problem. Secondary cataract results in opac 0015 While many efforts have been made to develop pro ity on the Surface of the remaining posterior capsule follow phylactic ortherapeutic agents for cataracts, there remained a ing extracapsular cataract extraction. Secondary cataract need for further elucidation of the mechanisms involved in results from migration and proliferation of residual lens epi cataract formation and agents that interfere with those mecha thelial cells, which are not completely removed at the time of nisms. In our Society where the average age of the population extraction of the lens cortex, onto the posterior capsule lead is increasing and the elderly are expecting a better quality of ing to posterior capsule opacification. Secondary cataract is life than in previous generations, the prevention and treatment also associated with abnormal proliferation of the residual of cataract is becoming more and more critical. Currently, the lens epithelial cells in the equator followed by formation of standard treatment of cataract involves the correction of Elschnig pearls. In cataract Surgery, it is impossible to remove vision using eyeglasses, contact lenses etc. or Surgical opera lens epithelial cells completely, and consequently it is diffi tions such as extracapsular cataract extraction and insertion of cult to always prevent secondary cataract. Secondary cata an intraocular lens. However, at the present time, there are no ract, also known as posterior capsular opacification (PCO), is proven therapeutic agents that have been shown to inhibit the very similar to ASC. development of cataract. Thus, there has been a real need for 0006 While various surgical techniques have been devel the development of an effective therapeutic agent for the oped for the treatment of cataracts, it is desirable to avoid treatment and/or prevention of cataract. surgery if possible. It is also desirable to prevent or slow down the development of cataracts and also to avoid the develop SUMMARY OF THE INVENTION ment of secondary cataracts post-operatively. Several 0016. The present invention addresses the need for novel attempts have been made in the field of cataract medication to therapeutic strategies to prevent or treat cataracts. find compositions that can be used to treat or prevent the 0017. In one aspect of the invention, a method of treating formation of cataracts. or preventing cataracts is provided. The method comprises 0007 U.S. Pat. No. 6,914,057 discloses a method of administering to a subject in need of Such treatment a thera reducing the risk of cataract development that comprises peutically effective amount of an agent that prevents E-cad administering a tetracycline derivative. The tetracycline herin destabilization. In a preferred embodiment, the agent derivative is preferably administered systemically or orally. that prevents E-cadherin destabilization is a matrix metallo US 2008/O 187572 A1 Aug.