Drug – bio-affecting and body treating compositions – Enzyme or coenzyme containing – Hydrolases
Reexamination Certificate
2002-03-13
2004-09-07
Casler, Brian L. (Department: 3763)
Drug, bio-affecting and body treating compositions
Enzyme or coenzyme containing
Hydrolases
C604S035000, C514S002600, C351S245000, C128S898000, C424S094610, C424S094620, C424S423000
Reexamination Certificate
active
06787135
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods of inhibiting the progression of various pathologies of the vitreous humor that are related to activity of matrix metalloproteinases. More particularly, the invention relates to methods of modifying the total activity of matrix metalloproteinases in the vitreous humor.
BACKGROUND OF THE INVENTION
Matrix metalloproteinases (MMPs) are a group of enzymes responsible for the degradation of extracellular matrix components. The activity of MMPs is dependent on the presence of zinc and is inhibited by the tissue inhibitors of metalloproteinases (TIMPs). Together, the MMPs and TIMPs are believed to play a significant role in a variety of physiological processes, including embryonic development, wound healing, bone growth, tissue remodeling, and vasculogenesis. Furthermore, the MMPs have been implicated in several pathological conditions, such as arthritis, glomerulonephritis, tumor invasion, metastasis, and angiogenesis. (Woesner, J. F. The matrix metalloprotease family. In: Parks, W C and Mechan R P. eds. Matrix Metalloproteinase. London Academic Press; 1998:1-13; Martrisian, L M. The matrix-degrading metalloprotease. Bioessays; 1992, 14:445-463; Krane, S M. The clinical importance of metalloprotease and their inhibitors. Ann NY Acad, Sci, 1994, 732:1-10).
Several MMPs have been identified in human vitreous. (Brown, D., Hamdi H, Bahei S, Keeney M C. Characterization of an endogenous metalloprotease in human vitreous. Curr Eye Res 1994; 13:639-647; Brown D J, Bishop P, Hamdi H, Keeney M C, Cleavage of structural components of mammalian vitreous by endogenous matrix metalloproteainase-2. Curr Eye Res 1996; 15:439-445; Plantner J J, Smine A, Quinn T A. Matrix metalloproteinases and metalloproteinase inhibitors in human interphotoreceptor matrix and vitreous. Curr Eye Res. 1998;17:132-140; De La Paz, M A, Itaoh Y, Toth Ca, Negase H. Matrix metalloproteinase and their inhibitors in human vitreous. Invest Opthalmol Vis Sci 1998;39:1256-1260). While the role of MMPs in the vitreous remains poorly understood, it is believed that these MMPs play a role in a variety of vitreal pathologies, such as proliferative diabetic retinopathy, proliferative vitreoretinopathy, vitreous liquefaction, and age-related macular degeneration. (Brown, D., Hamdi H, Bahei S, Keeney M C. Characterization of an endogenous metalloprotease in human vitreous. Curr Eye Res 1994; 13:639-647; De La Paz, M A, Itaoh Y, Toth Ca, Negase H. Matrix metalloproteinase and their inhibitors in human vitreous. Invest Opthalmol Vis Sci 1998;39:1256-1260; Das, A, McGuire P G, Eriqat C, et al. Human diabetic neovascular membranes contain high levels of urokinase and metalloproteinase enzymes. Invest Ophthalmol Vis Sci 1999;40:809-813; Limb, G A, Miller K, Chignell A H, et al. Metalloproteinase and TIMP-1 in proliferative vitreoretinopathy. Biochem Soc Trans 1997; 25:234S). Furthermore, vitreal MMPs have been identified in the subretinal space and are believed to play a role in non-pathological conditions, such as the normal turnover of components of the interphotoreceptor matrix. (Padgett, L C, Liu G_m, Werb Z, Lavail, M. Matrix metalloprotease-2 and tissue inhibitor of metalloprotease-1 in the retinal pigment epithelium and interphotoreceptor matrix: vectorial secretion and regulation. Exp Eye Res 1997;64:927-938).
Considering the functions of these enzymes, their presence in the vitreous, and their believed roles in a variety of pathological conditions, modification of vitreal MMP activity may provide therapeutic advantages, such as decrease in neovascularization, which is an important step in the establishment of pathological conditions such as proliferative diabetic retinopathy.
SUMMARY OF THE INVENTION
The present invention provides methods of modifying the total activity level of MMPs in the vitreous. Accordingly, the present invention also provides methods of inhibiting the progression of various vitreous pathologies that are related to the activity of MMPs. Methods according to the present invention include introducing plasmin into the vitreous. Plasmin is a non-specific protease best known for its fibrinolytic properties and role in the clotting cascade of blood. Plasmin has been shown to cleave laminin, fibronectin, and other components of the vitreoretinal juncture. (Liotta, L A, Goldfarb, R H, Brundage, R, Siegal, G P, Terranova, V, Garbisa. Effect of plasminogen activator (urokinase), plasmin, and thrombin on glycoprotein and collagenous components of basement membrane. Cancer Res 1981;41:4629-4636; Papp. B Kovacs, T. Lerent I et al. Conditions of formation of the heparinfibronectin-collagen complex and the effect of plasmin. Biochem Biophys Acts 1987;925:241-247.) Indeed, in U.S. Pat. No. 5,304,118, we have shown that plasmin can successfully be used to induce posterior detachment of the vitreous in a vitrectomy procedure. Plasmin is known to activate MMPs, which are capable of degrading vitreous collagen and producing vitreous liquefaction. (Williams G A. Pharmacologic manipulation of the vitreous during pars plana vitrectomy. In: Alfaro III D V & Liggett P E, eds. Vitreoretinal surgery of the injured eye. Philadelphia: Lipponcott-Raven Publishers, 1999; Kliener, D, Stettler-Stevenson, W. Structural biochemistry and activation of matrix metalloproteases. Curr Opin Cell Biol 1993; 5:891-897). Thus, we originally hypothesized that vitreal administration of plasmin would increase activity levels of vitreal MMPs, ultimately leading to liquefaction of the vitreous. Surprisingly, however, we discovered that, at optimized concentrations, the introduction of plasmin into the vitreous greatly reduces total MMP activity in the vitreous.
Accordingly, in one embodiment, a method according to the present invention comprises modifying total MMP activity in the vitreous by introducing plasmin into the vitreous. Preferably, the amount of plasmin utilized is less than one unit. (One unit of plasmin activity is measured by the hydrolysis of a chromogenic substrate S-2251. Friberger, et al. Methods for Determination of Plasmin, Antiplasmin and Plasminogen by Means of Substrate S-2251. Haemostasis 7: 138-145 1978).
The modulation of MMP activity in the vitreous can be used as part of a enzyme assisted vitrectomy procedure in order to provide therapeutic protection following the procedure. In a preferred embodiment of this method, the invention comprises introducing plasmin into the vitreous in an amount sufficient to induce posterior vitreous detachment, mechanically removing the vitreous from the eye, introducing a suitable replacement fluid into the eye, and introducing plasmin into the replacement fluid in an amount sufficient to modify the total MMP activity in the replacement fluid.
While the invention is described in the claims appended hereto, additional understanding of the invention can be obtained by referencing the following detailed description of preferred embodiments of the invention.
REFERENCES:
patent: 4135514 (1979-01-01), Zaffaroni et al.
patent: 5260059 (1993-11-01), Acott et al.
patent: 5304118 (1994-04-01), Trese et al.
patent: 6083155 (2000-07-01), Trese
patent: 6183692 (2001-02-01), Trese et al.
patent: 6207066 (2001-03-01), Trese et al.
patent: 6585972 (2003-07-01), Peyman
patent: 2002/0139178 (2002-10-01), Trese et al.
Trese et al, A new approach to stage 3 Macular holes, American Academy of opthalmology, Apr. 4, 2002.
Dailey Wendelin
Hartzer Michael
Trese Michael T.
Williams George A.
Casler Brian L.
Maiorino Roz
William Beaumont Hospital
LandOfFree
Modification of vitreal matrix metalloproteinase activity does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Modification of vitreal matrix metalloproteinase activity, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Modification of vitreal matrix metalloproteinase activity will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3227212