The purpose of this project is to develop clinically useful methods of inhibiting epiretinal membrane formation and contraction. We have developed a reproducible animal model of epiretinal membrane formation and traction retinal detachment in the aphakic, vitrectomized rabbit eye injected with tissue cultured retinal pigment epithelial cells. Repeated intraocular injection of 5-fluorouracil is capable of inhibiting traction retinal detachment. Nonetheless, reversible toxicity to the photoreceptor outer segments results from 5-FU at the present dosage. Further studies in the aphakic vitrectomized eye injected with tissue cultured cells are needed to accomplish the following goals: 1. Indentify clinically useful means of sustained and targeted delivery of antiproliferative drugs to the epiretinal cells including (a) incorporation into liposomes, (b) incorporation into antibody targeted liposoms, (c) incorporation no vitreous substitutes such as sodium hyaluronate, and (d) intraocular and subconjunctival injection. 2. Identify the role of (a) irradiation and (b) irradiation combined with chemotherapy in inhibiting epiretinal membrane formation and contraction. 3. Indentify other drugs capable of inhibiting epiretinal cellular proliferation and contraction. 4. Identify the ocular toxicity of effective antiproliferative drugs. Epiretinal membrane formation and contraction remains the single most important obstacle to long-term retinal reattachment following penetrating ocular trauma and rhegmatogenous retinal detachment. A clinically useful method for inhibiting the formation and contraction of epiretinal membranes will prevent blindness in a large number of eyes that are presently lost to this complication.

National Institute of Health (NIH)
National Eye Institute (NEI)
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University of California San Francisco
Schools of Medicine
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Kuzmic, P; Ng, K Y; Heath, T D (1992) Mixtures of tight-binding enzyme inhibitors. Kinetic analysis by a recursive rate equation. Anal Biochem 200:68-73
Kim, R Y; Stern, W H (1990) Retinoids and butyrate modulate fibroblast growth and contraction of collagen matrices. Invest Ophthalmol Vis Sci 31:1183-6
Comiskey, S J; Heath, T D (1990) Serum-induced leakage of negatively charged liposomes at nanomolar lipid concentrations. Biochemistry 29:3626-31
Comiskey, S J; Heath, T D (1990) Leakage and delivery of liposome-encapsulated methotrexate-gamma-aspartate in a chemically defined medium. Biochim Biophys Acta 1024:307-17
Heath, T D; Brown, C S; Stern, W H (1990) Ocular cicatricial disease. Drug effects in vitro on cell proliferation, contraction, and viability. Invest Ophthalmol Vis Sci 31:1245-51
Alvarado, J A (1989) The use of a liposome-encapsulated 5-fluoroorotate for glaucoma surgery: I. Animal studies. Trans Am Ophthalmol Soc 87:489-514
Hwang, D G; Stern, W H; Hwang, P H et al. (1989) Collagen shield enhancement of topical dexamethasone penetration. Arch Ophthalmol 107:1375-80
Heath, T D; Brown, C S (1989) Targeted drug delivery: a two-compartment growth inhibition assay demonstrates that fluorodeoxyuridine and fluorodeoxyuridine monophosphate are liposome-independent drugs. Sel Cancer Ther 5:179-84
Ng, K Y; Heath, T D (1989) Liposome-dependent delivery of pteridine antifolates: a two-compartment growth inhibition assay for evaluating drug leakage and metabolism. Biochim Biophys Acta 981:261-8
Johnson, R N; Balyeat, E; Stern, W H (1987) Heparin prophylaxis for intraocular fibrin. Ophthalmology 94:597-601

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