Wet age-related macular degeneration (AMD) is the leading cause of blindness in the developed world and represents a disease with a great unmet medical need. The blindness associated with wet AMD is caused by neovascularization and treatments are aimed at inhibiting this progress. The Advanced Vision Therapies, Inc. (AVT) strategy is to combine its gene delivery system with a novel and potent anti-angiogenic transgene to rapidly develop and market a superior product for wet AMD. AVT developed a state-of-the-art gene delivery system based on the bovine immunodeficiency virus (BIV), a bovine lentivirus that does not cause human disease. AVT will combine the BIV vector system with a novel anti-angiogenic transgene, T2-TrpRS, and evaluate this system in relevant rodent models of ocular neovascularization. There are three specific aims for this Phase I project. 1). Generation and in vitro characterization of T2-TrpRS expression cassettes. T2-TrpRS is a proteolytic cleavage fragment of the Trp tRNA synthetase, and is not normally secreted from cells. Therefore, several expression cassettes will be generated, containing alternative signal sequences, and evaluated for efficient secretion following transfection into human cells. 2) Generation and production of a BIV-T2-TrpRS vector. Using the best T2-TrpRS expression cassette from Specific Aim 1, a BIV vector will be made, scaled up for in vivo studies, and evaluated for T2-TrpRS expression following vector transduction of human cells. 3). Evaluation of the T2-TrpRS vector efficacy in a relevant rodent model of ocular neovascularization. The vector generated and characterized in Specific Aim 2 will be evaluated for efficacy following subretinal injection into a mouse model of retinal neovascularization. Inhibition of neovascularization/vascular leakage will be evaluated through several methods including fluorescein angiography and histological analyses. Phase II studies will focus on accruing sufficient data to warrant clinical development of the AVT vector.
