Evaluation of novel BIV-based vectors in vivo

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Advanced Vision Therapies, Inc. (AVT) is developing novel therapies for ocular disorders that are the major causes of blindness in the developed world. These diseases include wet age-related macular degeneration, diabetic proliferative retinopathy, and diabetic macular edema. Disease pathophysiology is characterized by abnormal neovascularization of the choroid or retina resulting in vessel leakage and hemorrhage, and ultimately to blindness. Therapies focused on inhibiting this process are showing promise in clinical trials however; these therapeutics must be repeatedly injected directly into the eyes. A better delivery system is needed. The AVT strategy is to combine its gene delivery system with novel and potent anti-angiogenic transgenes to rapidly develop and market a superior product for treatment of ocular disease. 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. In rodent models, the AVT vector demonstrated efficient and specific transduction of RPE cells, with expression sustained for at least nine months. When combined with an anti-angiogenic transgene, retinal neovascularization was effectively blocked in a transgenic mouse model of ocular disease. However, the rodent eye is significantly different than the primate eye, thus, the predictive value of these studies to human disease is not clear. Therefore, it is critically important to assess the AVT vector in primate models, prior to initiation of a clinical trial. This pivotal Phase I project will assess the AVT vector in two primate models, in vivo in monkeys, and in human organ culture, and has three specific aims: 1) Evaluation of retinal transduction efficiency, cell-type specificity, and duration of transgene expression in non-human primates. An AVT vector encoding green fluorescent protein (GFP) will be delivered subretinally to cynomolgus monkeys, and GFP expression will be monitored through several in vivo and histological analyses. 2) Establishment of human retina organ culture to assess AVT vector transduction efficiency and cell-type specificity. Both healthy and diseased tissue will be evaluated. The primate data will serve to validate the rodent models, and provide data critical to the initiation of a clinical trial. 3) Establishment of a "fail-safe" protocol in rodents to allow specific, laser-mediated ablation of the transduced RPE cells. This fail-safe will be utilized if, for any reason, termination of therapeutic gene expression is warranted. Phase II studies will include AVT vector efficacy studies in non-human primates, initiation of preclinical safety studies in rodent and monkey models, assessment of therapeutic gone expression in human retina culture, and evaluation of the fail-safe strategy in non-human primates. The objective of these studies will be to accrue sufficient data for IND submission and initiation of a Phase I clinical trial.