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 the neovascular ocular disorders, wet age-related macular degeneration (AMD) and diabetic proliferative retinopathy, and the retinal degenerative disorders, retinitis pigmentosa (RP), and dry AMD. AVT has developed a novel lentiviral gene transfer vector that following a single intra-ocular administration provides sustained delivery of a therapeutic protein to the retina in rodent models. The AVT strategy is to combine its gene delivery system with potent therapeutic transgenes to rapidly develop and market superior products for the treatment of blinding ocular diseases. As a potential therapy for the neovascular diseases, AVT currently is evaluating vectors encoding two potent anti-angiogenic agents. However, the identification of a therapeutic for RP and dry AMD is more challenging. RP and dry AMD are characterized by a progressive loss of photoreceptors, although the disease pathophysiology differs between the two diseases. The identification of a factor that would prolong the life of photoreceptors irrespective of the mechanism leading to their accelerated loss may be a generally applicable therapeutic for the treatment of retinal degenerative diseases. A recently discovered protein, Rod-derived Cone Viability Factor (RdCVF), was demonstrated to stimulate cone survival in a mouse model of retinal degeneration, and was described as a photoreceptor viability factor. RdCVF, a first-in-class protein, has an enormous potential as a therapeutic for a wide range of currently untreatable retinal degenerative disorders. The focus of this Phase I application is the evaluation of RdCVF as a potential therapeutic for RP and subsequently, dry AMD. There are five specific aims to this pivotal project. 1} Cloning of human RdCVF. Mouse RdCVF was recently isolated as a 109 aa secreted protein, while the human sequence was identified through homology to the murine protein. The human protein will be isolated from human retinal cDNA and expression and secretion efficiency evaluated. 2) Human RdCVF-specific assays will be developed. Antibodies will be generated for use in ELISA, Western, and immunohistochemical assays and biological activity assays will be established. 3} Comparison of mouse and human RdCVF protein function in vitro. The expected function of human protein will be verified and compared to that of the mouse protein using an in vitro photoreceptor viability assay. 4) Generation of vectors encoding both the human and mouse proteins, and in vitro verification of protein function. 5) Vector evaluation in a relevant mouse model of retinal degeneration, the rd1 mouse. Therapeutic benefit will be assessed following subretinal administration using immunohistochemical and quantitative PCR analyses. The Phase II studies will focus on vector efficacy in a targe animal model of RP, preclinical safety studies, and vector manufacturing. The objective of the Phase I and II studies is to accrue sufficient data for IND submission and initiation of a Phase I clinical trial for treatment of RP
