Evaluation of High-Capacity Adenovectors in the Eye

DESCRIPTION (provided by applicant): Exudative age-related macular degeneration (AMD) is due to aberrant neovascularization in the eye, and is one of the leading major causes of blindness in the U.S. Pigment Epithelium-Derived Factor (PEDF) is a potent angiogenic and neurotrophic factor and is a key regulator of vascularity in the eye. When delivered to the eye via an adenovirus vector, PEDF can block growth of new blood vessels and trigger the regression of established abnormal vessels in animal models for AMD and diabetic retinopathy. GenVec has recently demonstrated safety of an adenovector that expresses PEDF (AdPEDF. 11) in patients with AMD. However, two important risks to the commercialization of AdPEDF. 11 are transient PEDF expression that may require repeat administration and the potential for vector-induced inflammation at high doses, both of which have been observed in animal models. In this Phase II SBIR we propose to address these risks using high capacity (HC) adenovectors based on adenovirus type 5. This Small Business Innovation Research Phase II proposal aims take the next steps toward clinical testing of HC vectors. Building on successes in the Phase I effort the proposed research will provide breakthroughs needed to advance this promising vector system. The Specific Aims are: 1) To determine the full duration of increased PEDF expression in the eye following intravitreous delivery of HC.PEDF; 2) To test the hypothesis that long-term PEDF expression results in long-term ocular efficacy; 3) To build a system for the production of high quality HC vectors that is scalable, and applicable for GMP manufacturing. The results of these studies will provide critical elements of an IND submission. This SBIR proposal will allow direct application of HC technology to a rapidly advancing therapeutic product program. The long-term goal of this proposal is the clinical testing and commercialization of PEDF expressing HC vector for the treatment of AMD and other ocular neovascular diseases.