The goal of this application is to test the feasibility of a concept for improved treatment for ocular neovascular disease. The proposed strategy builds on the success of FDA approved agents that block Vascular Endothelial Growth Factor, VEGF, but are less than ideal in their requirement for frequent intravitreal injections. Our concept is to deliver a combination of anti-neovascular agents using a novel gene delivery platform based on adenovirus serotype 35. We have chosen this vector as our data indicates that it provides stable high level expression in the eye for up to at least 2 months. An additional important advantage is that GenVec has established methods suitable for the GMP production of Ad35 based vectors for clinical testing. Using Ad35 vectors, we propose to test the delivery of a potent anti-VEGF agent, sFlt-1 alone and in combination with the pleuripotent regulator Pigment Epithelium-Derived Factor, PEDF. We will establish the expression kinetics for both agents in the eye of experimental animals from vectors that encode one gene individually or both genes in a single construct. As sFlt-1 and PEDF act through differing mechanisms and have differing impact when delivered in vivo, we propose to test the hypothesis that prolonged delivery of these agents can result in improved treatment of neovascular lesions.
The specific aims, accordingly, are: 1) To build Ad35 vectors that express sFlt-1 alone or with PEDF; 2) To test whether transgene expression, particularly with two therapeutic gene products, is extended for longer period of time; and 3) To test whether Ad35 vectors with sFlt-1 ? PEDF will prevent abnormal blood vessel growth in an experimental model of choroidal neovascularization. With the successful conclusion of the proposed research we will propose a SBIR phase II to complete preclinical testing and file an IND. Existing therapies for wet age-related macular degeneration involve anti-VEGF (vascular endothelial growth factor) approaches that require frequent and repeat intraocular administrations, as often as every 4 weeks. This phase I SBIR will test the feasibility of an alternate drug delivery system that could provide extended delivery for out to 8 months or beyond as well as test whether combination of mechanistically different anti- angiogenesis agents may provide improved efficacy in preclinical models. If successful, the phase II SBIR application will be directed toward completing the rigorous efficacy and safety testing necessary for further clinical development. ? ? ?
| Hamilton, Melissa M; Byrnes, Gordon A; Gall, Jason G et al. (2008) Alternate serotype adenovector provides long-term therapeutic gene expression in the eye. Mol Vis 14:2535-46 |
