SBIR Phase I: Dual suppression of VEGF-A and PDGF-B with extended gene therapy for neovascular AMD

This SBIR Phase I project will determine the feasibility of a new high risk technology for treatment of age-related macular degeneration (AMD). The technology is an AAV2-mediated concurrent expression of recombinant proteins to intracellularly suppress the critical growth factors VEGF-A (vascular endothelial growth factor A) and PDGF-B (platelet-derived growth factor) in a single injection. AMD is the leading cause of blindness in the US. The standard of care intravitreal anti-VEGF (anti-vascular endothelial growth factor) injections (injected monthly) achieve an initial improvement in visual acuity in the first 3 or 4 months of treatment is followed by a plateau that persists for 2 years, followed by visual decline over the subsequent 5 years. Studies examining retinal remodeling provided initial clues as to the importance of VEGF and PDGF in wet AMD, while work in cancer models provided an impetus to pursue anti-VEGF/PDGF combination therapy for the treatment of wet AMD. This project will lead to an effective product for the treatment of wet AMD and related diseases. A long-term VEGF inhibition and PDGF suppression without repetitive intravitreal injections would significantly reduce the number of intraocular injections and the risks of infection, bleeding, retinal detachment, fibrosis, and pain for the patient. This project proposes an AAV2-delivery vehicle for expressing intraceptors which sequester VEGF-A and PDGF-B. The primary innovation is the development of a novel gene therapy to concurrently suppress VEGF-A and PDGF-B, using a bicistronic AAV2 vector. The proposed studies in mice will determine feasibility for potential commercialization of this alternative which would be injected annually and provide long-term sustained suppression of the two key mediators of neovascular AMD, including the potential for reduced fibrosis (scarring) with PDGF-B blockade. Further, this therapy?s ability to block intracellular autocrine loops may complement or improve upon the efficacy of current extracellular treatments, while avoiding neurotoxicity of diffuse extracellular VEGF suppression. This project?s innovations earned a patent in 2012 (US Patent No. 8,211,864 B2). The proposal will refine the product and develop a modified AAV virus with selective tropism for CNV and minimize off-target side effects. The proposed feasibility studies Aims 1 and 2 will establish a baseline for future safety and efficacy studies in non-human primates which is a key mile stone for investors. Aim 1 will involve AAV2 manufacture, while Aim 2 will evaluate safety and efficacy, using histology, fluorescein angiography, and optical coherence tomography.