Regulated Transgene Expression in the Retina

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DESCRIPTION (provided by applicant): This application addresses the broad Challenge Area of Genomics (area 08) and the specific Challenge Topic is 08-EY-101: Genomics of complex eye diseases. Diseases that affect visual acuity have emerged as potential candidates for gene therapy. Direct injection of viral vectors, such as those based on adeno- associated viruses (AAV), into different compartments of the eye leads to gene transfer and stable transgene expression into various cell types. High level transduction of retinal pigmented epithelial cells and photoreceptors can be achieved following sub-retinal injection of AAV vectors; this approach has been used to treat a congenital form of blindness called Leber congenital amaurosis in animal models and humans. Many other forms of acquired and inherited blindness are potential candidates for gene therapy although in many cases it will be necessary to regulate expression of the transgene so as to assure therapeutic expression without toxicity. This proposal will develop a method for pharmacologically regulating AAV-encoded genes after introduction into the retina for the treatment of the wet form of age-related macular degeneration (AMD). The method is based on the introduction of a gene encoding an antibody to vascular endothelial growth factor (VEGF) under the control of an inducible promoter together with genes encoding an engineered transcription factor that can be activated by a small molecule to specifically enhance expression of the transgene. This method of inducible transgene expression called ARGENT will be developed in retina of mice and monkeys using convenient reporter genes. Studies will be performed with vectors encoding the humanized VEGF antibody called Avastin in mouse models of AMD; these vectors will also be tested in monkeys for safety and pharmacokinetics. Development of the ARGENT system for AMD will provide a platform of gene therapy that can be applied to a broad array of retinal diseases. Funding of this application will create 2 new jobs. Candidates have been identified for these positions as described in the Budget Justification. PUBLIC HEALTH RELEVANCE: Age-related macular degeneration (AMD) is a growing disease: 1.7 million people developed AMD in 1995 while it is projected that 6.3 million will be affected in 2030. The disease is a major cause for visual disability among persons over 60 years of age that with the increase in life expectancy is not only a medical problem but also one with a significant socio-economic impact. This proposal is designed to develop a gene therapeutic that will provide significant medical relief to patients, develop technologies applicable to other indications in the eye and minimize therapeutic interventions and the burden on the healthcare system.