Overcoming the Challenge of Large Gene Transfer for the Therapy of Inherited Photoreceptor Diseases

Inherited retinal diseases (IRD) are a major cause of blindness worldwide for which no treatment is available. The majority are due to mutations in gene expressed in photoreceptor cells (PR) in the retina. Recently we and others have shown that gene therapy using adeno-associated viral vectors (AAV) is safe and effective in patients with a rare form of inherited childhood blindness and this bodes well for treatment of the more common photoreceptor-specific IRD. Several genes expressed in PR and involved in IRD are larger in size than what tolerated by AAV vectors. Other gene therapy vectors derived from either adenovirus (Ad) or lentiviruses (LV) have larger cargo capacity than AAV but poor ability to infect PR. Our goal is to overcome the challenge of transferring large gene to PR to develop therapies for common IRD. We propose to achieve this by using a system to increase AAV cargo capacity by splitting a large gene into 2 halves contained in 2 separate AAV vectors, or, alternatively, by screening a series of LV and Ad vectors variants for their ability to infect and transduce PR of small and large animals. Our preliminary results suggest that one LV and two Ad variants are capable of efficiently transducing PR. We propose to then test the therapeutic efficacy of the most efficient system for large gene transfer to PR in animal models of retinal degenerations. The results from this project may provide novel treatment options for common severe blinding conditions.