Gene Therapy for Retinal Diseases

Inherited retinal dystrophies (IRDs) are caused by mutations resulting in progressive functional loss of photoreceptors. The onset of these disorders could be by birth or affect an individual across various ages. Patients diagnosed with Leber congenital amaurosis, retinitis pigmentosa, Stargardt disease, macular dystrophies, choroideremia, etc. experience gradual vision impairment or blindness. Several genes responsible for these dystrophies are known based on extensive genetic studies which led to an understanding of their structure, function, and involvement in cellular pathways making them potential targets for therapeutics. Gene therapy using various delivery vectors such as recombinant adeno-associated virus (rAAV) as a treatment modality offers hope in such conditions that currently have no cure. This chapter provides an overview of different retinal diseases, key genes involved and their mutations resulting in pathological and clinical features, and gene therapy approaches applied. Safety and efficacy are the primary considerations for any gene therapy study. Developments in vector design, promoter modifications, split-gene strategies to express large expression cassettes, compatible vector serotypes or strains to use for efficient retinal cell transduction, alternate gene delivery systems, immune challenges such as the presence of neutralizing antibodies and other toxicity would be given special emphasis in this chapter. Some of the recent success stories of retinal gene therapy preclinical studies and clinical trials are discussed.