Sight of Action: the Rationale and Evolution of Gene Therapy Approaches to the Treatment of Retinal Diseases

This review will summarize ocular gene therapy clinical trials and associated technology that have been initiated within the last 5 years. Initial programs utilized subretinal administration of an AAV2 serotype coupled with a ubiquitous promoter and a transgene targeting both monogenic inherited retinal diseases and acquired chronic ocular diseases polygenic in origin such as age-related macular degeneration and diabetic retinopathy. Cellular specific viral vectors with optimization of the expression cassette to include cellular-specific promoters and cassette regulatory elements to improve yields and durability with less invasive administration routes are now being clinically evaluated. These developments open the door for potential treatment of rare monogenic diseases and more common polygenic heterogeneous ocular disorders, where in situ expression of therapeutic proteins may reduce the need for repeated intravitreal injections. While initial reports are promising, only time will confirm whether sustained durable “curative” expression is a reality.