What Is Gene Therapy?
Gene-replacement therapy involves identifying a defective gene that causes disease, and introducing a normal copy of the gene back into a patient’s cells. For retinal disease, this involves delivering genetic material directly into a patient’s eye. The most common way to deliver genetic material is by engineering a virus, where the virus’s own genes are removed and replaced with the human gene to be delivered. The engineered virus is now harmless and is referred to as a gene therapy vector.
Gene therapy is most useful in situations where the disease has a known genetic basis, and where the main cell type expressing the defective gene is still intact and can be targeted for therapy. As such its greatest potential benefit will be for treating patients who are still in early stages of disease development.
Retinal dystrophies are an especially promising target for gene therapy because 1) the eye is a very accessible organ and is amenable to both delivery of gene therapy vectors and evaluating clinical outcomes, and 2) many gene mutations responsible for causing inherited retinal disease are known and are being actively studied. Much work has been done in the past 20 years to further the potential of gene therapy for clinical use, including identifying animal models of retinal disease, designing gene therapy vectors to correct disease in animal models, and conducting early stage clinical trials in human patients to evaluate safety and efficacy of treatment.
View: Gene Therapy for Eye Disease (Powerpoint)
Mutations in the RPE65 gene lead to Leber congenital amaurosis (LCA), a severe form of retinal degeneration where vision is affected from birth and eventually leads to blindness. LCA associated with RPE65 mutations has been an early target for gene therapy approaches to treat retinal degeneration, since 1) the genetic basis of the disease is well understood, 2) the photoreceptor cells that are the target of gene therapy remain intact during early stages of disease, and 3) gene replacement therapy of RPE65 in small and large animal models of disease effectively restores visual function.
Recent pioneering clinical trials in human patients demonstrated that administration of gene therapy for RPE65 to LCA patients is safe, and results in improvements to vision. We are now optimizing our therapy vector to provide further improvements to visual function, and will initiate new clinical trials to test the improved therapy in patients.
The proof-of-concept safety and efficacy studies done to date show that gene therapy is a safe and promising avenue for treating retinal degeneration. In addition to further clinical studies to evaluate the efficacy of RPE65-based therapies, we are also working to develop gene therapy based approaches for treating LCA caused by mutations in other genes such as RDH12, and numerous other inherited retinal dystrophies such as retinitis pigmentosa and achromatopsia.