The approval of voretigene neparvovec-rzyl by the US Food and Drug Administration (FDA), in December 2017, marked the beginning of a new era in medicine in which many inherited diseases will be essentially corrected by gene therapy. Voretigene neparvovec-rzyl, with the trade name of Luxturna, is the first gene therapy for an inherited disease. It is intended for the treatment of RPE65 mutation-associated retinal dystrophy, making it the second commercially available treatment for inherited retinal disease (IRD) after retinal prostheses (Argus II and Alpha IMS) which were commercialized a few years earlier. Unlike retinal prostheses, voretigene neparvovec-rzyl modifies the course of the disease. Voretigene neparvovec-rzyl is composed of human RPE65 cDNA along with a cytomegalovirus enhancer and a hybrid chicken b-actin promoter incorporated into a recombinant adeno-associated virus 2 (AAV2). Following injection into the subretinal space, AAV2 enters retinal pigment epithelial (RPE) cells. While the viral vector remains in episomal form in the nucleus, without integrating into the host DNA, the enhancer and promoter facilitate expression of RPE65. Retinitis pigmentosa (RP) is the most common IRD, and Leber's congenital amaurosis (LCA) is a severe form of IRD presenting at birth or childhood. Affected patients present with nyctalopia and peripheral visual field defect followed by central vision loss in advanced stages of the disease. Currently, mutations in approximately 300 genes are known to cause IRD. Mutations in RPE65 account for approximately 2% of autosomal recessive RP and 16% of LCA. 1 Although an uncommon cause of IRD, several factors have made RPE65 a favorite target for gene therapy: 1) It causes autosomal recessive IRD, in which gene replacement is sufficient to treat the disease. 2) About two decades ago, when gene delivery methods were being developed, RPE65 was one of only over a dozen genes that were known to cause IRD. 3) The relatively small size of RPE65 gene makes it possible to be carried by AAV2. 4) The clinical course of LCA in which photoreceptor cell loss significantly lags behind the functional loss, provides a window in which retinal function may be restored in the residual cells. 5) The existence of a large animal model of LCA with RPE65 mutation made it possible to carry out gene therapy in dogs and paved the way for human clinical trials. RPE65 mutations were first implicated in childhood IRD in 1997 by two independent groups of investigators. 2, 3 In 2001, briard dogs with RPE65 mutation were successfully treated by gene therapy delivered through subretinal injection; the same study indicated that intravitreal delivery was not effective. 4 The positive results of a phase 1 human clinical trial in 2009 followed by a successful phase 3 trial in 2017 lead to the approval of voretigene neparvovec-rzyl. 5, 6 The future of gene therapy for IRD is promising; however, there are challenges ahead:

1) Gene therapy requires viable cells and hence will not be effective in advanced stages of IRD with severe photoreceptor degeneration. Optogenetics, in which ganglion cells are transformed into photosensitive cells via gene therapy, is an exception. However, since photoreceptors and outer retinal image processing are bypassed, the vision recovery in this approach may be limited. The results of an ongoing phase 1/2 clinical trial will provide first information regarding safety and efficacy of this method in human.