Gene therapy of the human retina

Retinal gene therapy holds a promise in treating different forms of non-inherited and inherited blindness. In 2008, three independent research groups reported that patients with the rare genetic retinal disease Leber's congenital amaurosis had been successfully treated using gene therapy with adeno-associated virus (AAV). In all three studies, an AAV vector was used to deliver a functional copy of the RPE65 gene, which restored vision in children suffering from LCA. These results were widely seen as a success in the gene therapy field, and have generated excitement and momentum for AAV-mediated applications in retinal disease. In retinal gene therapy, the most widely used vectors for ocular gene delivery are based on adeno-associated virus. The great advantage in using adeno-associated virus for the gene therapy is that it poses minimal immune responses and mediates long-term transgene expression in a variety of retinal cell types. For example, tight junctions that form the blood-retina barrier, separate subretinal space from the blood supply, providing protection from microbes and decreasing most immune-mediated damages. Preclinical studies in mouse models of Leber's congenital amaurosis (LCA) were published in 1996 and a study in dogs published in 2001. In 2008, three groups reported results of clinical trials using adeno-associated virus for LCA. In these studies, an AAV vector encoding the RPE65 gene was delivered via a 'subretinal injection', where a small amount of fluid is injected underneath the retina in a short surgical procedure. Development continued, and in December 2017 the FDA approved Voretigene neparvovec (Luxturna), an adeno-associated virus vector-based gene therapy for children and adults with biallelic RPE65 gene mutations responsible for retinal dystrophy, including Leber congenital amaurosis. People must have viable retinal cells as a prerequisite for the intraocular administration of the drug. Following the successful clinical trials in LCA, researchers have been developing similar treatments using adeno-associated virus for age-related macular degeneration (AMD). To date, efforts have focused on long-term delivery of VEGF inhibitors to treat the wet form of macular degeneration. Whereas wet AMD is currently treated using frequent injections of recombinant protein into the eyeball, the goal of these treatments is long-term disease management following a single administration. One such study is being conducted at the Lions Eye Institute in Australia in collaboration with Avalanche Biotechnologies, a US-based biotechnology start-up. Another early-stage study is sponsored by Genzyme Corporation. In October 2011, the first clinical trial was announced for the treatment of choroideremia. Dr. Robert MacLaren of the University of Oxford, who lead the trial, co-developed the treatment with Dr. Miguel Seabra of the Imperial College, London. This Phase 1/2 trial used subretinal AAV to restore the REP gene in affected patients.Initial results of the trial were reported in January 2014 as promising as all six patients had better vision. Recent research has shown that AAV can successfully restore color vision to treat color blindness in adult monkeys. Although this treatment has not yet entered clinical trials for humans, this work was considered a breakthrough for the ability to target cone photoreceptors. The vertebrate neural retina composed of several layers and distinct cell types (see anatomy of the human retina). A number of these cell types are implicated in retinal diseases, including retinal ganglion cells, which degenerate in glaucoma, the rod and cone photoreceptors, which are responsive to light and degenerate in retinitis pigmentosa, macular degeneration, and other retinal diseases, and the retinal pigment epithelium (RPE), which supports the photoreceptors and is also implicated in retinitis pigmentosa and macular degeneration.