Gene Therapy, Diet and Drug Approaches to Treating Inherited Retinal Disease

Inherited retinal diseases are the commonest cause of vision loss in the working-age populace. They comprise a heterogeneous group of conditions, with over 300 genes and loci identified to date. The general aim of treatment until recently had been to slow progression: however, some degree of functional restoration is possible with specific therapies (e.g., gene therapy). Medical treatments include vitamins and nutritional supplements, but the evidence for their utility is weak. Methods of neuroprotection of remaining photoreceptors include neurotrophic factors, inhibitors of apoptosis, calpain inhibitors and rod-derived cone viability factor; none have yet to reach the clinic. Clinical trials are underway investigating therapies for visual cycle modulation, anti-oxidant medications, anti-inflammatory agents, complement inhibitor and microglial modulation. Some of these have the advantage of repurposing medications widely prescribed for other indications, such as N-acetylcysteine. There has been considerable progress in retinal gene therapy, culminating in the first approved gene therapy for RPE65-associated retinopathy, affecting around 1% of patients with inherited retinal degeneration. Future directions are likely to involve an expansion of causative mechanism-independent approaches, such as neuroprotection, optogenetics and photoswitches, which address the issue of genetic diversity. Furthermore, in the field of retinal gene therapy, payload delivery continues to undergo significant development to address current limitations, such as payload size, tropism and immunogenicity. The concept of combination therapies—which are well developed in other fields—are also yet to be explored fully in retinal gene therapy.