Gene-Based Therapies for Dominant Retinopathies

G.      Jane Farrar; Arpad      Palfi; Paul      F.Kenna; Mary      O'Reilly

Abstract

Over the past two decades, significant progress has been made in defining the molecular pathogenesis of hereditary retinal degenerations. Many of these are characterised by immense genetic heterogeneity. For example, in retinitis pigmentosa (RP), the most common form of this group of disorders, approximately 50 disease causing genes have been implicated, 20 of which are inherited in an autosomal dominant manner. Knowledge of the underlying genetic pathogenesis together with the availability of animal models and vectors for delivery has enabled exploration of gene-based therapies for inherited retinopathies. Notably, many studies have focused on treatment of recessive forms of these disorders and significant progress including ongoing clinical trials has been achieved. Progress in developing gene therapies for dominant retinopathies has been slower. One reason for this is that gene therapies for many dominant diseases, which are targeted to correcting the primary genetic defect, are likely to require suppression of the mutant gene. Alternative therapeutic approaches, which involve modulating secondary features associated with the disease pathology (such as ER stress or apoptosis) are also being explored. This review is focused on the development of gene-based therapies for dominantly inherited retinopathies. The main topics discussed are suppression technologies, preclinical animal models, retinal gene delivery and therapeutic strategies.

Keywords: Retina, Gene therapy, RNA interference, Dominant retinopathies, retinal degenerations, retinitis pigmentosa, Leber congenital amaurosis, LCA, Usher syndrome, Congenital stationary night blindness, CSNB, Vitelliform macular dystrophy, Stargardt disease and cone rod dystrophy, adeno associated, virus (AAV), RHO-adRP, C. elegans, RNAi, age-related macular degeneration, ELOVL4, Stargardt disease 3, STGD3, electroretinogram, ERG, Leber hereditary optic neuropathy, zinc-finger nucleases, rod-derived cone viability factor, RdCVF, Catalase, SOD2, IMPDH1