The Natural History of Inherited Retinal Dystrophy Due to Biallelic Mutations in the RPE65 Gene

International audiencePURPOSE:To delineate the natural history of visual parameters over time in individuals with biallelic RPE65 mutation-associated inherited retinal dystrophy (IRD); describe the range of causative mutations; determine potential genotype/phenotype relationships; and describe the variety of clinical diagnoses.DESIGN:Global, multicenter, retrospective chart review.METHODS:Study Population: Seventy individuals with biallelic RPE65 mutation-associated IRD.PROCEDURES:Data were extracted from patient charts.MEASUREMENTS:Visual acuity (VA), Goldmann visual field (GVF), optical coherence tomography, color vision testing, light sensitivity testing, and electroretinograms (retinal imaging and fundus photography were collected and analyzed when available).RESULTS:VA decreased with age in a nonlinear, positive-acceleration relationship (P < .001). GVF decreased with age (P < .0001 for both V4e and III4e), with faster GVF decrease for III4e stimulus vs V4e (P = .0114, left eye; P = .0076, right eye). On average, a 1-year increase in age decreased III4e GVF by ∼25 sum total degrees in each eye while V4e GVF decreased by ∼37 sum total degrees in each eye, although individual variability was observed. A total of 78 clinical diagnoses and 56 unique RPE65 mutations were recorded, without discernible RPE65 mutation genotype/phenotype relationships.CONCLUSIONS:The number of clinical diagnoses and lack of a consistent RPE65 mutation-to-phenotype correlation underscore the need for genetic testing. Significant relationships between age and worsening VA and GVF highlight the progressive loss of functional retina over time. These data may have implications for optimal timing of treatment for IRD attributable to biallelic RPE65 mutations

Safety and durability of effect of contralateral-eye administration of AAV2 gene therapy in patients with childhood-onset blindness caused by RPE65 mutations: a follow-on phase 1 trial

Safety and efficacy have been shown in a phase 1 dose-escalation study involving a unilateral subretinal injection of a recombinant adeno-associated virus (AAV) vector containing the RPE65 gene (AAV2-hRPE65v2) in individuals with inherited retinal dystrophy caused by RPE65 mutations. This finding, along with the bilateral nature of the disease and intended use in treatment, prompted us to determine the safety of administration of AAV2-hRPE65v2 to the contralateral eye in patients enrolled in the phase 1 study