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

Abstract

Summary Background 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. Methods In this follow-on phase 1 trial, one dose of AAV2-hRPE65v2 (1·5 × 1011 vector genomes) in a total volume of 300 μL was subretinally injected into the contralateral, previously uninjected, eyes of 11 children and adults (aged 11–46 years at second administration) with inherited retinal dystrophy caused by RPE65 mutations, 1·71–4·58 years after the initial subretinal injection. We assessed safety, immune response, retinal and visual function, functional vision, and activation of the visual cortex from baseline until 3 year follow-up, with observations ongoing. This study is registered with ClinicalTrials.gov, number NCT01208389. Findings No adverse events related to the AAV were reported, and those related to the procedure were mostly mild (dellen formation in three patients and cataracts in two). One patient developed bacterial endophthalmitis and was excluded from analyses. We noted improvements in efficacy outcomes in most patients without significant immunogenicity. Compared with baseline, pooled analysis of ten participants showed improvements in mean mobility and full-field light sensitivity in the injected eye by day 30 that persisted to year 3 (mobility p=0·0003, white light full-field sensitivity p<0·0001), but no significant change was seen in the previously injected eyes over the same time period (mobility p=0·7398, white light full-field sensitivity p=0·6709). Changes in visual acuity from baseline to year 3 were not significant in pooled analysis in the second eyes or the previously injected eyes (p>0·49 for all time-points compared with baseline). Interpretation To our knowledge, AAV2-hRPE65v2 is the first successful gene therapy administered to the contralateral eye. The results highlight the use of several outcome measures and help to delineate the variables that contribute to maximal benefit from gene augmentation therapy in this disease. Funding Center for Cellular and Molecular Therapeutics at The Children’s Hospital of Philadelphia, Spark Therapeutics, US National Institutes of Health, Foundation Fighting Blindness, Institute for Translational Medicine and Therapeutics, Research to Prevent Blindness, Center for Advanced Retinal and Ocular Therapeutics, Mackall Foundation Trust, F M Kirby Foundation, and The Research Foundation—Flanders.

Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65 -mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial

“…Improvements in both navigational abilities and light sensitivity were evident within the first 30 days after subretinal delivery and remained stable for 1 year, as they have for at least 3 years in the participants of the phase 1 follow-on trial. 18 Approximately two thirds of intervention participants achieved the maximum MLMT improvement possible, the ability to pass at 1 lux. Likewise, improvements in visual fields were also apparent soon after intervention, and also persisted throughout the 1 year follow-up.…”

“…A follow-on study, in which 11 of these 12 participants underwent injection of the contralateral eye at the dose of 1·5×10 11 vg, demonstrated the safety of contralateral eye injection, as well as gains in visual and retinal function in the second eye. 18 This improvement has remained durable over at least 3 years, with observation ongoing. 18,19 In addition, a subset of participants in this study was enrolled in a separate functional magnetic resonance imaging study 20 that showed increased activation of the visual cortex and evidence of improved function and structure of the visual pathways after intervention.…”

“…18 This improvement has remained durable over at least 3 years, with observation ongoing. 18,19 In addition, a subset of participants in this study was enrolled in a separate functional magnetic resonance imaging study 20 that showed increased activation of the visual cortex and evidence of improved function and structure of the visual pathways after intervention. Other RPE65 gene therapy trials, which were administered to only one eye per individual using different gene constructs, vector formulations, or surgical approaches, have shown improvements in retinal function but variable durability of effect.…”

A New Promoter Allows Optogenetic Vision Restoration with Enhanced Sensitivity in Macaque Retina

“…25 Therefore, we chose AAV2 for its known safety and efficacy in targeting RGCs in NHP studies [27][28][29] and the large body of work using this vector in human clinical trials. [20][21][22][23]44 High-level expression with a limited viral dose being a major parameter in obtaining functional expression, we designed a new RGC-specific promoter, driving strong transgene expression in RGCs. We show that this promoter, named SNCG, drives expression in twice as many RGCs compared to the ubiquitous CMV promoter.…”

Utilities of AAV vectors in in vivo phenotypic screening and functional studies

“…AAV is a small single-stranded DNA virus. Vectors based on AAV have been used as gene delivery vehicle in both preclinical and clinical studies [2]. Multiple AAV serotypes have been isolated from human and nonhuman primates.…”