Agent in gene therapy promising for retinal dystrophy


Use of voretigene neparvovec in gene therapy demonstrates positive outcomes to treat a gene mutation in patients with retinal dystrophy.

Take-home: Use of voretigene neparvovec in gene therapy demonstrates positive outcomes to treat a gene mutation in patients with retinal dystrophy.

Reviewed by Jean Bennett, PhD

Philadelphia-In a phase I trial, voretigene neparvovec proved successfully in gene therapy administered to the contralateral eye in patients with inherited retinal dystrophy, caused by mutations of the gene RPE65, according to results published in Lancet.1

Use of a recombinant adeno-associated virus-voretigene neparvovec (Spark Therapeutics)-introduces the wild-type version of the missing gene RPE65 into the diseased cells, said study author Jean Bennett, PhD, the F.M. Kirby Professor of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia. “This virus is incapable of replicating and causing disease. Its sole purpose is to deliver the normal gene,” she said.

A previous phase I, dose-escalation study with a unilateral subretinal injection of a recombinant adeno-associated virus vector with the RPE65 gene (voretigene neparvovec) in the worst-seeing eye addressed safety and efficacy in patients with inherited retinal dystrophy caused by RPE65 mutations,2 Dr. Bennett said. That work prompted Dr. Bennett and colleagues to analyze the safety of the administration of voretigene neparvovec to the contralateral eye in patients from the phase I study.

“After the success of the unilateral injections, we hypothesized that functional vision and retinal and visual function could be further improved by delivering (voretigene neparvovec) to the contralateral, originally better-seeing eye,” the study authors wrote.

Data of study


Data of study

The recently published, follow-up study included 11 eyes from children and adults between the ages of 11 and 46, all of whom had inherited retinal dystrophy caused by RPE65 mutations. Voretigene neparvovec (300 ml) was injected subretinally into the contralateral eye that was not previously injected.

Investigators verified the presence of sufficient retinal cells through ophthalmoscopy, fundus photography, and optical coherence tomography and targeted the central superior retina or macula. The injection occurred 1.71 to 4.58 years after the initial injection.

After baseline, patients were reassessed at days 1, 3, 14, 30, 90, and 180, and then annually during years 1 to 5. Researchers analyzed safety, immune response, retinal and visual function, functional vision, and activation of the visual cortex, starting at baseline and continuing for 3 years of follow-up and more.

“Compared with baseline, pooled analysis of 10 participants showed improvements in mean mobility and full-field light sensitivity in the injected eye by day 30 that persisted to year 3, but no significant change was seen in the previously injected eyes over the same time period,” the study investigators wrote.

There were no adverse events associated with voretigene neparvovec, and the only adverse events associated with the procedure itself were dellen formation in 3 patients and cataracts in 2 patients. There was 1 patient who developed bacterial endophthalmitis, and they were excluded from the analysis.

In the pooled analysis of the second eyes or the previously injected eye, there were no significant changes in visual acuity from baseline to year 3. Researchers also tracked long-term improvements in various measures of rod photoreceptor function and a measure of cone photoreceptor function in most participants, according to the study.

After a second administration of voretigene neparvovec, 8 of 10 study participants were able to navigate under dimmer lighting conditions with their second injected eye, the investigators reported. 

More analysis planned

During third quarter of 2016, the makers of voretigene neparvovec plan to present analyses of both the 1-year, post-administration data from the crossover subjects and 2-year, follow-up data from intervention subjects in a phase III trial, Spark Therapeutics said in a press release. Spark Therapeutics has initiated a rolling submission of the biologics license application with the FDA on voretigene neparvovec, according to the release.

Pending the results, there may eventually be more treatment options available for ophthalmologists. “There could be an approved treatment for this debilitating form of retinal disease,” Dr. Bennett said. “This could be the first approved gene therapy in the United States and the first approved therapy for a retinal degenerative disease worldwide.”

The findings could also pave the way for future gene therapy studies, she added.



1. Bennett J, Wellman J, Marshall KA, et al. 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. Lancet. 2016 Aug 13;388(10045):661-72. doi: 10.1016/S0140-6736(16)30371-3. Epub 2016 Jun 30.

2. Maguire AM, High KA, Auricchio A, et al. Age-dependent effects of RPE65 gene therapy for Leiber’s congenital amaurosis: a phase 1 dose-escalation trial. Lancet. 2009;374:1597-1605.


Jean Bennett, PhD


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