Gene Therapy Breakthrough

Optogenetic therapy partially restores visual function in blind patients. Dermot McGrath reports from the EURETINA 2021 Virtual Congress

An important milestone in gene therapy research has been attained with the first case report of the partial recovery of visual function in a blind patient with late-stage retinitis pigmentosa (RP), according to JoséAlain Sahel MD.

“We published the report in Nature Medicine in May 2021 detailing the partial recovery of visual function in a 58-yearold patient who has been blind for 15 years and who was first diagnosed with RP 40 years ago. After optogenetics therapy, he could locate and count objects on a table and identify crosswalks in the street,” Prof Sahel reported.

RP is an inherited retinal disease with more than 100 known mutations, he explained. It causes sequential photoreceptor degeneration with a slow and irreversible evolution leading to blindness, which affects an estimated 1.5 to 2 million people worldwide.

Prof Sahel said the 58-year-old male was one of nine patients enrolled in the ongoing PIONEER clinical trial of GS030 optogenetic therapy (GenSight Biologics). The phase 1/2a safety and tolerability study is underway at three sites: Moorfields Eye Hospital in the United Kingdom, Quinze-Vingts Hospital in France, and the University of Pittsburgh Medical Center in the United States. The work is a collaboration with Botond Roska in Basel, Switzerland, with the Institut de la Vision and sponsored by GenSight, where Dr Sahel is a co-founder.

The study population is end-stage, non-syndromic RP patients who received a single intravitreal gene therapy injection in the worst-affected eye.

Optogenetic therapies combine cellular expression of lightsensitive opsins with light stimulation using a medical device, Prof Sahel noted.

“Once the photoreceptors have degenerated, we can try to reactivate the remaining cells using optogenetics, especially on the remaining cone photoreceptors or ganglion cells. And once everything has disappeared in terms of photoreceptors, we can try to use the remainder of the retinal circuitry to activate therapy by a prosthetic source,” he said.

In this trial, the GS030 therapy uses an optimised viral vector to express the light-sensitive opsin ChrimsonR in retinal ganglion cells. This is then combined with proprietary light-stimulating goggles to project the right wavelength and intensity of light onto the treated retina.

The patient in the case report had only light perception prior to receiving GS030. Training using the special goggles began four months after his intravitreal injection. Seven months after the start of his training, he started to report signs of visual improvement. Visual function tests showed he acquired the ability to perceive, locate, count, and touch objects when his treated eye was stimulated with the goggles. Without the goggles, he could not perform the tasks.

While the patient performed vision-oriented tasks, multichannel electroencephalography (EEG) signals showed distinct neurophysiological activity in the visual cortex, Prof Sahel said.

Summing up, Prof Sahel said the interim results showed the therapy was safe and well-tolerated and represented real progress for inherited retinal disease treatment.

“The clinical site in France reports visual improvement after training in real-life conditions. New tests have been implemented and existing tests modified to avoid ceiling/ flooring effects and detect improvements observed in realworld scenarios,” he said.

“The clinical site in France reports visual improvement after training in real-life conditions.”

José-Alain Sahel MD, PhD is Distinguished Professor and Chairman, Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. He is also a co-founder of GenSight Biologics. sahelja@upmc.edu