Author: José-Alain Sahel (United States)
Co-authors: Elise Boulanger-Scemama, Joseph N Martel, Chloé Pagot, Angelo Arleo, Francesco Galluppi, Botond Roska
Purpose
Retinitis pigmentosa (RP) is a neurodegenerative eye disease in which loss of photoreceptors can lead to complete blindness. RP is a progressive, inherited, monogenic or rarely digenic blinding disease caused by mutations in more than 71 different genes. It affects more than two million people worldwide. With the exception of a gene replacement therapy for one form of early-onset RP caused by mutation in the gene RPE65, there is no approved therapy for RP. Optogenetic vision restoration is a mutation-independent approach for restoring visual function at late stages of RP after vision is lost. The open-label phase I/IIa study named PIONEER (NCT03326336) was designed to evaluate the safety (primary objective) and efficacy (secondary objective) of an investigational treatment for patients with advanced non-syndromic RP that combines injection of an optogenetic vector (GS030-DP) with the wearing of a light-stimulating goggles (GS030-MD).
Setting/Venue
The optogenetic vector, a serotype 2.7m8 adeno-associated viral vector encoding the light-sensing channelrhodopsin protein ChrimsonR fused to the red fluorescent protein tdTomato, was administered by a single intravitreal injection into the worse-seeing eye to target mainly foveal retinal ganglion cells. The light-stimulating goggles capture images from the visual world using a neuromorphic camera that detects changes in intensity, pixel by pixel, as distinct events. The goggles then transform the events into monochromatic images and project them in real-time as local 595-nm light pulses onto the retina.
Methods
We describe the partial recovery of vision in one subject of the PIONEER study. This 58-year-old male, who was diagnosed with RP 40 years ago, had a visual acuity limited to light perception at the inclusion in the study. The worse-seeing eye was treated with 5.0E10 vector genomes of optogenetic vector. Both before and after injection, we performed ocular examinations and assessed the anatomy of the retina on several occasions over 15 visits spanning 84 weeks according to the protocol. We analyzed the visual improvement under 3 conditions with 3 psychophysical tests. The 3 conditions were: ‘natural binocular’ (both eyes open without the light-stimulating goggles); ‘natural monocular’ (non-treated eye covered, treated eye open without the goggles); and ‘stimulated monocular’ (non-treated eye covered, treated eye open and stimulated with the goggles). The first test consisted of perceiving, locating, and touching a single object placed on a white table. The second test included perceiving, counting, and locating more than one object. For the third test, the subject had to assess the presence or absence of a tumbler placed in front of him. The behavioral responses and brain activity were simultaneously recorded during the third visual test.
Results
We tested the light-stimulating goggles on the subject three times before vector injection. On none of these occasions did the subject report any change of vision nor any photophobia. The subject could not visually detect any objects before injection with or without the goggles, or after injection without the goggles. The subject perceived, located, counted, and touched different objects using the vector-treated eye alone whilst wearing the goggles. During visual perception, multi-channel electroencephalographic recordings revealed object-related activity above the visual cortex. There was no intraocular inflammation, no changes in the anatomy of the retina, and no ocular or systemic adverse events over the period of follow-up. The treated eye retained light perception over the 84 weeks of testing.
Conlusions
This is the first reported case of partial functional recovery after optogenetic therapy for a neurodegenerative disease. Taken together, the psychophysical and neurophysiological evidence suggest that the optogenetic stimulation of human retinal ganglion cells by a light-projection system linked to a camera is a promising way to partially restore vision in blind patients affected with advanced RP.
Financial Disclosure
Personal financial interests in GenSight Biologics, Pixium Vision, Sparing Vision, Prophesee, Tilak, VegaVect, NewSight and Chronolife
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