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Stunning Success Reported in Partially Restoring Sight in Blind Patient Using Optogenetics Gene Therapy; Recovery “Breathtaking to Witness,” Says Senior Author

On May 25, 2021, GenSight Biologics (Euronext: SIGHT, ISIN: FR0013183985, PEA-PME eligible) (https://www.gensight-biologics.com/), a biopharma company focused on developing and commercializing innovative gene therapies for retinal neurodegenerative diseases and central nervous system disorders, announced that the highly-regarded journal Nature Medicine has published the first case report of partial recovery of visual function in a blind patient with late-stage retinitis pigmentosa (RP). The subject is a participant in the ongoing PIONEER Phase I/II clinical trial of GenSight Biologics’ GS030 optogenetic therapy. Published online on May 24, 2021, under the title “Partial Recovery of Visual Function in a Blind Patient After Optogenetic Therapy,” the open-access paper is the first peer-reviewed documentation of visual recovery after a blind patient was treated with optogenetic therapy. “These are truly groundbreaking findings that move the promise of optogenetics (https://en.wikipedia.org/wiki/Optogenetics) another step from therapeutic concept to clinical use,” commented Bernard Gilly, PhD, Co-Founder and Chief Executive Officer of GenSight. “These could not have occurred without the close collaboration we enjoyed with our partners at the Institut de la Vision, the Institute of Ophthalmology Basel, and Streetlab. We are especially grateful to the patients who are participating in our trial, whose experiences and input will help us design the next stage of GS030’s clinical development. We will now accelerate the GS030 program to make it our second product to reach the market after LUMEVOQ.” Optogenetic therapies combine cellular expression of light-sensitive opsins with light stimulation using a medical device. GS030 uses an optimized viral vector (GS030-DP) to express the light-sensitive opsin ChrimsonR in retinal ganglion cells and proprietary light-stimulating goggles (GS030-MD) to project the right wavelength and intensity of light onto the treated retina. GS030-DP is administered via an intravitreal injection.

“It was breathtaking to witness the first recovery of some visual function in a blind patient,” commented Dr. Botond Roska, MD, PhD, senior and co-corresponding author, and a pioneer in the field of optogenetic vision restoration. Dr. Roska is Founding Director of the Institute of Molecular and Clinical Ophthalmology Basel (IOB) in Switzerland and a Co-Founder of GenSight.

“We have worked on optogenetic therapy in the lab for 16 years and now seeing the proof of concept in a patient is a unique experience,” he said. “I am most grateful to have shared this long journey with José Sahel, MD, PhD, a fellow founder of GenSight; the dedicated team at GenSight; and our other collaborators.”

The subject in the case report, who had been diagnosed with RP 40 years prior to enrollment, had such low visual acuity that prior to receiving GS030, he could only perceive light. His gene therapy injection was followed four and a half months later by training on the use of the GS030-MD device. Seven months after the start of his training, he began 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 GS030-MD goggles. Without the goggles, he could not perform the tasks.

While the patient performed vision-oriented tasks, recordings were taken using extracranial multi-channel electroencephalography (EEG), a non-invasive technique that provides a readout of neuronal activity across the cortex. The EEG signals suggest that the act of carrying out the visual perception tests was accompanied by neurophysiological activity in the visual cortex.

In addition, the patient also reported significant improvements in his ability to conduct day-to-day activities such as navigating in outdoor and indoor environments and detecting household objects and furniture.

“Watching a patient benefit for the first time from this trial using optogenetics to treat blindness has been a uniquely rewarding experience,” commented Dr. Sahel, lead and co-corresponding author, Co-Founder of GenSight, and Founder of the Institut de la Vision (Sorbonne-Université/Inserm/CNRS), Paris, France.

Dr. Sahel is also Director of Institut Hospitalo-Universitaire FOReSIGHT, Paris, France, and Distinguished Professor and Chairman of the Department of Ophthalmology at the University of Pittsburgh School of Medicine and UPMC (University of Pittsburgh Medical Center), USA.

He added, “Being able to take part in bringing this new scientific approach to the clinic reflects the long-term collaboration with Botond Roska, the scientists of the Vision Institute, our clinicians, the Streetlab and psychophysics teams, and GenSight.”

A video of the patient performing the tests, which was submitted as supplementary material to Nature Medicine, can be viewed at http://www.gensight-biologics.com.

KEY OPINION LEADER WEBCAST: JUNE 4, 2021 AT 2:00 PM CEST/8:00 AM EDT

Dr. Sahel and Dr. Roska will discuss the case report on a KOL webcast dedicated to Optogenetics and GS030 and hosted by GenSight Biologics. Details will be announced at a later date.

CONTEXT

Retinitis pigmentosa (RP) is the leading cause of inherited blindness and is caused by mutations in more than 71 different genes. By using gene therapy to induce light sensitivity in unaffected retinal ganglion cells, GS030 overcomes the challenge among genetics-based treatments of exclusively addressing a specific underlying mutation and thus offers a treatment that is independent of the underlying pathogenic mutation.

PIONEER is the Phase I/II first-in-human, multi-center, open-label dose-escalation clinical trial to evaluate the safety and tolerability of GS030 in subjects with late-stage RP. A total of 12 to 18 subjects are planned to be enrolled. Three cohorts with three subjects each will be administered an increasing dose of GS030-DP via a single intravitreal injection in their worse-seeing eye. An extension cohort will receive the highest tolerated dose. A Data Safety Monitoring Board (DSMB) reviews the safety data of all treated subjects in each cohort and makes recommendations before the next cohort is enrolled. The primary outcome analysis will be the safety and tolerability at one year post-injection.

In line with the PIONEER protocol, the subject received the lowest dose (5.0E10 vector genomes) of GS030-DP in his worse-seeing eye. Four and a half months after injection, the patient began systematic training at Streetlab, a specialized visual rehabilitation facility, to learn how to use the light-stimulating goggles. The timing of the training was based on the estimated time it takes for the expression of light-sensitive opsin to stabilize in foveal ganglion cells.

HIGHLIGHTS OF VISUAL FUNCTION FINDINGS FROM CASE REPORT

In the first visual test, the subject was asked to perceive, locate, and touch a single object placed in front of him on a white table. The subject had no success without the goggles. When the subject’s treated eye was stimulated by the GS030-MD goggles, his ability to perceive, locate, and touch an object depended on the size of the object, with a significantly higher rate of successful trials with a large object (a notebook; 92%) than with the smaller object (a staple box; 36%). The success rate was similar for objects at different contrasts, suggesting that even objects at lower contrasts generated enough retinal activity for perception. Finally, the success rate was similar for the different tasks of perceiving, locating, and touching, suggesting that once the object was perceived, the patient could coordinate his motor system with the percept.

The second visual test required the subject to perceive, count, and locate two or three tumblers of different contrasts placed in front of him on a white table. As in the first test, the subject had no success without the goggles. When the subject’s treated eye was stimulated by the GS030-MD goggles, the patient perceived, correctly counted, and located the objects in the majority (58-63%) of the trials. As in the first test, the success rate was similar for objects of different contrasts.

In the third visual test, the patient had to assess the presence or absence of a tumbler on a white table. The success rate with the goggles stimulating the treated eyes was statistically significantly higher than without the goggles (41% vs. 6%; p < 0.001).

HIGHLIGHTS OF SAFETY FINDINGS FROM CASE REPORT

In-depth ocular examinations were performed regularly before and after injection, and potential intraocular inflammation was monitored according to international guidelines of the Standardization of Uveitis Nomenclature (SUN) Working Group. Both eyes of the subject showed no intraocular inflammation and no changes in the anatomy of the retina; there were no ocular or systemic adverse events over the 84 weeks of assessment.

The subject tested the light-stimulating goggles three times before being injected with the gene therapy. On each of these occasions, he reported no change of vision or photophobia.

GENSIGHT BIOLOGICS

GenSight Biologics S.A. (https://www.gensight-biologics.com/), headquartered in Paris, France, is a clinical-stage biopharma company focused on developing and commercializing innovative gene therapies for retinal neurodegenerative diseases and central nervous system disorders. GenSight Biologics’ pipeline leverages two core technology platforms, the Mitochondrial Targeting Sequence (MTS) and optogenetics, to help preserve or restore vision in patients suffering from blinding retinal diseases. GenSight Biologics’ lead product candidate, LUMEVOQ® (GS010; lenadogene nolparvovec), has been submitted for marketing approval in Europe for the treatment of Leber hereditary optic neuropathy (LHON), a rare mitochondrial disease affecting primarily teens and young adults that leads to irreversible blindness. Using its gene therapy-based approach, GenSight Biologics’ product candidates are designed to be administered in a single treatment to each eye by intravitreal injection to offer patients a sustainable functional visual recovery.

IMAGE

The experimental set-up, where the volunteer was asked to say whether or not the cup was on the white table. Behavioral responses and brain activity were recorded simultaneously during the test. (Credit: Nature Medicine).

[News release] [Nature Medicine article]

[NY Times article] [BBC News article] [New Scientist article] [Medscape article] [Ophthalmology Times article] [Genome Web article]