Gene-Independent Therapeutic Strategies for Retinal Degeneration


Researchers are exploring gene-independent therapeutic strategies to circumvent the challenges of gene-replacement therapies.

This content originally appeared on our sister site, Ophthalmology Times.

Gene therapies are being investigated in RPE65-associated Leber congenital amaurosis (approved in 2017), Leber hereditary optic neuropathy, and other inherited retinal degenerative diseases.

José-Alain Sahel, MD, and colleagues hope to avoid the challenges posed by gene replacement therapies, i.e., extensive genetic heterogeneity and dominant transmission, with another line of research to benefit patients with inherited retinal degenerations.

“Gene-independent strategies could offer promising treatment avenues for these blinding diseases,” he commented.

Dr. Sahel is chairman of the Department of Ophthalmology, and director of the University of Pittsburgh Medical Center Eye Center University of Pittsburgh.

He explained that cones are critical to vision and preserving them may save vision in patients with inherited retinal degenerative diseases.

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The focus of his team’s work, rod-derived cone viability factor, promotes cone survival by stimulating aerobic glycolysis.

In previous work, he and Saddek Mohand-Said, MD, and Thierry Léveillard from the Institut de la Vision, Paris, showed in a murine model of retinitis pigmentosa that rod transplantation delayed cone loss, which depends on functioning rod photoreceptor cells.

These finding could benefit patients with retinitis pigmentosa and other inherited retinal diseases (trial in preparation by SparingVision).

Optogenetics involves use of artificial photoreceptors from specific retinal cells to restore visionby transferring a gene that encodes for a light-sensitive protein that causes neuronal cells to respond to light stimulation (GS030, GenSight Biologics).

This technology combines gene therapy and a medical device to restore retinal light sensitivity by modifying and training retinal ganglion cells to act as photoreceptor, Dr. Sahel explained.

The PIONEER Study is the first trial to test how GS030 optogenetic therapy works in 9 patients with end-stage retinitis pigmentosa.

Patients received 1 intravitreal injection in the eye with the worse vision.

The primary endpoint was the safety and tolerability of the treatment at the 1-year timepoint. The study also is evaluating he effects of 3 doses of the treatment.

Three patients were injected with the lowest dose in March 2019, 3 with the medium dose in February 2020, and 3 with the highest dose in June 2020 and June 2021.

The injections are part of the combined therapy that includes the use of goggles that project light onto the retina.

An extension cohort is planned for the end of 2021. Thus far, the therapy has been well tolerated up to 2.5 years after the intravitreal therapy.

The most common adverse event was anterior chamber or intermediate intraocular inflammation that responded to steroids in 5 of the 9 patients.

Dr. Sahel reported that 1 patient had partial recovery of visual function after this treatment.1 He was the only one who could perform training during the COVID pandemic. Others are now training.

There is great hope that this treatment can benefit patients with many type of retinal degenerations included age-related macular degeneration.

1. Sahel J-A, Boulanger-Scemama E, Pagot C, et al. Partial recovery of visual function in a blind patient after optogenetic therapy. Nature Med 2021;27:1223-9;
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