Optogenetic therapy may partially restore vision in retinitis pigmentosa
1. In this phase 1 trial involving subjects with advanced retinitis pigmentosa, optogenetic therapy was associated with improved light sensitivity and partial recovery of visual function.
2. Most ocular adverse events were mild or moderate, although a severe, transient central retinal artery occlusion occurred immediately after injection and resolved within minutes.
Evidence Rating Level: 2 (Good)
Study Rundown: Retinitis pigmentosa describes a group of inherited retinal disorders in which progressive photoreceptor loss can result in irreversible blindness. Gene augmentation has benefited some patients with a specific genetic subtype, but treatment options remain limited for most affected individuals. Optogenetic therapy may serve as an alternative treatment pathway by conferring light-sensitivity to surviving retinal neurons, such as ganglion cells. This multicenter, open-label study evaluated the safety and exploratory visual effects of an intravitreal viral vector encoding ChrimsonR, a light-sensitive protein, combined with goggles that projected amber-light patterns onto the retina. Treatment was associated with increased light sensitivity in several participants. Additionally, a subset of individuals also experienced partial improvements in object detection, localization, and orientation discrimination. Functional gains were generally variable, and there was no restoration of high-acuity vision. All but one ocular adverse event was mild or moderate, and the single severe event was a retinal arterial occlusion after injection which resolved promptly with treatment. This study was limited by the small sample size and the exploratory nature of visual outcomes. Overall, these findings were promising and may justify continued investigation of optogenetic therapy advanced retinitis pigmentosa.
Click to read the study in NEJM
In-Depth [prospective cohort]: The multicenter PIONEER study was a phase 1, open-label, dose-escalation study involving 10 adults with advanced retinitis pigmentosa. Participants received a single intravitreal injection of an AAV2.7m8 vector encoding ChrimsonR–tdTomato into the worse-seeing eye. Doses were 5.0 × 10¹⁰, 1.5 × 10¹¹, or 5.0 × 10¹¹ vector genomes per eye. Safety was the primary outcome, and exploratory functional assessments included full-field stimulus threshold (FST) testing and various behavioral tasks. A total of four participants completed five-year follow-up. Nine participants experienced 34 ocular adverse events: 23 mild, 10 moderate, and one severe event. The single severe event was a central retinal artery occlusion which resolved within minutes after iopidine administration. Intraocular inflammation occurred in seven participants and also resolved with treatment without sequelae. No systemic adverse events were attributed to the vector or injection procedure, although three mild systemic events were attributed to the goggles. Light sensitivity increased in 7 participants, with improvements ranging from 2.0-fold to 62.3-fold. Of these, six met the threshold for clinically meaningful improvement, defined as approximately fourfold greater sensitivity. Eight participants completed the principal behavioral tests and were classified as responders. Exploratory electroencephalographic testing in five selected participants showed a mean improvement in decoding accuracy for periodic visual stimuli of 7.6 percentage points (95% confidence interval, -0.1 to 15.4). Overall, these results suggest that optogenetic therapy for retinitis pigmentosa was tolerable and may demonstrate some small efficacy signals.
Citation: Sahel JA, Futterknecht S, Audo I, Martel JN, Ling S, Pagot C, et al. Optogenetic Therapy for Restoring Aspects of Visual Function. N Engl J Med. 2026 Oct 8;395(14):1399-1408. doi: 10.1056/nejmoa2602215. Epub 2026 Oct 7. PMID: 42842903.
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