N Engl J Med. 2026 Oct 8;395(14):1399-1408. doi: 10.1056/NEJMoa2602215.
ABSTRACT
BACKGROUND: Retinitis pigmentosa is an inherited degenerative retinal disease that can lead to irreversible blindness. Optogenetic therapy has shown potential for restoring visual function at late stages of the disease.
METHODS: In this open-label study, we evaluated the safety of ganglion cell-directed optogenetic therapy in 10 participants with blindness due to advanced retinitis pigmentosa. Each participant received a single intravitreal injection of an adeno-associated viral (AAV) vector encoding the red-shifted channelrhodopsin ChrimsonR in the worse-seeing eye. The primary outcome was safety. Secondary outcomes included changes in light sensitivity as measured by full-field stimulus threshold (FST) testing conducted with the untreated eye patched and with the use of light-stimulating goggles designed to activate ChrimsonR. The definition of a clinically meaningful improvement in the FST (based on evidence from the literature and not prespecified in the protocol) was a decrease of at least 0.6 log units (i.e., an increase in light sensitivity by a factor of approximately 4).
RESULTS: A total of 34 ocular adverse events occurred among 9 of the 10 participants, including 23 mild events and 10 moderate events. One severe event occurred: transient occlusion of the central retinal artery that occurred immediately after intravitreal injection and resolved within minutes after instillation of iopidine. Light sensitivity increased in 7 of the 10 participants, with increases ranging from a factor of 2.0 to a factor of 62.3; 6 participants had a clinically meaningful increase in light sensitivity.
CONCLUSIONS: Within the limits of this small study, intravitreal administration of a ChrimsonR-expressing AAV vector targeting retinal ganglion cells combined with use of light-stimulating goggles was safe. Additional research is needed to further assess safety and efficacy. (Funded by GenSight Biologics; PIONEER ClinicalTrials.gov number, NCT03326336.).
PMID:42842903 | DOI:10.1056/NEJMoa2602215
