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  • Pediatric Ophth/Strabismus, Retina/Vitreous

    Review of: Gene editing for CEP290-associated retinal degeneration

    Pierce E, Aleman T, Jayasundera K, et al. The New England Journal of Medicine, May 2024

    CEP290-associated inherited retinal degeneration is caused by a pathogenic IVS26 variant in CEP290. Characterized by photoreceptor disorganization, retinal pigmentation, and early rod death, this condition leads to severe, early-onset vision loss. The CRISPR-associated protein 9 (Cas9) gene-editing complex EDIT-101 was designed to remove the pathogenic IVS26 variant responsible for CEP290-associated inherited retinal degeneration. In this small, early-phase clinical trial, administration of EDIT-101 resulted in no treatment-related adverse effects and showed potential therapeutic benefits, supporting continued research into this and other CRISPR-associated–Cas9-mediated therapies for patients with inherited retinal degeneration.

    Study Design

    In this phase 1/2, open-label, ascending-dose study, 14 eyes of 14 patients (12 adults and 2 children aged ≥3 years) with CEP290-associated inherited retinal degeneration were treated with subretinal injection of EDIT-101 during pars plana vitrectomy. Two adults received a low dose (6 × 1011 vector genomes [vg] per milliliter), 5 adults and 2 children received an intermediate dose (1 × 1012 vg per milliliter), and 5 adults received a high dose (3 × 1012 vg per milliliter) in their worse-seeing eye. Patients were monitored for up to 2 years. Safety was the primary outcome, with secondary outcomes including change in BCVA, full-field stimulus testing (FST), Ora-Visual Navigation Challenge mobility testing, and results on vision-functioning questionnaires.


    No treatment-related ocular serious adverse events or dose-limiting toxic effects were noted. Overall, the mean change from baseline in BCVA was −0.21 logMAR in the study eyes vs −0.01 logMAR in the untreated contralateral (control) eyes. Eleven patients (79%) had improvement in at least 1 of the 4 secondary outcomes, with 6 (43%) improving in 2 or more outcomes.


    The study is mainly limited by its small size, and safety signals should be understood in this context. Given the nature of subretinal delivery, no sham comparator group is available. Moreover, improvements in the studied functional outcomes varied across patients. Longer-term follow-up will be needed to assess the durability of treatment effect over time.

    Clinical Significance

    Data from this phase 1/2 study did not reveal serious adverse events or dose-limiting toxicity associated with subretinal administration of EDIT-101 for the treatment of IVS26-variant CEP290-related inherited retinal degeneration. The study helps support further research into CRISPR-Cas9–mediated therapies for inherited retinal degenerations.

    Financial Disclosures: Dr. M. Ali Khan discloses financial relationships with Allergan, Apellis Pharmaceuticals, Genentech (Consultant/Advisor); Regeneron Pharmaceuticals (Grant Support).