Gene Editing for CEP290 -Associated Retinal Degeneration.
Level 4 - case-series / case-control
Phase 1-2 open-label single-ascending-dose study without a concurrent control group.
PubMed 38709228 · doi:10.1056/NEJMoa2309915
What was done
A phase 1-2, open-label, single-ascending-dose trial evaluated EDIT-101 (a CRISPR-Cas9 gene-editing therapy targeting the IVS26 variant in intron 26 of CEP290) delivered via subretinal injection into the worse-seeing eye. The study enrolled 14 participants (12 adults aged 17 to 63 years, median age 37; 2 children aged 9 and 14 years) with homozygous or compound heterozygous CEP290 IVS26 mutations. Cohorts received a low dose (2 adults), intermediate dose (5 adults, 2 children), or high dose (5 adults). The primary outcome was safety (adverse events and dose-limiting toxicities). Key secondary outcomes were changes from baseline in best corrected visual acuity, full-field stimulus testing retinal sensitivity, Ora-Visual Navigation Challenge mobility testing, and vision-related quality-of-life scores.
What was found
Baseline median best corrected visual acuity in the study eye was 2.4 logMAR (range, 0.6 to 3.9). No treatment-related or procedure-related serious adverse events and no dose-limiting toxic effects were reported. Six participants had a meaningful improvement from baseline in cone-mediated vision on full-field stimulus testing, 5 of whom also improved in at least one other key secondary outcome. Nine participants (64%) had meaningful improvement from baseline in best corrected visual acuity, red-light sensitivity on full-field stimulus testing, or mobility test scores. Six participants had meaningful improvement in vision-related quality-of-life scores.
Why it matters
This study provides early clinical proof-of-concept and safety data for in vivo CRISPR-Cas9 editing in human photoreceptors to treat CEP290-associated inherited retinal degeneration.
Limits
The study is limited by a small sample size of 14 participants, an open-label single-ascending-dose design without a control group, and a wide baseline visual acuity range (0.6 to 3.9 logMAR). Pediatric data were limited to two participants, and long-term durability was not detailed in the abstract.
Cited by
- partial CRISPR gene editing injected into the back of the eye has been used to treat a specific form of congenital blindness.