Gene Editing for CEP290-Associated Retinal Degeneration

Abstract

Background: CEP290-associated inherited retinal degeneration causes severe early-onset vision loss due to pathogenic variants in CEP290. EDIT-101 is a clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) gene-editing complex designed to treat inherited retinal degeneration caused by a specific damaging variant in intron 26 of CEP290 (IVS26 variant).

Methods: We performed a phase 1-2, open-label, single-ascending-dose study in which persons 3 years of age or older with CEP290-associated inherited retinal degeneration caused by a homozygous or compound heterozygous IVS26 variant received a subretinal injection of EDIT-101 in the worse (study) eye. The primary outcome was safety, which included adverse events and dose-limiting toxic effects. Key secondary efficacy outcomes were the change from baseline in the best corrected visual acuity, the retinal sensitivity detected with the use of full-field stimulus testing (FST), the score on the Ora-Visual Navigation Challenge mobility test, and the vision-related quality-of-life score on the National Eye Institute Visual Function Questionnaire-25 (in adults) or the Children's Visual Function Questionnaire (in children).

Results: EDIT-101 was injected in 12 adults 17 to 63 years of age (median, 37 years) at a low dose (in 2 participants), an intermediate dose (in 5), or a high dose (in 5) and in 2 children 9 and 14 years of age at the intermediate dose. At baseline, the median best corrected visual acuity in the study eye was 2.4 log₁₀ of the minimum angle of resolution (range, 3.9 to 0.6). No serious adverse events related to the treatment or procedure and no dose-limiting toxic effects were recorded. Six participants had a meaningful improvement from baseline in cone-mediated vision as assessed with the use of FST, of whom 5 had improvement in at least one other key secondary outcome. Nine participants (64%) had a meaningful improvement from baseline in the best corrected visual acuity, the sensitivity to red light as measured with FST, or the score on the mobility test. Six participants had a meaningful improvement from baseline in the vision-related quality-of-life score.

Conclusions: The safety profile and improvements in photoreceptor function after EDIT-101 treatment in this small phase 1-2 study support further research of in vivo CRISPR-Cas9 gene editing to treat inherited retinal degenerations due to the IVS26 variant of CEP290 and other genetic causes. (Funded by Editas Medicine and others; BRILLIANCE ClinicalTrials.gov number, NCT03872479.).

Figure 1.. Change from Baseline in Key Efficacy Outcomes.

Changes from baseline to the latest follow-up assessment in the sensitivity to red light as measured with full-field stimulus testing (Panel A), the best corrected visual acuity (Panel B), the score on the Ora–Visual Navigation Challenge (VNC) mobility test (Panel C), and the vision-related quality-of-life score on the National Eye Institute Visual Function Questionnaire–25 (for adults) or the Children’s Visual Function Questionnaire (for children) (Panel D) are shown for 14 participants who received EDIT-101 gene-editing therapy and had a follow-up duration of at least 6 months. Cohort 1 comprised adults who received a low dose (6×10¹¹ vector genomes [vg] per milliliter) of EDIT-101 in the worse (study) eye; cohort 2, adults who received an intermediate dose (1×10¹² vg per milliliter); cohort 3, adults who received a high dose (3×10¹² vg per milliliter); and cohort 4, children who received the intermediate dose. The contralateral (control) eye was untreated. Improvements in the full-field red light–sensitivity threshold and the best corrected visual acuity are shown as negative values, and improvements in the score on the VNC mobility test and the score on the vision-related quality-of-life questionnaires are shown as positive values. The dashed lines indicate the thresholds for meaningful improvement. The direction of improvement and the number of participants with improvement for each metric are indicated to the right of each panel. Participant identifiers (defined according to cohort [C] number and participant [P] number) and lengths of follow-up are shown on the x axis. Data from the red-light full-field stimulus test for Participant C1P2 were not available. logMAR denotes log₁₀ of the minimum angle of resolution.

Figure 2.. Structural–Functional Relationships.

Shown in Panel A are images of the retinal structure in the two pediatric participants (C4P1 and C4P2). En face views show near-infrared fundus autofluorescence (NIR-FAF) that originates mainly from the melanin in the retinal pigment epithelium (RPE). The NIR-FAF images obtained at month 6 have been coregistered to the images obtained at baseline to allow for comparison of the images. Cross-sectional views are optical coherence tomographic scans along the horizontal meridian crossing the fovea. Lower signals in Participant C4P1 were caused by corneal scarring and cataracts resulting from eye poking. Calibration bars are shown on the lower right. BrM denotes Bruch’s membrane, EZ ellipsoid zone, and ONL outer nuclear layer. Shown in Panel B are sensitivities determined with the use of full-field stimulus testing (FST) in the study eyes and control eyes in Participants C4P1 and C4P2. Differences in spectral sensitivities showed that sensitivities in both participants were mediated by cones. Treatment with EDIT-101 led to recovery of the cone-mediated sensitivities (arrows), which were close to the lower limit of the normal range (dashed lines) by month 6. Panel C shows the change from baseline in the full-field stimulus testing sensitivity in response to red light in 13 participants with available data. Data are from the latest follow-up examination for each participant. The dashed line indicates the cutoff for meaningful improvement. Unfilled symbols indicate control eyes.