Twelve-month Natural History Study of CEP290-associated Retinal Degeneration

Objective To define the clinical characteristics of CEP290-associated inherited retinal degeneration (IRD) and determine which assessments may provide reliable endpoints in future interventional trials. Design Participants in this natural history study were enrolled into two best-corrected visual acuity (BCVA) cohorts: light perception to > 1.0 logMAR and 1.0 logMAR to 0.4 logMAR. Each comprised four age cohorts (3–5, 6–11, 12–17, and ≥ 18 years). Participants Patients with CEP290-associated IRD caused by the intron 26 c.2991+1655A>G mutation and BCVA ranging from light perception to 0.4 logMAR. Methods BCVA, full-field stimulus threshold (FST) sensitivity, Ora–Visual Navigation Challenge (Ora–VNCTM) composite score, and optical coherence tomography–outer nuclear layer (OCT–ONL) average thickness were assessed at screening, baseline, 3 months, 6 months, and 12 months. Main outcomes BCVA, FST sensitivity, Ora–VNC™ composite score, and OCT–ONL average thickness. Results Twenty-six participants were included in this analysis. Nineteen were female. All participants were White and four reported Hispanic ethnicity. At screening, 13/16 adult and 9/10 pediatric participants had BCVA > 1.0 logMAR. Baseline BCVA was variable (median [range] = 2.0 [0.5, 3.9] logMAR) and was uncorrelated with age, as were VNC composite score, FST sensitivity, and OCT–ONL average thickness. Mean (95% CI) test-retest variability was -0.04 (-0.09, 0.01) logMAR for BCVA [n = 25]; 0.6 (-0.1, 1.3) for VNC composite score [n = 18]; and 0.10 (-0.07, 0.27) log cd.s/m2 for red FST [n = 14]. A greater than expected test-retest variability (5 [0, 10] μm, n = 14) was observed for OCT–ONL average thickness as nystagmus impacted ability to repeat measures at the same retinal location. Functional assessments were stable over 12 months. Mean (95% CI) change from baseline was 0.06 (-0.17, 0.29) logMAR for BCVA [n = 23]; -0.1 (-1.2, 1.0) for VNC composite score [n = 21]; and -0.15 (-0.43, 0.14) log cd.s/m2 for red FST [n =16]. Conclusions Vision was stable over 12 months. BCVA, FST, and VNC composite score are potentially viable endpoints for future studies in CEP290-associated IRD. Repeatability of OCT measures poses challenges for quantifying anatomical changes in this population.