Twelve-month Natural History Study of Centrosomal Protein 290 (CEP290)-associated Inherited Retinal Degeneration

Purpose To define the clinical characteristics of centrosomal protein 290 ( 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 2 best-corrected visual acuity (BCVA) cohorts: light perception to > 1.0 logarithm of the minimum angle of resolution (logMAR) and 1.0 logMAR to 0.4 logMAR. Each comprised 4 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 Best-corrected visual acuity, full-field stimulus threshold (FST) sensitivity, Ora–Visual Navigation Challenge (Ora–VNC) composite score, and OCT–outer nuclear layer (OCT–ONL) average thickness were assessed at screening, baseline, 3 months, 6 months, and 12 months. Main Outcome Measures Best-corrected visual acuity, 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 4 reported Hispanic ethnicity. At screening, 13 of 16 adult and 9 of 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% confidence interval [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/m 2 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/m 2 for red FST (n = 16). Conclusions Vision was stable over 12 months. Best-corrected visual acuity, 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. Financial Disclosure(s) Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.