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

Abstract

Purpose : Biallelic mutations to the Centrosomal protein 290 gene (CEP290) cause severe degenerative inherited retinal diseases (IRDs) resulting in childhood blindness. Currently, there is no treatment for this condition. This 12-month prospective study (NCT03396042) aimed to describe the natural history and characteristics of CEP290-associated IRD and to determine which assessments may provide reliable endpoints in future interventional trials.

Methods : Patients with CEP290-associated IRD and best-corrected visual acuity (BCVA) of light perception to 0.4 logMAR were recruited in eight cohorts spanning four age ranges (3–5, 6–11, 12–17, ≥ 18 years) and two BCVA ranges (light perception to > 1.0 logMAR, 1.0 logMAR to 0.4 logMAR). Functional outcomes included BCVA, full-field stimulus threshold sensitivity (FST), and multi-luminance Visual Navigation Challenge (VNC) composite score. Optical coherence tomography–outer nuclear layer (OCT–ONL) thickness was included as an anatomical outcome. BCVA, FST, VNC score, and OCT–ONL thickness were assessed at screening, baseline (test/retest), and months 3, 6 and 12.

Results : A total of 26 participants were enrolled, 19 of whom 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 to 3.9] logMAR) with no correlation to age, similar to findings for VNC score, FST, and OCT–ONL thickness. Mean test-retest variability (95% CI) was -0.04 (-0.09–0.01) logMAR for BCVA, n = 25; 0.6 (-0.1–1.3) for VNC score, n = 18; and 0.10 (-0.07–0.27) log cd/m² for red FST, n = 14. For OCT–ONL thickness, a greater than expected mean test-retest variability of 5 (0–10) μm, n = 14 was observed. Nystagmus impacted scan quality and ability to repeat measures at the same retinal location. Functional assessments were mostly stable over 12 months. Mean (95% CI) change from baseline to 12 months was 0.06 (-0.17–0.29) logMAR for BCVA, n = 23; -0.1 (-1.2–1.0) score level for VNC, n = 21; and -0.15 (-0.43–0.14) log cd/m² for red FST, n = 16.

Conclusions : Visual function was stable over the 12-month study period with BCVA, FST, and VNC score being potentially viable endpoints for future clinical studies in patients with CEP290-associated IRD. Repeatability of OCT measures poses potential challenges for quantifying anatomical changes in this patient population.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.