ABSTRACT Background The lack of validated and sensitive clinical endpoints remains a major challenge in the design of gene therapy trials for inherited retinal dystrophies (IRDs). This prospective longitudinal cohort study describes the natural disease progression of IRDs caused by pathogenic mutations in the Crumbs homologue 1 ( CRB1 ) gene, and identifies sensitive clinical endpoints. Methods In this single‐centre study, patients with genetically confirmed CRB1‐ associated IRD were assessed at baseline, 2‐year and 4‐year follow‐up. The phenotyping protocol included best‐corrected visual acuity (BCVA), Goldmann perimetry, mesopic microperimetry, full‐field stimulus testing (FST), ophthalmoscopy and assessment of retinal structural integrity on spectral‐domain optical coherence tomography and fundus autofluorescence. Results Twenty of the 22 enrolled patients completed the 4‐year follow‐up, including patients with retinitis pigmentosa ( n = 17), cone‐rod dystrophy ( n = 2) or macular dystrophy ( n = 1). Significant decreases were observed for BCVA (−6.2 ETDRS letters, 95% confidence interval CI −10.1 to −2.3; p = 0.003), V4e isopter seeing retinal area (−43.9 mm 2 , 95% CI, −72.3 to −15.5; p = 0.003) and mean sensitivity on microperimetry (−2.5 dB, 95% CI, −3.3 to −1.6; p < 0.001). FST thresholds for white, blue and red stimuli did not significantly change over 4 years ( p = 0.24; p = 0.78; p = 0.60, respectively). The continuity of the ellipsoid zone (EZ) and the external limiting membrane (ELM) on SD‐OCT were increasingly disrupted in six patients over the course of this study. Conclusion Except for FST responses, a significant decrease was observed over 4 years in the visual function parameters of BCVA, Goldmann perimetry and microperimetry and these may thus be used as sensitive clinical endpoints.
Karuntu et al. (Sat,) studied this question.