Katarina Stingl

Purpose To investigate the changes in retinal arterial architecture after treatment with voretigene neparvovec in patients with retinal dystrophy caused by bi‐allelic mutations in the RPE65 gene. Methods Sixteen eyes treated with voretigene neparvovec at the University Eye Clinic in Tuebingen, Germany, underwent adaptive optics ophthalmoscopy (AO) imaging at baseline and 2 weeks, 1, 3, 6 and 12 months after treatment. Follow‐up was performed in six eyes of four patients. For each eye, five different positions at arterial vessels were selected and the wall‐to‐lumen ratio (WLR), the lumen diameter (LD) and the wall cross‐sectional area (WCSA) were measured by the manufacturer's software over the observational period. Results Vast retinal atrophy dominated all gained AO images. WLR fluctuated in the observation period without statistically significant change. LD and WCSA changed significantly after 2 weeks from the baseline examination and returned to values similar to baseline thereafter. There were no signs of inflammation such as macrophages or perivascular accumulated fluid visible. Conclusion AO imaging of the retinal vessels in RPE65‐ associated retinal dystrophies (IRD) is challenging. There was no change in the retinal arterial vasculature over the observation period of 12 months that would indicate inflammatory changes. Decrease of the LD and WCSA shortly after treatment might be caused by the perioperative prednisolone intake. AO of retinal vessels can be used as a diagnostic module to complement monitoring the disease and effects of genetic treatments if the acquisition is possible in selected cases.

Biallelic pathogenic variants in TULP1 are mostly associated with severe rod-driven inherited retinal degeneration. In this study, we analyzed clinical heterogeneity in 17 patients and characterized the underlying biallelic variants in TULP1. All patients underwent thorough ophthalmological examinations. Minigene assays and structural analyses were performed to assess the consequences of splice variants and missense variants. Three patients were diagnosed with Leber congenital amaurosis, nine with early onset retinitis pigmentosa, two with retinitis pigmentosa with an onset in adulthood, one with cone dystrophy, and two with cone-rod dystrophy. Seventeen different alleles were identified, namely eight missense variants, six nonsense variants, one in-frame deletion variant, and two splice site variants. For the latter two, minigene assays revealed aberrant transcripts containing frameshifts and premature termination codons. Structural analysis and molecular modeling suggested different degrees of structural destabilization for the missense variants. In conclusion, we report the largest cohort of patients with TULP1-associated IRD published to date. Most of the patients exhibited rod-driven disease, yet a fraction of the patients exhibited cone-driven disease. Our data support the hypothesis that TULP1 variants do not fold properly and thus trigger unfolded protein response, resulting in photoreceptor death.