Exogenous Photoreceptor-Specific N-Glycosylated PROM1 Rescues Retinal Degeneration in Patient and Animal Models

The mechanisms underlying this retina-specific vulnerability remain poorly understood, and no effective treatment currently exists for PROM1-associated inherited retinal dystrophies (IRDs). To address these gaps, we employed retinal organoids (ROs) to delineate the spatiotemporal expression patterns of PROM1, identifying its co-localization with the ciliary marker ARL13B and the outer segment (OS) marker PRPH2 during photoreceptor differentiation.

Furthermore, using hiPSCs, hiPSC-RPE cells, and ROs, we discovered photoreceptor-specific mRNA alternative splicing isoforms and distinct protein N-glycosylation patterns of PROM1. To investigate disease mechanisms and therapeutic potential, personalized hiPSCs and ROs were derived from an individual with a PROM1 c.619G>T (p.E207X) homozygous mutation and his unaffected heterozygous mother. The mutation induced pronounced nonsense-mediated decay (NMD) and nonsense-associated altered splicing (NAS), resulting in complete loss of PROM1 protein and severe disruption of OS-like structure in patient-derived ROs (Hom-ROs).