AAV-Mediated Human Prominin-1 Gene Therapy Rescues Photoreceptor Degeneration in Prominin-1 Knockout Model.

More recent reports have identified recessive mutations in prominin-1 (PROM1) in patients with cone-rod dystrophy (CRD), which is associated with early-onset, severe pan-retinal degeneration with early central loss of vision, for which there are currently no effective therapies. A Prominin-1 knockout (Prom1-KO) mouse model recapitulates key features of this retinal recessive disorder, manifesting as intrinsic photoreceptor defects in disk formation, abnormal visual pigment tracking, and impaired visual function. A human PROM1 gene expression cassette driven by a shorter rhodopsin kinase (RK) promoter was packaged into a recombinant adeno-associated virus (rAAV) serotype 2 mutant (AAV2/Cap-C14) vector in this study. Following subretinal injection of this vector into Prom1-KO mice, human PROM1 protein was expressed specifically at the basal part of the outer segment (OS) of retinal photoreceptors. Electroretinography and histological examinations showed better preservation of photoreceptor function and improved photoreceptor survival in the vector-treated Prom1-KO eyes, respectively. This gene replacement therapy also demonstrated the rescue effects even if the intervention was initiated after the onset of photoreceptor degeneration in vivo. Our study conclusively validates the efficacy of this gene therapy in the Prom1-KO mouse model and highlights its significant clinical potential in patients with biallelic recessive mutations in PROM1.