Abstract
PURPOSE: Retinitis pigmentosa (RP) is the most common and genetically heterogenous inherited retinal degeneration described. Although vascular attenuation is a notable phenotype in later stages of the disease, the temporal nature of this attenuation and its contribution to disease are not well understood. Despite a growing body of research suggesting that blood-brain barrier (BBB) disruption can drive neurological deficits across a wide range of conditions, there is a paucity of data related to the contribution of inner blood-retina barrier (iBRB) disruption in RP. METHODS: Here, we sought to examine retinal vascular changes in three established mouse models of RP, Rho-/-, Rd10, and Rpe65D477G. Each model was also established on a claudin-5 heterozygous (Cldn5+/-) background to examine retinal pathology in the context of a "leaky" iBRB. Additionally, we quantitatively examined iBRB integrity in patients with RP (n = 14) harboring autosomal dominant variants in either the RHO or RPE65 genes. RESULTS: Our results show decreased perfusion capacity and disruptions to retinal vascular plexuses within these models, highlighting a perturbed vascular state across Rho-/-, Rd10, and Rpe65D477G models. We highlight a specific loss of the deeper vascular plexus in more rapidly degenerating Rho-/- and Rd10 models, while still observing a global loss of CLDN5 vascular coverage in Rpe65D477G models despite lack of deep plexus degeneration. Moreover, our novel retinal degenerative models on a background of Cldn5 heterozygosity allow us to investigate retinal pathology of these models in the context of a "leaky" iBRB and highlight a specific sensitivity of the larger retinal macrovessels in these models. Furthermore, we find similar phenotypic patterns in a cohort of patients with RP with temporal iBRB changes that phenocopy these preclinical models. CONCLUSIONS: Cumulatively, these findings represent the first quantitative profiling of iBRB disruption in RP and suggest that retinal vascular stabilization may represent a gene agnostic approach to treating this devastating form of blindness.