Dynamic Inner Blood Retina Barrier Disruption in Retinitis Pigmentosa.

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.