Inner Blood Retinal Barrier integrity in the pathogenesis of Retinitis Pigmentosa

Abstract

Retinitis Pigmentosa (RP) is the most prevalent form of Inherited Retinal Degeneration, estimated to impact 1 in 4000 people across Ireland. The disease is characterized by enhanced genetic complexity which restricts the scope of many treatment interventions that target a specific causative gene. There is therefore a great need for research to aid in the development of novel therapeutic approaches which will serve a greater majority of RP patients. The inner Blood Retinal Barrier (iBRB) which constitutes the inner retinal vasculature may represent a novel target in this regard. Notably, vascular attenuation is a hallmark feature of RP pathology, however, limited research has been done to infer more about earlier vascular manifestations which may impact pathological progression. Thus, the central aim of this thesis is to provide a characterisation of the iBRB in the context of RP pathology. These aims are facilitated through a variety of genetic animal strains which model the disease, as well as through the analysis of fundus imagery from a cohort of genetically diverse RP patients. Key findings from this thesis include shared vascular manifestations of decreased levels of claudin-5, a key barrier forming component, within the inner retina, across the genetically diverse cohort of mice under investigation. These findings are additionally associated with decreased circulation capability of the inner retinal vasculature as well as enhanced degeneration of the deeper vascular layers within these models. Moreover, within the RP patient cohort under investigation, distinct lesions are observed which phenocopy novel animal strains developed, in which expression of Cldn5 is downregulated. Cumulatively, these results indicate a more potent role of the iBRB in the context of RP pathology and highlight the inner vasculature as a promising target for future therapeutic intervention.