Oral administration of the novel small molecule drug OCX063 protects against inflammation and vascular pathology in a rat diabetic retinopathy (DR) model

Abstract

Purpose : DR is the main cause of vision loss among adults and is associated with neuroinflammation, vascular pathology and ultimately, fibrosis. Current treatments do not prevent disease progression, highlighting a need for drugs that target fibrosis. OCX063 is a novel small molecule drug with anti-inflammatory and anti-fibrotic properties that is hypothesized to have retinoprotective effects in an established model of DR.

Methods : 48 hours post diabetes induction via streptozotocin injection, heterozygous Ren2 rats received either OCX063 (20, 50 or 100 mg/kg) or vehicle once daily by oral gavage. 4 weeks post treatment, one retina was stained for ionized calcium binding adapter molecule 1 and glial fibrillary acidic protein, signifying microglia and Muller cell activation, respectively, and the other was analyzed for pro-inflammatory gene expression via qPCR. 8 weeks post treatment, animals were perfused with rhodamine-conjugated concanavalin A lectin to label and quantify adherent leukocytes in the retinal vasculature. Standard safety pharmacology and toxicology studies were also conducted in rats and dogs.

Results : Retinal inflammation was increased in diabetic versus non-diabetic rats as indicated by a 1 to 2-fold increase in microglia density (p<0.001), reactive gliosis (p<0.05) and leukocyte adhesion (p<0.05). Retinal inflammation was reduced in OCX063-treated diabetic animals such that the extent of reactive gliosis (p<0.05, 20 mg/kg/day) and leukocyte adhesion (p<0.05, 50 mg/kg/day) was comparable to non-diabetic controls, while microglia density was reduced 1.5-fold (20, 50, 100 mg/kg/day, p<0.001) relative to vehicle-treated diabetic rats. Inflammatory/adhesion gene expression in the retina of diabetic rats was also modulated by OCX063 treatment, with a decrease in interleukin 1β, intracellular adhesion molecule 1 and integrin. Finally, no adverse findings were observed in rats or dogs orally dosed with up to 100 mg/kg/day in 28-day repeat dose toxicity and safety pharmacology studies.

Conclusions : Orally administered OCX063 prevents retinal inflammation and vascular pathology in a model of DR, highlighting its potential for treating proliferative retinal diseases. Given OCX063’s favorable efficacy, safety and toxicity profile, this compound is expected to be translated into a clinical trial for patients.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.