A novel PPAR-a agonist for treating retinal inflammation and vascular hyper-permeability

PROJECT SUMMARY The aim of this proposal is to develop a small molecule suitable for long term systemic administration to prevent treat DRCurrent standard of care for diabetic retinopathyDRor other ocular diseases with an obvious dysfunctional microvasculature basisrely on treatment options that are inherently challenged with technical limitations and financial constraintsFor examplehigh costrequirement of specialized facilitiesrepetitive intravitreal injectionsand limited patient responsiveness are some of the critical barriers to progress in care for DRHencedeveloping small molecules that can address one or more therapeutic targets by systemic administration will significantly improve various aspects of the current standard of careAs shown in FIELD and ACCORD clinical studieslong term oral administration of Fenofibrate yielded promising clinical effects on DRfor which mechanism of action is attributed to activation of peroxisome proliferatoractivated receptorPPARHoweverclinical application of pharmacological activation of PPARfor DR still remains unexploitedThe proposed research in Phase I will focus on evaluating the in vivo efficacy of Aa novel PPARselective agonistin a diabetic animal model by examining the two important aspects of DRvascular inflammation and vascular permeabilityAimwill study whether Acan ameliorate inflammation in the retinal vasculature in diabetic conditionand Aimwill test its functional relevance by assessing the vascular permeability in the retina and visual acuityUpon successful demonstration of its efficacyPhase II studies will be proposed to further develop Aas a potential therapeutic agent for DR PROJECT NARRATIVE Diabetic retinopathyDRis a serious complication of diabetes and a leading cause of vision loss in the U SWhile several treatment options exist for a selective group of DR patientsthat are unresponsive to anti VEGF therapy and nearly all typediabetic patients that require longterm treatment still lack proper means of interventionThereforedeveloping an alternative therapeutic strategy with non VEGF targets suited for long term systemic administration holds a tremendous potential to improve the patient coverage and treatment accessibility