UMIP-238/-356 – The use of Ezetimibe in the treatment of patients with Alport Syndrome and Chronic Kidney Disease

Problem: AlportSyndrome (AS) is rare genetic disease, affecting glomerularbasement membranes (GBM) linked to mutations in genes coding for different chains of collagen type IV, COL4A3, COL4A4, and COL4A5. Thedisease is characterized by progressive renal failure, hypertension,proteinuria, greatly increased risk of cardiovascular disease, and loss ofhearing and vision. ASaffects approximately 30,000 to 60,000 people in the United States. Currenttherapy is aimed at ameliorating the symptoms and includesangiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers(ARB). Such treatments only slow the loss of kidney function or manage bloodpressure and do not treat or prevent the other effects of the disease. Thereremains a need for therapeutic options for Alport Syndrome and otherCol4-related diseases or more broadly chronic kidney diseases to improvecardiac and kidney function, as well as hearing and vision. Technology: By studying the mechanisms of AS, researchers at theUniversity of Miami have discovered that althoughthe GBM is primarily composed of laminin and Collagen type IV, the de novoproduction of the α1 chain of collagen type I (Col I) has been observed inexperimental models of AS. In the AS mouse model, increased expression of Discoidindomain receptor 1 (DDR1) results in the increased expression of CD36, a proteinassociated with fatty acid uptake, leading to podacyte injury. DDR1-induced podocyteinjury in AS requires CD36-dependent fatty acid and cholesterol uptake, andinhibition of CD36-dependent lipotoxicity with Ezetimibe can prevent theprogression of kidney disease in AS in mice. Therefore, Ezetimibe may provebeneficial in the treatment of renal disease in patients with AS, andre-purposing strategies for the use of Ezetimibe in patients with AS should berapid, safe and effective, as Ezetimibeis already FDA-approved drug currently labeled for the treatment of patientswith hypercholesterolemia. Peter Gutenberg pxg372@miami.edu 305-243-4604