Synvista Collaboration Demonstrates in Preclinical Studies, the Mechanism for Defective Cholesterol Transport in Patients with Diabetes
In a press release, dated Nov. 5th, Synvista Therapeutics, Inc. announced the results of a series of preclinical studies designed to explain the mechanism underlying dysfunctional high density lipoprotein (HDL), that creates a defect in reverse cholesterol transport in patients with Diabetes Mellitus (DM). The studies reveal that a common blood protein, Haptoglobin, binds to the core of HDL and that a defective Haptoglobin variant (Hp2-2), found in 40% of the population, may induce dysfunctionality in HDL. The studies also report that exposure to Vitamin E can restore HDL functionality and the process of reverse cholesterol transport. The study was also being presented on Nov. 5th at the American Heart Association's (AHA) Scientific Sessions 2007 in Orlando, Florida.
Noah Berkowitz, M.D., Ph.D., President and Chief Executive Officer of Synvista stated "We are very pleased with the outcome of these studies, as we believe they provide scientific rationale for our current development platform, including our work developing a diagnostic test for Haptoglobin type, to determine cardiovascular risk and a therapeutic product to decrease HDL oxidation and restore reverse cholesterol transport function. This study further demonstrates that the Hp2-2 phenotype, a risk factor for cardiovascular events in patients with diabetes, may function by interfering with the function of HDL and promoting inflammatory atherosclerosis."
The experiments of Rabea Asleh, M.D., of the Rappaport Faculty of Medicine and Research Institute, at the Technion, Haifa, Israel, who received the AHA's Council on Nutrition, Physical Activity and Metabolism's 2007 New Investigator Award on Nov. 5th, provided a mechanistic explanation for the defect in reverse cholesterol transport observed in many patients with diabetes mellitus (DM). Reverse cholesterol transport describes the process of moving cholesterol out of the atherosclerotic plaque and into HDL particles ("good cholesterol"). This process is thought to be the mechanism by which high levels of HDL protect patients from atherosclerotic disease. Dr. Asleh reports the presence of Haptoglobin-Hemoglobin (Hp-Hb) complexes in HDL particles and observes that Hp2-2-Hb complexes promote less efficient reverse cholesterol transport in DM, which can be reversed by antioxidants such as vitamin E. He proposes that strategies targeted to decrease oxidation of HDL in Hp2-2 patients may improve HDL function. Synvista has completed enrolling two cohorts of a three cohort Phase 2 clinical trial, evaluating among other endpoints, the impact of the Company's oxidized lipid metabolizing agent, ALT- 2074, on functional reverse cholesterol transport.
Radiolabeled Hp2-2-Hb complexes injected into mice and rats with and without diabetes demonstrated significantly longer half-life then radiolabeled Hp1-1-Hb complexes (e.g. 2-3 fold longer in non-DM animals, p=0001; and doubled in DM mice, p= 0.005). Co-immunoprecipitation studies showed that there is 10-fold more Hp2-2-Hb complex associated with HDL in diabetic mice than Hp1-1-Hb in non-DM mice. This was also shown in human sera where significantly more radioactive hemoglobin is associated with HDL particles in Hp2-2 individuals than Hp1-1 individuals. Reverse cholesterol transport, as measured by radiolabeled cholesterol efflux from pre-loaded macrophages, was significantly impaired (p=0.0001) by incubation with serum from Hp2-2 diabetic mice versus serum from non-DM Hp2-2 mice. This impairment was restored to normal levels when the mice received vitamin E.