Cardiovascular Structure and Function in the Mucopolysaccharidoses

Cardiovascular disease (CVD) is the leading cause of death in the world despite public health emphases upon treatment of hyperlipidemia, hypertension, and diabetes mellitus. Cardiovascular manifestations are also a leading cause of mortality in two inherited conditions, Mucopolysaccharidosis (MPS) types I and IVA. These rare diseases invite further investigation because affected individuals accumulate large quantities of glycosaminoglycans (GAGs). While GAGs are normal proteoglycan components of healthy cardiac valves, arterial parenchyma, and endothelial glycocalyx, excess quantities contribute to CVD pathogenesis but via poorly understood pathomechanisms. We present three interrelated, yet parallel aims: a clinical, a hybrid clinical/preclinical, and a preclinical trial which leverage our combined clinical and translational research expertise. This project examines human and murine MPS I and IVA to robustly probe the relationships between derangements in cardiovascular GAG content and cardiovascular structure and function. Aim 1 of this project prospectively assesses cardiac and arterial structure and function in a large cohort of MPS I and IVA patients, rigorously comparing with an equally large cohort of healthy matched controls to establish a MPS CVD natural history. Results from this aim will provide a clinical basis for evaluation of therapies targeting MPS cardiovascular symptoms. Aim 2 of this proposal will define and validate prognostic biomarkers of both human and murine MPS CVD. Results of these studies will greatly expand the understanding of proteoglycan function in cardiovascular health and disease. Aim 3 of this proposal will utilize the foundations previously established to evaluate efficacy of click-xyloside modulators of GAG biosynthesis and an inhibitor of elastin proteolysis to mitigate murine MPS cardiovascular manifestations. The result of these studies will determine preclinical efficacy of therapeutic compounds and inform future human therapeutic trials. The long-term goal of this study is to understand roles of cardiovascular GAGs and proteoglycans, validate biomarkers, and develop treatments to stop progression in MPS cardiovascular pathology.