Hereditary Multiple Exostosis Syndrome: Pathogenesis and Treatment

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DESCRIPTION (provided by applicant): This application addresses the Challenge Area (15) "Translational Science" and the Challenge Topic 15- OD(ORDR)-101 "Pilot Projects for Prevention, Early Detection and Treatment of Rare Diseases". Hereditary Multiple Exostosis Syndrome (HME) is a rare autosomal dominant disorder that affects about 1 in 50,000 children and adolescents. HME is characterized by cartilage-capped tumors that grow adjacent to the growth plates of skeletal elements and protrude into, and impinge onto, surrounding tissues and organs. The exostoses can thus cause growth retardation, compression of nerves and tendons, skeletal deformities and early onset osteoarthritis, and become malignant in about 5% of patients. Current therapies are palliative, and patients struggle with pain, limited mobility and fatigue and undergo multiple surgeries throughout their lives. This situation is particularly frustrating because the genes responsible for over 70% of HME cases have been known for several years. The genes are EXT1 and EXT2 that encode Golgi-associated glycosyltransferases responsible for heparan sulfate (HS) synthesis. The patients are heterozygous for EXT1 or EXT2 loss-of-function mutations and their cells produce lower HS amounts. HS chains regulate key physiologic processes and do so by various mechanisms and most notably by restricting the topographical distribution of signaling factors within tissues, but it is not known whether defects in such signal-restriction mechanisms subtend HME. In Preliminary Studies using mouse mutants expressing low HS-PGs (perlecan and syndecans), we found that a key growth plate signaling factor -Indian hedgehog- was widely and abnormally distributed within growth plate and adjacent perichondrium, and this was followed by exostosis formation. In additional Preliminary Studies, we created Ext mutant mice that develop exostoses in long bones and ribs and that are the first genuine model of human HME. Using these novel findings and innovative animal models, we propose to identify and test mechanisms of HME pathogenesis. Our central hypothesis is that deficiency in HS production causes leakage of chondrogenic factors (most notably Indian hedgehog) from upper growth plate zones into adjacent perichondrium, altering the developmental program of perichondrium-associated progenitor cells and inciting ectopic chondrogenesis and exostosis formation (Aim 1). We will then test whether exostosis formation can be prevented by pharmacologic interference with hedgehog signaling and associated transcriptional chondrogenic switches (Aim 2). This Challenge Grant will jump-start mechanistic research on HME pathogenesis by exploiting our novel mouse models of this neglected, painful and debilitating human disorder, will identify molecular targets of intervention, and will test a specific therapeutic strategy to prevent exostosis formation. The number of HME patients is small, but the community of their families is large. This project will thus provide a renewed sense of hope to patients and families alike that this neglected disease will actively be studied and a cure may one day be found. Hereditary Multiple Exostosis Syndrome (HME) is a serious disease that affects about 1 in 50,000 children and adolescents, causes growth retardation, continuous pain, limited mobility and fatigue, and are associated with bone malignant tumors. There are no cures or effective treatments at the moment, and this project thus aims to identify the mechanisms of pathogenesis and test a specific therapeutic treatment to prevent formation of tumor-like bone (exostosis) typical of this disease.