Hereditary Multiple Exostosis Syndrome: Pathogenesis and Treatment

描述（由申请人提供）：本申请涉及挑战领域（15）“转化科学”和挑战主题15- OD(ORDR)-101“罕见疾病预防、早期发现和治疗试点项目”。遗传性多发性外生性增生综合征（HME）是一种罕见的常染色体显性遗传病，在儿童和青少年中发病率约为五万分之一。HME的特征是软骨覆盖的肿瘤生长在骨骼生长板附近，并向周围组织和器官突出和撞击。因此，外植骨会导致生长迟缓、压迫神经和肌腱、骨骼畸形和早发性骨关节炎，并在约5%的患者中变为恶性。目前的治疗方法是姑息性的，患者一生都在与疼痛、行动不便和疲劳作斗争，并接受多次手术。这种情况尤其令人沮丧，因为导致70%以上HME病例的基因已被发现多年。基因是EXT1和EXT2，它们编码高尔基相关糖基转移酶，负责硫酸肝素（HS）的合成。患者是杂合的EXT1或EXT2功能丧失突变，他们的细胞产生较低的HS量。HS链通过各种机制调节关键的生理过程，最显著的是通过限制组织内信号因子的地形分布，但尚不清楚这些信号限制机制中的缺陷是否与HME有关。在对表达低hs - pg的小鼠突变体（perlecan和syndecans）的初步研究中，我们发现一种关键的生长板信号因子-印度刺猬-广泛且异常地分布在生长板和邻近的软骨膜中，并随后形成外生瘤。在进一步的初步研究中，我们创造了Ext突变小鼠，这些小鼠在长骨和肋骨中发生外骨骼增生，这是第一个真正的人类HME模型。利用这些新发现和创新的动物模型，我们建议确定和测试HME的发病机制。我们的中心假设是HS产生的缺乏导致软骨生成因子（最明显的是印度刺猬）从生长板上部区域渗漏到邻近的软骨膜，改变软骨膜相关祖细胞的发育程序，并刺激异位软骨形成和外生骨骺形成（Aim 1）。然后，我们将测试是否可以通过药物干预刺猬信号传导和相关的转录软骨生成开关来阻止外生性增生的形成（目的2）。这项挑战基金将通过开发这种被忽视的、痛苦的、使人衰弱的人类疾病的新型小鼠模型，启动对HME发病机制的研究，将确定干预的分子靶点，并将测试一种特殊的治疗策略来防止外生骨骺形成。HME患者的数量很少，但他们的家庭社区很大。因此，这个项目将给病人和家属带来新的希望，即这种被忽视的疾病将得到积极研究，并有一天可能找到治疗方法。遗传性多发性外生症候群（HME）是一种严重的疾病，大约每5万名儿童和青少年中就有1人患病，导致生长迟缓、持续疼痛、行动受限和疲劳，并与骨恶性肿瘤有关。目前还没有治愈或有效的治疗方法，因此本项目旨在确定发病机制，并测试一种特定的治疗方法，以防止形成肿瘤样骨（外生骨骺）的典型这种疾病。

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.