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（ORR）-101“罕见疾病预防、早期检测和治疗试点项目”。遗传性多发性外生骨疣综合征（HME）是一种罕见的常染色体显性遗传病，影响约1/50，000的儿童和青少年。HME的特征在于邻近骨骼元件的生长板生长并突出到周围组织和器官中并撞击周围组织和器官的软骨帽肿瘤。因此，外生骨疣可导致生长迟缓、神经和肌腱受压、骨骼畸形和早发性骨关节炎，并在约5%的患者中变成恶性。目前的疗法是姑息性的，患者在痛苦、行动不便和疲劳中挣扎，一生中要接受多次手术。这种情况特别令人沮丧，因为超过70%的HME病例的基因已经知道了好几年。这些基因是编码负责硫酸乙酰肝素（HS）合成的高尔基体相关糖基转移酶的EXT 1和EXT 2。患者是EXT 1或EXT 2功能丧失突变的杂合子，他们的细胞产生较低的HS量。HS链调节关键的生理过程，并通过各种机制，最值得注意的是通过限制组织内信号传导因子的拓扑分布，但尚不清楚这种信号限制机制的缺陷是否对着HME。在使用表达低HS-PG（串珠素和多配体蛋白聚糖）的小鼠突变体的初步研究中，我们发现一种关键的生长板信号传导因子-印度刺猬-在生长板和邻近的软骨膜内广泛且异常地分布，随后形成外生骨疣。在额外的初步研究中，我们创建了Ext突变小鼠，这些小鼠在长骨和肋骨中发展外生骨疣，并且是第一个真正的人类HME模型。利用这些新的发现和创新的动物模型，我们建议确定和测试HME发病机制。我们的中心假设是，HS生产的缺陷导致软骨形成因子（最明显的是印度刺猬）从上生长板区泄漏到相邻的软骨膜，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疣形成（目的1）。然后，我们将测试外生骨疣的形成是否可以通过药物干扰刺猬信号和相关的转录软骨形成开关来预防（目的2）。这项挑战赠款将通过利用我们这种被忽视，痛苦和衰弱的人类疾病的新型小鼠模型来启动对HME发病机制的机制研究，将确定干预的分子靶点，并将测试特定的治疗策略以防止外生骨疣形成。HME患者的数量很少，但他们的家庭社区很大。因此，该项目将为患者和家庭带来新的希望，即积极研究这种被忽视的疾病，有朝一日可能找到治愈方法。遗传性多发性外生骨疣综合征（HME）是一种严重的疾病，每50，000名儿童和青少年中就有1人受到影响，导致生长迟缓、持续疼痛、活动受限和疲劳，并与骨恶性肿瘤有关。目前还没有治愈或有效的治疗方法，因此该项目旨在确定发病机制并测试特定的治疗方法，以防止这种疾病典型的肿瘤样骨（外生骨疣）的形成。

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.