PHASE II STUDY OF COMBINED LARONIDASE (ALDURAZYME) ENZYME REPLACEMENT THERAPY (E

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 霍勒综合征(MPS-IH)是一种遗传性代谢性疾病，以进行性智力下降和5-8岁死亡为特征。造血干细胞移植(HSCT)是唯一被证实可以稳定赫勒综合征患者神经认知发育和提高存活率的治疗方法。然而，患有赫勒综合征的儿童有很高的风险发生与移植相关的并发症，特别是肺出血和上呼吸道阻塞，经常导致需要机械通气。重组人α-L-艾杜糖醛酸酶、丙二酸酶(阿杜拉西米)酶替代疗法(ERT)已获FDA批准用于治疗MPS-I。当每周给药时，Llaronidase ERT可以减少MPS-I患者体内异常堆积的糖胺多聚糖(GAG)的负荷及其症状，如上呼吸道阻塞(阻塞性睡眠呼吸暂停)、内脏沉积(肝细胞肿大)和尿中GAG排泄。然而，ERT并未被证明有益于神经认知的恶化或提高存活率；因此，HSCT仍然是Hurler综合征患者的主要治疗手段。由于ERT可以减少MPS-I患者的呼吸道GAG沉积和阻塞性睡眠呼吸暂停，我们假设在HSCT前12周和HSCT后8周每周应用一次LLNIDase(0.58 mg/kg/剂量IV)可以减少GAG负担，这与改善HSCT后1年的总存活率和降低HSCT后Hurler相关肺部并发症的风险有关，如肺出血和呼吸道阻塞所致的呼吸机治疗。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hurler Syndrome (MPS-IH), an inherited metabolic disease is characterized by progressive mental decline and death by 5 to 8 years of age. Hematopoietic stem cell transplatation (HSCT) is the only proven therapy that can stabilize neurocognitive development and improve survival in patients with Hurler syndrome. However, children with Hurler syndrome are at high risk for transplant related complications, particularly pulmonary hemmorrhage and upper airway obstruction often leading to requirement for mechanical ventilation. Recombinant human alpha-L-iduronidase, laronidase (Aldurazyme) enzyme replacement therapy (ERT) is FDA-approved for MPS-I. Laronidase ERT, when administered on a weekly basis, decreases body load of abnormally accumulated glycosaminoglycans (GAG) and its symptomatology, such as upper airway obstruction (obstructive sleep apnea), visceral deposits (hepatospenomegaly) and urinary excretion of GAG in patients with MPS-I. However, ERT has not been shown to benefit the neurocognitive deterioration or improve survival; therefore, HSCT remains the mainstay of therapy for patients with Hurler syndrome. As ERT can decrease airway GAG deposits and obstructive sleep apnea in patients with MPS-I, we hypothesize that weekly laronidase (0.58 mg/kg/dose IV) ERT for 12 weeks prior to HSCT and 8 weeks following HSCT will result in a decreased GAG burden that is associated with improved 1-year overall survival and decreased risk of Hurler-related pulmonary complications following HSCT, such as ventilator therapy due to pulmonary hemmorrhage and airway obstruction.