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

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。Hurler综合征（MPS-IH）是一种遗传性代谢疾病，其特征是进行性智力下降和5至8岁时死亡。造血干细胞移植（HSCT）是唯一被证明可以稳定神经认知发育并提高Hurler综合征患者生存率的治疗方法。然而，患有Hurler综合征的儿童发生移植相关并发症的风险很高，特别是肺出血和上呼吸道阻塞，通常需要机械通气。重组人α-L-艾杜糖醛酸酶，laronidase（Aldurazyme）酶替代疗法（ERT）已获得FDA批准用于MPS-I。Laronidase ERT每周给药一次，可降低MPS-I患者糖胺聚糖（GAG）异常蓄积的身体负荷及其代谢，如上呼吸道阻塞（阻塞性睡眠呼吸暂停）、内脏沉积（肝脾肿大）和尿GAG排泄。然而，ERT尚未被证明有利于神经认知恶化或改善生存率;因此，HSCT仍然是Hurler综合征患者的主要治疗方法。由于ERT可以减少MPS-I患者气道GAG沉积和阻塞性睡眠呼吸暂停，我们假设每周一次的laronidase（0.58 mg/kg/剂IV）ERT在HSCT前12周和HSCT后8周将导致GAG负荷降低，这与HSCT后1年总生存期改善和Hurler相关肺部并发症风险降低相关，例如由于肺出血和气道阻塞而进行呼吸机治疗。

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.