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

这个子项目是众多研究子项目之一

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.