Intravenous and Intrathecal Enzyme Replacement Before and After Hematopoietic Cell Transplantation for Hurler Syndrome

Hurler syndrome (HS; mucopolysaccharidosis type I) is a lysosomal storage disorder caused by a deficiency of iduronidase, with resultant accumulation of glycosaminoglycans in viscera and brain. Hematopoietic cell transplantation (HCT) has been shown to be a life-saving measure for children with HS. To decrease the toxicity of HCT we have offered intravenous iduronidase enzyme replacement therapy (IV ERT) before and after HCT. Twelve children with HS at a median age of 1.5 years at the time of myeloablative HCT were eligible. Iduronidase (0.58 mg/kg/dose) was administered intravenously in 11–14 weekly doses before HCT and 8 weekly doses after HCT. The infusions were well tolerated. All patients developed antibodies to iduronidase, but on day 100 had >90% donor hematopoiesis, suggesting that ERT prior to HCT is unlikely to alter donor engraftment. All are alive and well, with a median follow-up of more than 1 year after HCT. Patients with HS, however, also develop central nervous system (CNS) pathology, and IV-administered iduronidase has been shown ineffective in crossing the blood-brain barrier. Encouraged by the results of intrathecal ERT (IT ERT) studies in the animal model of HS, we reasoned that clinical investigations incorporating IT ERT, IV ERT, and HCT may provide increased benefit to HS patients. To date, we have enrolled 3 patients with HS on this IT ERT study. The dose administered is 0.05 mg/kg iduronidase in 3 mL of Elliot's B solution. Four doses of drug are administered: the first beginning at the time of IV ERT, the second just prior to transplantation, the third 100 days post HCT, and the last 180 days post transplantation. This timing was chosen to deliver enzyme to the brain until it is anticipated that donor microglial cells are present in sufficient numbers to deliver enzyme to the CNS. At present, one patient has received all doses, while the others continue on study. The 2 patients who were transplanted are alive and fully engrafted at day 100. Magnetic resonance imaging and cerebrospinal fluid analysis at the time of IT ERT showed no evidence of brain inflammation. Our data thus demonstrate that multimodal cellular and enzyme therapy in HS is feasible. Importantly, it affirms the safety of IT ERT, IV ERT, and HCT combination therapy, and provides a rationale for application of this strategy to additional HS patients in order to assess fully its impact on long-term neuropsychological function of HS patients.