High-dose enzyme replacement therapy in murine Hurler syndrome

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disease that is systemic, including progressive neurodegeneration, mental retardation and death before the age of 10years. MPS I results from deficiency of α-l-iduronidase (IDUA) in lysosomes and subsequent accumulation of glycosaminoglycans (GAG). Clinical enzyme replacement therapy (ERT) with intravenous laronidase reverses some aspects of MPS I disease (e.g., hepatomegaly, splenomegaly, glycosaminoglycanuria) and ameliorates others (e.g., pulmonary function, cardiac disease, arthropathy, exercise tolerance). However, neurologic benefits are thought to be negligible because the blood–brain barrier (BBB) blocks enzyme from reaching the central nervous system (CNS). We considered the possibility that a very high dose of intravenous laronidase might be able to traverse the BBB in small quantities, and provide some metabolic correction in the brain. To address this question, high-dose laronidase was administered (11.6mg/kg, once per week, 4weeks) to adult MPS I mice. IDUA enzyme activity in the cortex of treated mice increased to 97% of that in wild type mice (p