High-dose enzyme replacement therapy in murine Hurler syndrome

Li Ou, Tyler Herzog, Brenda L. Koniar, Roland Gunther, Chester B. Whitley

Research output: Contribution to journalArticlepeer-review

42 Scopus citations


Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disease that is systemic, including progressive neurodegeneration, mental retardation and death before the age of 10. years. 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 (11.6. mg/kg, once per week, 4. weeks) to adult MPS I mice. IDUA enzyme activity in the cortex of treated mice increased to 97% of that in wild type mice (p < 0.01). GAG levels in cortex were reduced by 63% of that from untreated MPS I mice (p < 0.05). Further, immunohistochemical analysis showed that treatment reduced secondary GM3-ganglioside accumulation in treated MPS I mice. Water T-maze tests showed that the learning abnormality in MPS I mice was reduced (p < 0.0001). In summary, repeated, high-dose ERT facilitated laronidase transit across the BBB, reduced GAG accumulation within the CNS, and rescued cognitive impairment.

Original languageEnglish (US)
Pages (from-to)116-122
Number of pages7
JournalMolecular Genetics and Metabolism
Issue number2
StatePublished - 2014

Bibliographical note

Funding Information:
The investigators thank Brenda Diethelm-Okita for design of ELISA assays and regulatory compliance and Evelyn Redtree for editorial review. The investigators also thank Miriam Gannon (Genzyme-Sanofi) and Jeff Prosch and Tom Blissenbach (Fairview Pharmacy) for assistance in the purchase of Aldurazyme (laronidase).This work was supported by the National Institutes of Health (NICHD) grant P01HD032652 and there was no industry support or other involvement in this study.


  • Blood-brain-barrier
  • Enzyme replacement therapy
  • High dose
  • Hurler syndrome
  • Mucopolysaccharidosis I


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