Mucopolysaccharidosis type I (Hurler syndrome) is caused by a deficiency of the enzyme α-L-iduronidase (IDUA), and is characterized by widespread lysosomal glycosaminoglycan (GAG) accumulation. Successful treatment of central nervous system (CNS) diseases is limited by the presence of the blood-brain barrier, which prevents penetration of the therapeutic enzyme. Given that the brain capillary endothelial cells that form this barrier express high levels of the transferrin receptor (TfR), we hypothesized that the coupling of IDUA to transferrin (Tf) would facilitate IDUA delivery to the CNS. A plasmid bearing a fusion gene consisting of Tf and IDUA was constructed which, when delivered in vivo, resulted in the production of high levels of an enzymatically active protein that was transported into the CNS by TfR-mediated endocytosis. Short-term treatment resulted in a decrease in GAGs in the cerebellum of mucopolysaccharidosis type I (MPS I) mice. This approach, therefore, represents a potential strategy for the delivery of therapeutic enzyme to the CNS.
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We thank R. Scott McIvor for helpful discussions and Andrew Price, Kevin Tram, and Christopher Lees for technical assistance. This work was supported by an award from the American Heart Association (to M.J.O.) and National Institutes of Health Grants R01 HL49997 and HL52952 (to B.R.B).