1. ¹University of Minnesota Cancer Center, Minneapolis, Minnesota, USA
2. ²Department of Pediatrics, Division of Bone Marrow Transplant, University of Minnesota, Minneapolis, Minnesota, USA

Correspondence: Bruce R. Blazar, University of Minnesota, 420 Delaware Street SE, MMC 109, Minneapolis, Minnesota 55455. E-mail: blaza001@umn.edu

The last two authors contributed equally to this work.

Received 12 December 2007; Accepted 6 May 2008; Published online 3 June 2008.

Abstract

Mucopolysaccharidosis type I (Hurler syndrome) is caused by a deficiency of the enzyme -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.