Targeting of the CNS in MPS-IH Using a Nonviral Transferrin-alpha-L-iduronidase Fusion Gene Product

Overview

Journal Mol Ther

Publisher Cell Press

Specialties Molecular Biology
Pharmacology

Date 2008 Jun 5

PMID 18523448

Citations 25

Authors

Mark J Osborn

Ron T McElmurry

Brandon Peacock

Jakub Tolar

Bruce R Blazar

Affiliations

Soon will be listed here.

Abstract

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