Affiliation:
1. From the Departments of Haematology and Metabolic Medicine, Royal Manchester Children's Hospital; and CRC Gene Therapy Group and Medical Oncology, Paterson Institute for Cancer Research, Christie Hospital NHS Trust; both of Manchester, United Kingdom.
Abstract
We have investigated the utility of bone marrow–derived mesenchymal stem cells (MSCs) as targets for gene therapy of the autosomal recessive disorder mucopolysaccharidosis type IH (MPS-IH, Hurler syndrome). Cultures of MSCs were initially exposed to a green fluorescent protein–expressing retrovirus. Green fluorescent protein–positive cells maintained their proliferative and differentiation capacity. Next we used a vector encoding α-l-iduronidase (IDUA), the enzyme that is defective in MPS-IH. Following transduction, MPS-IH MSCs expressed high levels of IDUA and secreted supernormal levels of this enzyme into the extracellular medium. Exogenous IDUA expression led to a normalization of glycosaminoglycan storage in MPS-IH cells, as evidenced by a dramatic decrease in the amount of 35SO4sequestered within the heparan sulfate and dermatan sulfate compartments of these cells. Finally, gene-modified MSCs were able to cross-correct the enzyme defect in untransduced MPS-IH fibroblasts via protein transfer.
Publisher
American Society of Hematology
Subject
Cell Biology,Hematology,Immunology,Biochemistry
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