title: Retrovirally mediated correction of bone marrow-derived mesenchymal stem cells from patients with mucopolysaccharidosis type I.
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 alpha-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 (35)SO(4) sequestered 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.
authors.affiliation: Department of Haematology, Royal Manchester Children's Hospital, United Kingdom.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Baxter
authors.forename: Robert F
authors.initials: RF
authors.lastname: Wynn
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Deakin
authors.forename: Ilaria
authors.initials: I
authors.lastname: Bellantuono
authors.forename: Kirsten G
authors.initials: KG
authors.lastname: Edington
authors.forename: Alan
authors.initials: A
authors.lastname: Cooper
authors.forename: Guy T N
authors.initials: GT
authors.lastname: Besley
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Church
authors.forename: J Ed
authors.initials: JE
authors.lastname: Wraith
authors.forename: Trevor F
authors.initials: TF
authors.lastname: Carr
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Fairbairn
mesh_terms: D000293:Adolescent; D001854:Bone Marrow Cells / Q000473:pathology; D018929:Cell Culture Techniques; D002648:Child; D002675:Child, Preschool; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000494:pharmacology; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D007068:Iduronidase / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D007223:Infant; D007231:Infant, Newborn; D008648:Mesoderm / Q000187:drug effects / Q000473:pathology*; D008059:Mucopolysaccharidosis I / Q000473:pathology / Q000628:therapy*; D012190:Retroviridae / Q000235:genetics*; D013234:Stem Cells / Q000187:drug effects* / Q000473:pathology; D014161:Transduction, Genetic
chemical_list: D017077:Culture Media, Conditioned; D007068:Iduronidase