Retrovirally mediated correction of bone marrow-derived mesenchymal stem cells from patients with mucopolysaccharidosis type I.
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.
Baxter
Melissa A
MA
Department of Haematology, Royal Manchester Children's Hospital, United Kingdom.
Wynn
Robert F
RF
Deakin
Jonathan A
JA
Bellantuono
Ilaria
I
Edington
Kirsten G
KG
Cooper
Alan
A
Besley
Guy T N
GT
Church
Heather J
HJ
Wraith
J Ed
JE
Carr
Trevor F
TF
Fairbairn
Leslie J
LJ
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
D017077:Culture Media, Conditioned; D007068:Iduronidase