RESUMEN

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.

Asunto(s)

Mesodermo/patología , Mucopolisacaridosis I/terapia , Retroviridae/genética , Células Madre/efectos de los fármacos , Adolescente , Células de la Médula Ósea/patología , Técnicas de Cultivo de Célula , Niño , Preescolar , Medios de Cultivo Condicionados/química , Medios de Cultivo Condicionados/farmacología , Terapia Genética/métodos , Humanos , Iduronidasa/genética , Iduronidasa/metabolismo , Iduronidasa/farmacología , Lactante , Recién Nacido , Mesodermo/efectos de los fármacos , Mucopolisacaridosis I/patología , Células Madre/patología , Transducción Genética