tailieunhanh - Báo cáo Y học: In vitro gene therapy of mucopolysaccharidosis type I by lentiviral vectors

Mucopolysaccharidosis type I (MPS I) results from a deficiency in the enzyme a-L-iduronidase (IDUA), and is characterized by skeletal abnormalities, hepatosplenomegaly and neurological dysfunction. In this study, we used a late generation lentiviral vector to evaluate the utility of this vector system for the transfer and expression of the human IDUA cDNA in MPS I fibroblasts. We observed that the level of enzyme expression in transduced cells was the level found in normal cells; the expression persisted for at least two months | Eur. J. Biochem. 269 2764-2771 2002 FEBS 2002 doi In vitro gene therapy of mucopolysaccharidosis type I by lentiviral vectors Paola Di Natale1 Carmela Di Domenico1 Guglielmo R. D. Villani1 Angelo Lombardo2 Antonia Follenzi2 and Luigi Naldini2 1Department of Biochemistry and Medical Biotechnologies University of Naples Federico II Italy laboratory for Gene Transfer and Therapy Institute for Cancer Research and Treatment University of Turin Italy Mucopolysaccharidosis type I MPS I results from a deficiency in the enzyme a-L-iduronidase IDUA and is characterized by skeletal abnormalities hepatosplenomegaly and neurological dysfunction. In this study we used a late generation lentiviral vector to evaluate the utility of this vector system for the transfer and expression of the human IDUA cDNA in MPS I fibroblatss. We observed dan the level of enzyme expression in transduced cells was the level found in normal cells the expression persisted for at least two months. In addition transduced MPS I fibroblasts were capable of clearing intracellular radiolabeled glycosaminoglycan GAG . Pulse-chase experiments on transduced fibroblasts showed that the recombinant enzyme was synthesized as a 76-kDa precursor form and processed to a 66-kDa mature form it was released from transduced cells and was endocytosed into a second population of untreated MPS I fibroblasts via a mannose 6-phosphate receptor. These results suggest that the lentiviral vector may be used for the delivery and expression of the IDUAgene to cells in vivo for treatment of MPS I. Keywords MPS I Hurler syndrome a-L-iduronidase gene therapy. Mucopolysaccharidosis type I MPS I is a lysosomal disease due to mutations in the gene encoding a-L-iduronidase IDUA EC . The gene defect causes a specific deficiency that results in the intracellular accumulation and storage of the unprocessed glycosaminoglycans GAG dermatan sulfate and heparan sulfate. Patients with MPS I .

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