Bicistronic lentiviral vector corrects beta-hexosaminidase deficiency in transduced and cross-corrected human Sandhoff fibroblasts
Articolo
Data di Pubblicazione:
2005
Citazione:
Bicistronic lentiviral vector corrects beta-hexosaminidase deficiency in transduced and cross-corrected human Sandhoff fibroblasts / A. Arfi, C. Bourgoin, L. Basso, C. Emiliani, B. Tancini, V. Chigorno, Y.T. Li, A. Orlacchio, L. Poenaru, S. Sonnino, C. Caillaud. - In: NEUROBIOLOGY OF DISEASE. - ISSN 0969-9961. - 20:2(2005 Nov), pp. 583-593.
Abstract:
Sandhoff disease is an autosomal recessive neurodegenerative disease characterized by a GM2 ganglioside intralysosomal accumulation. It is due to mutations in the beta-hexosaminidases beta-chain gene, resulting in a beta-hexosaminidases A (alpha beta) and B (alpha beta) deficiency. Mono and bicistronic lentiviral vectors containing the HEXA or/and HEXB cDNAs were constructed and tested on human Sandhoff fibroblasts. The bicistronic SIV.ASB vector enabled a massive restoration of beta-hexosaminidases activity on synthetic substrates and a 20% correction on the GM2 natural substrate. Metabolic labeling experiments showed a large reduction of ganglioside accumulation in SIV.ASB transduced cells, demonstrating a correct recombinant enzyme targeting to the lysosomes. Moreover, enzymes secreted by transduced Sandhoff fibroblasts were endocytosed in deficient cells via the mannose 6-phosphate pathway, allowing GM2 metabolism restoration in cross-corrected cells. Therefore, our bicistronic lentivector supplying both alpha- and beta-subunits of beta-hexosaminidases may provide a potential therapeutic tool for the treatment of Sandhoff disease. (c) 2005 Elsevier Inc. All rights reserved.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
Cross-correction; Gene therapy; Lentiviral vector; Sandhoff disease
Elenco autori:
A. Arfi, C. Bourgoin, L. Basso, C. Emiliani, B. Tancini, V. Chigorno, Y.T. Li, A. Orlacchio, L. Poenaru, S. Sonnino, C. Caillaud
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