Bicistronic lentiviral vector corrects β-hexosaminidase deficiency in transduced and cross-corrected human Sandhoff fibroblasts

@article{Arfi2005BicistronicLV,
  title={Bicistronic lentiviral vector corrects $\beta$-hexosaminidase deficiency in transduced and cross-corrected human Sandhoff fibroblasts},
  author={A. Arfi and C. Bourgoin and L. Basso and C. Emiliani and B. Tancini and V. Chigorno and Yu-Teh Li and A. Orlacchio and L. Poenaru and S. Sonnino and C. Caillaud},
  journal={Neurobiology of Disease},
  year={2005},
  volume={20},
  pages={583-593}
}
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 (alphabeta) and B (betabeta) 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… Expand
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TLDR
It is demonstrated that the bicistronic vector can reverse the biochemical defects and down‐stream consequences in Sandhoff neurons, reinforcing its potential for Sandhoff disease in vivo gene therapy. Expand
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β-Hexosaminidase over-expression affects lysosomal glycohydrolases expression and glycosphingolipid metabolism in mammalian cells
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Evidence for the existence of a coordinated mechanism regulating the expression/activity of both lysosomal and PM-associated glycohydrolases is reported, and it is shown that the over-expression of the acidic glycoHydrolase β-hexosaminidase α-subunit in mouse NIH/3T3 fibroblasts induces the increased expression of the Hex β-sub unit necessary to form the active isoenzyme dimers. Expand
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References

SHOWING 1-10 OF 48 REFERENCES
Retrovirus-mediated enzymatic correction of Tay-Sachs defect in transduced and non-transduced cells.
TLDR
The alpha-chain was secreted in the culture medium and taken up by HexA-deficient cells via mannose-6-phosphate receptor binding, allowing for the restoration of intracellular HexA activity in non-transduced cells. Expand
Adenoviral gene therapy of the Tay-Sachs disease in hexosaminidase A-deficient knock-out mice.
TLDR
It is demonstrated that intravenous co-administration of adenoviral vectors coding for both alpha- and beta-subunits, resulting in preferential liver transduction, was essential to obtain the most successful results and confirmed that the liver was the preferential target organ to deliver a large amount of secreted proteins. Expand
Restoration of hexosaminidase A activity in human Tay-Sachs fibroblasts via adenoviral vector-mediated gene transfer.
TLDR
The Hex alpha encoded by the adenovirus was shown to be correctly transported into the lysosomes and to normalize the impaired degradation of GM2 ganglioside in TSD fibroblasts. Expand
Absence of Metabolic Cross-correction in Tay-Sachs Cells
TLDR
Results showed that delivery of the therapeutic HexA was not sufficient to correct the phenotype of TS cells, and the hypothesis is that transduced cells overexpressing and secreting large amounts of the enzyme would lead to a measurable activity in defective cells via a secretion-recapture mechanism. Expand
Correction of mucopolysaccharidosis type IIIb fibroblasts by lentiviral vector-mediated gene transfer.
TLDR
It is shown that lentiviral vectors may provide a therapeutic approach for the treatment of MPS IIIB disease with high transduction efficiency and high levels of enzymic activity, 20-fold above normal levels, persisting for at least 2 months. Expand
Restoration of normal lysosomal function in mucopolysaccharidosis type VII cells by retroviral vector-mediated gene transfer.
Retroviral vectors were constructed containing a rat beta-glucuronidase cDNA driven by heterologous promoters. Vector-mediated gene transfer into human and canine beta-glucuronidase-deficientExpand
Metabolic correction and cross-correction of mucopolysaccharidosis type II (Hunter syndrome) by retroviral-mediated gene transfer and expression of human iduronate-2-sulfatase.
To explore the possibility of using gene transfer to provide iduronate-2-sulfatase (IDS; EC 3.1.6.13) enzyme activity for treatment of Hunter syndrome, an amphotropic retroviral vector, L2SN,Expand
Expression and secretion of human glucocerebrosidase mediated by recombinant lentivirus vectors in vitro and in vivo: implications for gene therapy of Gaucher disease.
TLDR
This study showed that vascular and hepatic delivery of a HIV-1-based lentivirus vector encoding human GC cDNA produced therapeutic levels of GC protein in cultured fibroblasts derived from patients with Gaucher disease. Expand
High level expression and export of beta-glucuronidase from murine mucopolysaccharidosis VII cells corrected by a double-copy retrovirus vector.
TLDR
To determine if this effect was controlled by the GUSB promoter, a vector was constructed using the thymidine kinase (TK) promoter to drive the human GUSB cDNA (NTK beta H), indicating that the variation in enzymatic activity was not a function of the G USB promoter. Expand
Biochemical consequences of mutations causing the GM2 gangliosidoses.
  • D. Mahuran
  • Biology, Medicine
  • Biochimica et biophysica acta
  • 1999
TLDR
It appears that the detrimental effect of most mutations associated with the GM2 gangliosidoses is not specifically on functional elements of the protein, but rather on the proteins' overall folding and/or intracellular transport. Expand
...
1
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3
4
5
...