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- W2064081311 abstract "Top of pageAbstractSandhoff disease is an autosomal recessive neurodegenerative disorder characterized by the intralysosomal accumulation of GM2 ganglioside. It is due to mutations in the hexosaminidases |[beta]|-chain gene, resulting in a hexosaminidases A (|[alpha]||[beta]|) and B (|[beta]||[acirc]|) deficiency. This neurolipidosis, exhibiting a predominant involvement of the central nervous system (CNS), has a dramatic evolution leading to early death. There is no efficient treatment for GM2 gangliosidosis to date.In order to develop a gene therapy approach, a bicistronic lentiviral vector was constructed, containing both the HEXA and HEXB cDNAs encoding the hexosaminidase |[alpha]| and |[beta]| chains respectively. We have previously demonstrated that this bicistronic SIV.ASB vector was able to correct |[beta]|-hexosaminidase deficiency not only in transduced but also in cross-corrected human Sandhoff fibroblasts. Recent advances in the neuropathophysiology of Sandhoff disease showed a mechanistic link between GM2 accumulation, reduction of either SERCA activity (the sarco/endoplasmic reticulum Ca2+ -ATPase) or axonal outgrowth, and neuronal cell death. To examine the ability of the SIV.ASB vector to prevent these pathophysiologic events, hippocampal neurons cultured from embryonic Sandhoff mice were transduced by the bicistronic vector. The enhanced sensitivity of neurons to cell death induced by thapsigargin and the reduced rate of Ca2+ -uptake via the SERCA were corrected in SIV.ASB-transduced deficient neurons, subsequently to the decrease in GM2 storage. A normal rate of axonal and minor process growth was observed in transduced Sandhoff neurons by comparison with non-corrected neurons. Finally, we demonstrated for the first time that our bicistronic vector could reverse some of the known pathophysiologic mechanisms implied in the etiology of Sandhoff disease, reinforcing its potential for in vivo gene therapy of this disorder.Therefore, an in vivo therapeutic strategy is now planned in the Hexb-/- murine model using a lentivirally-modified bone marrow transplantation. Preliminary steps showed a large transduction of hematopoietic stem cells (HSC) and an efficient differentiation in colonies specific of hematopoietic lineages. We will now investigate the engraftment of transduced HSCs into irradiated Sandhoff mice, as well as correction of enzymatic expression, GM2 ganglioside degradation, pathophysiologic and phenotypic parameters." @default.
- W2064081311 created "2016-06-24" @default.
- W2064081311 date "2005-05-01" @default.
- W2064081311 modified "2023-09-24" @default.
- W2064081311 title "233. Towards Reversing Sandhoff Pathology by Lentiviral-Mediated Gene Therapy" @default.
- W2064081311 doi "https://doi.org/10.1016/j.ymthe.2005.06.236" @default.
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