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Induced secretion of beta-hexosaminidase by human brain endothelial cells: a novel approach in Sandhoff disease?

Abstract
Sandhoff disease is an autosomal recessive lysosomal disorder due to mutations in the beta-hexosaminidase beta-chain gene, resulting in beta-hexosaminidases A (alphabeta) and B (betabeta) deficiency and GM2 ganglioside accumulation in the brain. In this study, our aim was to demonstrate that transduction of cerebral endothelial cells cultured in two-chamber culture inserts with a lentiviral vector encoding the hexosaminidases alpha and beta chains could induce a vectorial secretion of hexosaminidases. Therefore, the human cerebral endothelial cell line hCMEC/D3 was infected with the bicistronic vector from the apical compartment, and beta-hexosaminidase activity was measured in transduced cells and in deficient fibroblasts co-cultured in the basal (i.e. brain) compartment. Induced beta-hexosaminidase secretion by transduced hCMEC/D3 cells was sufficient to allow for a 70-90% restoration of beta-hexosaminidase activity in deficient fibroblasts. On the basis of these in vitro data, we propose that brain endothelium be considered as a novel therapeutic target in Sandhoff disease.
AuthorsLionel Batista, Florence Miller, Céline Clave, Audrey Arfi, Gaëlle Douillard-Guilloux, Pierre-Olivier Couraud, Catherine Caillaud
JournalNeurobiology of disease (Neurobiol Dis) Vol. 37 Issue 3 Pg. 656-60 (Mar 2010) ISSN: 1095-953X [Electronic] United States
PMID20005954 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright2009 Elsevier Inc. All rights reserved.
Chemical References
  • G(M2) Ganglioside
  • beta-N-Acetylhexosaminidases
Topics
  • Cell Line, Transformed
  • Cerebral Arteries (cytology, enzymology)
  • Cerebrum (blood supply, enzymology, physiopathology)
  • Coculture Techniques
  • Diffusion Chambers, Culture
  • Endothelial Cells (enzymology, metabolism)
  • Fibroblasts (enzymology, metabolism)
  • G(M2) Ganglioside (metabolism)
  • Genetic Therapy (methods)
  • Genetic Vectors (pharmacology, therapeutic use)
  • Humans
  • Lentivirus (genetics)
  • Sandhoff Disease (enzymology, genetics, therapy)
  • Transduction, Genetic (methods)
  • beta-N-Acetylhexosaminidases (genetics, metabolism)

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