Human Molecular Genetics, Vol 8, 831-838, Copyright © 1999 by Oxford University Press
JE Guidotti, A Mignon, G Haase, C Caillaud, N McDonell, A Kahn and L Poenaru
The severe neurodegenerative disorder, Tays-Sachs disease, is caused by a
beta-hexosaminidase alpha-subunit deficiency which prevents the formation
of lysosomal heterodimeric alpha-beta enzyme, hexosaminidase A (HexA). No
treatment is available for this fatal disease; however, gene therapy could
represent a therapeutic approach. We previously have constructed and
characterized, in vitro, adenoviral and retroviral vectors coding for
alpha- and beta-subunits of the human beta- hexosaminidases. Here, we have
determined the in vivo strategy which leads to the highest HexA activity in
the maximum number of tissues in hexA -deficient knock-out mice. We
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. Only the
supply of both subunits allowed for HexA overexpression leading to massive
secretion of the enzyme in serum, and full or partial enzymatic activity
restoration in all peripheral tissues tested. The enzymatic correction was
likely to be due to direct cellular transduction by adenoviral vectors
and/or uptake of secreted HexA by different organs. These results confirmed
that the liver was the preferential target organ to deliver a large amount
of secreted proteins. In addition, the need to overexpress both subunits of
heterodimeric proteins in order to obtain a high level of secretion in
animals defective in only one subunit is emphasized. The endogenous
non-defective subunit is otherwise limiting.
ARTICLES
Adenoviral gene therapy of the Tay-Sachs disease in hexosaminidase A- deficient knock-out mice
Institut Cochin de Genetique Moleculaire (ICGM), INSERM U129 and CHU Cochin-Port Royal, 24 rue du Faubourg Saint Jacques, 75014 Paris, France. guidotti@cochin.inserm.fr
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