Journal Article

Adenoviral Gene Therapy of the Tay-Sachs Disease in Hexosaminidase A-Deficient Knock-Out Mice

J. E. Guidotti, A. Mignon, G. Haase, C. Caillaud, N. McDonell, A. Kahn and L. Poenaru

in Human Molecular Genetics

Volume 8, issue 5, pages 831-838
Published in print May 1999 | ISSN: 0964-6906
Published online May 1999 | e-ISSN: 1460-2083 | DOI:
Adenoviral Gene Therapy of the Tay-Sachs Disease in Hexosaminidase A-Deficient Knock-Out Mice

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The severe neurodegenerative disorder, Tays-Sachs disease, is caused by a β-hexosaminidase α-subunit deficiency which prevents the formation of lysosomal heterodimeric α-β 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 α- and β-subunits of the human β-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 α- and β-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.

Journal Article.  6083 words.  Illustrated.

Subjects: Genetics and Genomics

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