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Human Molecular Genetics Advance Access published online on June 16, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi216
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received March 2, 2005
Revised May 4, 2005
Accepted June 10, 2005

Article

A direct gene transfer strategy via brain internal capsule reverses the biochemical defect in Tay-Sachs disease

Martino S. 1, Marconi P. 2, Tancini B. 1, Dolcetta D. 3, Cusella De Angelis M.G. 4, Montanucci P. 1, Bregola G. 5, Sandhoff K. 6, Bordignon C. 3, Emiliani C. 1, Manservigi R. 2, and Orlacchio A. 1*

1 Dipartimento di Medicina Sperimentale e Scienze Biochimiche, Sezione di Biochimica e Biologia Molecolare University of Perugia, Perugia
2 Dipartimento di Medicina Sperimentale e Diagnostica, Sezione di Microbiologia, University of Ferrara, Ferrara
3 San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milano
4 Dipartimento di Medicina Sperimentale, University of Pavia, Italy
5 Dipartimento di Medicina Clinica e Sperimentale, Sezione di Farmacologia, University of Ferrara, Ferrara
6 Kekulè-Institut f. Organische Chemie und Biochemie, University of Bonn, Germany

* To whom correspondence should be addressed.
Orlacchio A., E-mail: orly{at}unipg.it


  Abstract

Therapy for neurodegenerative lysosomal Tay-Sachs (TS) disease requires active Hexosaminidase (Hex) A production in the central nervous system and an efficient therapeutic approach that can act faster than human disease progression. We combined the efficacy of a non-replicating Herpes simplex vector encoding for the Hex A alpha-subunit (HSV-T0alphaHex) and the anatomic structure of the brain internal capsule to distribute the missing enzyme optimally. With this gene transfer strategy, for the first time, we re-established the Hex A activity and totally removed the GM2 ganglioside storage in both injected and controlateral hemispheres, in the cerebellum and spinal cord of TS animal model in the span of one month's treatment. In our studies no adverse effects were observed due to the viral vector, injection site or gene expression and, based on these results, we feel confident that the same approach could be applied to similar diseases involving an enzyme defect.


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