Human Molecular Genetics Advance Access originally published online on June 16, 2005
Human Molecular Genetics 2005 14(15):2113-2123; doi:10.1093/hmg/ddi216
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A direct gene transfer strategy via brain internal capsule reverses the biochemical defect in Tay–Sachs disease
1Dipartimento di Medicina Sperimentale e Scienze Biochimiche, Sezione di Biochimica e Biologia Molecolare University of Perugia, Via del Giochetto, 06126 Perugia, Italy, 2Dipartimento di Medicina Sperimentale e Diagnostica, Sezione di Microbiologia, University of Ferrara, Ferrara, Italy, 3San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milano, Italy, 4Dipartimento di Medicina Sperimentale, University of Pavia, Pavia, Italy, 5Dipartimento di Medicina Clinica e Sperimentale, Sezione di Farmacologia, University of Ferrara, Ferrara, Italy and 6Kekulè-Institut f. Organische Chemie und Biochemie, University of Bonn, Bonn, Germany
* To whom correspondence should be addressed. Tel: +39 755852187; Fax: +39 755852185/7443; Email: orly{at}unipg.it
Received March 2, 2005; Revised May 4, 2005; Accepted June 10, 2005
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 on the basis of these results, we feel confident that the same approach could be applied to similar diseases involving an enzyme defect.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
The authors contributed equally to this paper.
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