title: A direct gene transfer strategy via brain internal capsule reverses the biochemical defect in Tay-Sachs disease.
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 on the basis of these results, we feel confident that the same approach could be applied to similar diseases involving an enzyme defect.
authors.affiliation: Dipartimento di Medicina Sperimentale e Scienze Biochimiche, Sezione di Biochimica e Biologia Molecolare University of Perugia, Via del Giochetto, 06126 Perugia, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Martino
authors.forename: P
authors.initials: P
authors.lastname: Marconi
authors.forename: B
authors.initials: B
authors.lastname: Tancini
authors.forename: D
authors.initials: D
authors.lastname: Dolcetta
authors.forename: M G Cusella
authors.initials: MG
authors.lastname: De Angelis
authors.forename: P
authors.initials: P
authors.lastname: Montanucci
authors.forename: G
authors.initials: G
authors.lastname: Bregola
authors.forename: K
authors.initials: K
authors.lastname: Sandhoff
authors.forename: C
authors.initials: C
authors.lastname: Bordignon
authors.forename: C
authors.initials: C
authors.lastname: Emiliani
authors.forename: R
authors.initials: R
authors.lastname: Manservigi
authors.forename: A
authors.initials: A
authors.lastname: Orlacchio
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000378:metabolism*; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D054818:Hexosaminidase A; D020772:Internal Capsule / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018139:Simplexvirus / Q000235:genetics; D013116:Spinal Cord / Q000378:metabolism*; D013661:Tay-Sachs Disease / Q000378:metabolism / Q000628:therapy*; D001619:beta-N-Acetylhexosaminidases / Q000235:genetics* / Q000378:metabolism
chemical_list: D054818:Hexosaminidase A; D001619:beta-N-Acetylhexosaminidases