title: Effective gene therapy in an authentic model of Tay-Sachs-related diseases.
abstract: Tay-Sachs disease is a prototypic neurodegenerative disease. Lysosomal storage of GM2 ganglioside in Tay-Sachs and the related disorder, Sandhoff disease, is caused by deficiency of beta-hexosaminidase A, a heterodimeric protein. Tay-Sachs-related diseases (GM2 gangliosidoses) are incurable, but gene therapy has the potential for widespread correction of the underlying lysosomal defect by means of the secretion-recapture cellular pathway for enzymatic complementation. Sandhoff mice, lacking the beta-subunit of hexosaminidase, manifest many signs of classical human Tay-Sachs disease and, with an acute course, die before 20 weeks of age. We treated Sandhoff mice by stereotaxic intracranial inoculation of recombinant adeno-associated viral vectors encoding the complementing human beta-hexosaminidase alpha and beta subunit genes and elements, including an HIV tat sequence, to enhance protein expression and distribution. Animals survived for >1 year with sustained, widespread, and abundant enzyme delivery in the nervous system. Onset of the disease was delayed with preservation of motor function; inflammation and GM2 ganglioside storage in the brain and spinal cord was reduced. Gene delivery of beta-hexosaminidase A by using adeno-associated viral vectors has realistic potential for treating the human Tay-Sachs-related diseases.
authors.affiliation: *Department of Medicine, University of Cambridge, Level 5, Box 157, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, United Kingdom.
authors.forename: M Begoña
authors.initials: MB
authors.lastname: Cachón-González
authors.affiliation: *Department of Medicine, University of Cambridge, Level 5, Box 157, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, United Kingdom.
authors.forename: Susan Z
authors.initials: SZ
authors.lastname: Wang
authors.affiliation: Centre for Applied Medical Statistics, Department of Public Health and Primary Care, University Forvie Site, Robinson Way, Cambridge CB2 2SR, United Kingdom; and.
authors.forename: Andrew
authors.initials: A
authors.lastname: Lynch
authors.affiliation: Genzyme Corporation, 31 New York Avenue, Framingham, MA 01701-9322.
authors.forename: Robin
authors.initials: R
authors.lastname: Ziegler
authors.affiliation: Genzyme Corporation, 31 New York Avenue, Framingham, MA 01701-9322.
authors.forename: Seng H
authors.initials: SH
authors.lastname: Cheng
authors.affiliation: *Department of Medicine, University of Cambridge, Level 5, Box 157, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, United Kingdom; tmc12@medschl.cam.ac.uk.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Cox
mesh_terms: D000818:Animals; D001835:Body Weight / Q000235:genetics; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006028:Glycosphingolipids / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D013661:Tay-Sachs Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D001619:beta-N-Acetylhexosaminidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D006028:Glycosphingolipids; D021122:Protein Subunits; D001619:beta-N-Acetylhexosaminidases