title: Plasmid-based gene transfer ameliorates visceral storage in a mouse model of Sandhoff disease.
abstract: Sandhoff disease is a severe neurodegenerative disorder with visceral involvement caused by mutations in the HEXB gene coding for the beta subunit of the lysosomal hexosaminidases A and B. HEXB mutations result in the accumulation of undegraded substrates such as GM2 and GA2 in lysosomes. We evaluated the efficacy of cationic liposome-mediated plasmid gene therapy using the Sandhoff disease mouse, an animal model of a human lysosomal storage disease. The mice received a single intravenous injection of two plasmids, encoding the human alpha and beta subunits of hexosaminidase cDNAs. As a result, 10-35% of normal levels of hexosaminidase expression, theoretically therapeutic levels, were achieved in most visceral organs, but not in the brain, 3 days after injection with decreased levels by day 7. Histochemical staining confirmed widespread enzyme activity in visceral organs. Both GA2 and GM2 were reduced by almost 10% and 50%, respectively, on day 3, and by 60% and 70% on day 7 compared with untreated age-matched Sandhoff disease mice. Consistent with the biochemical results, a reduction in GM2 was observed in liver cells histologically as well. These initial findings support further development of the plasmid gene therapy against lysosomal diseases with visceral pathology.
authors.affiliation: Department of Pathology, School of Medicine, Yokohama City University, 236-0004 Yokohama, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Yamaguchi
authors.forename: Kayoko
authors.initials: K
authors.lastname: Katsuyama
authors.forename: Kyoko
authors.initials: K
authors.lastname: Suzuki
authors.forename: Kenji
authors.initials: K
authors.lastname: Kosaka
authors.forename: Ichiro
authors.initials: I
authors.lastname: Aoki
authors.forename: Shoji
authors.initials: S
authors.lastname: Yamanaka
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D005678:G(M2) Ganglioside / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D054819:Hexosaminidase B; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010957:Plasmids; D012497:Sandhoff Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D014018:Tissue Distribution; D001619:beta-N-Acetylhexosaminidases / Q000235:genetics / Q000378:metabolism
chemical_list: D005678:G(M2) Ganglioside; D054819:Hexosaminidase B; D001619:beta-N-Acetylhexosaminidases