characterization of inducible models of tay-sachs and related disease家族黑蒙性白痴的诱导模型和相关疾病的特征.pdfVIP

Characterization of Inducible Models of Tay-Sachs and Related Disease 1 2 1 1 1. Timothy J. Sargeant *, Deborah J. Drage , Susan Wang , Apostolos A. Apostolakis , Timothy M. Cox , ˜ ´ ´ 1. M. Begona Cachon-Gonzalez 1 Department of Medicine, Addenbrooke’s Hospital, University of Cambridge, Cambridge, United Kingdom, 2 Central Biomedical Services, School of Clinical Medicine, Addenbrooke’s Hospital, University of Cambridge, Cambridge, United Kingdom Abstract Tay-Sachs and Sandhoff diseases are lethal inborn errors of acid b-N-acetylhexosaminidase activity, characterized by lysosomal storage of GM2 ganglioside and related glycoconjugates in the nervous system. The molecular events that lead to irreversible neuronal injury accompanied by gliosis are unknown; but gene transfer, when undertaken before neurological signs are manifest, effectively rescues the acute neurodegenerative illness in Hexb 2/ 2 (Sandhoff) mice that lack b- hexosaminidases A and B. To define determinants of therapeutic efficacy and establish a dynamic experimental platform to systematically investigate cellular pathogenesis of GM2 gangliosidosis, we generated two inducible experimental models. Reversible transgenic expression of b-hexosaminidase directed by two promoters, mouse Hexb and human Synapsin 1 promoters, permitted progression of GM2 gangliosidosis in Sandhoff mice to be modified at pre-defined ages. A single auto-regulatory tetracycline-sensitive expression cassette controlled expression of transgenic Hexb in the brain of Hexb 2/ 2 mice and provided long-term