title: Enhanced survival in Sandhoff disease mice receiving a combination of substrate deprivation therapy and bone marrow transplantation.
abstract: Sandhoff disease is a lysosomal storage disorder characterized by G(M2) ganglioside accumulation in the central nervous system (CNS) and periphery. It results from mutations in the HEXB gene, causing a deficiency in beta-hexosaminidase. Bone marrow transplantation (BMT), which augments enzyme levels, and substrate deprivation (using the glycosphingolipid biosynthesis inhibitor N-butyldeoxynojirimycin [NB-DNJ]) independently have been shown to extend life expectancy in a mouse model of Sandhoff disease. The efficacy of combining these 2 therapies was evaluated. Sandhoff disease mice treated with BMT and NB-DNJ survived significantly longer than those treated with BMT or NB-DNJ alone. When the mice were subdivided into 2 groups on the basis of their donor bone marrow-derived CNS enzyme levels, the high enzyme group exhibited a greater degree of synergy (25%) than the group as a whole (13%). Combination therapy may therefore be the strategy of choice for treating the infantile onset disease variants.
authors.affiliation: Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, United Kingdom.
authors.forename: M
authors.initials: M
authors.lastname: Jeyakumar
authors.forename: F
authors.initials: F
authors.lastname: Norflus
authors.forename: C J
authors.initials: CJ
authors.lastname: Tifft
authors.forename: M
authors.initials: M
authors.lastname: Cortina-Borja
authors.forename: T D
authors.initials: TD
authors.lastname: Butters
authors.forename: R L
authors.initials: RL
authors.lastname: Proia
authors.forename: V H
authors.initials: VH
authors.lastname: Perry
authors.forename: R A
authors.initials: RA
authors.lastname: Dwek
authors.forename: F M
authors.initials: FM
authors.lastname: Platt
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D000818:Animals; D016026:Bone Marrow Transplantation; D001921:Brain / Q000378:metabolism; D003943:Diagnostic Techniques, Neurological; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006028:Glycosphingolipids / Q000378:metabolism; D054819:Hexosaminidase B; D051379:Mice; D012497:Sandhoff Disease / Q000628:therapy*; D013116:Spinal Cord / Q000378:metabolism; D015996:Survival Rate; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D006028:Glycosphingolipids; D017485:1-Deoxynojirimycin; C059896:miglustat; D054819:Hexosaminidase B; D001619:beta-N-Acetylhexosaminidases