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: M Jeyakumar, F Norflus, C J Tifft, M Cortina-Borja, T D Butters, R L Proia, V H Perry, R A Dwek, F M Platt
• Journal: Blood (Blood) Vol. 97 Issue 1 Pg. 327-9 (Jan 01 2001) ISSN: 0006-4971 [Print] United States
• PMID: 11133779 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Glycosphingolipids
• 1-Deoxynojirimycin
• miglustat
• Hexosaminidase B
• beta-N-Acetylhexosaminidases

Topics

• 1-Deoxynojirimycin (analogs & derivatives, therapeutic use)
• Animals
• Bone Marrow Transplantation
• Brain (metabolism)
• Diagnostic Techniques, Neurological
• Disease Models, Animal
• Enzyme Inhibitors (therapeutic use)
• Glycosphingolipids (metabolism)
• Hexosaminidase B
• Mice
• Sandhoff Disease (therapy)
• Spinal Cord (metabolism)
• Survival Rate
• beta-N-Acetylhexosaminidases (metabolism)