Dr. Frances Platt
University of Oxford
webpageLysosomal Storage Diseases: therapy and pathogenesis
The glycosphingolipid (GSL) storage diseases result from the inheritance of defective genes encoding the catabolic enzymes required for the breakdown of GSLs in lysosomes. Little progress has been made in developing therapeutic agents to treat the majority of these disorders and new therapeutic strategies are urgently required.
We have discovered two novel inhibitors of GSL biosynthesis. These compounds provide a means for partially inhibiting GSL biosynthesis in vitro and in vivo. By limiting the biosynthesis of the substrates for the defective enzymes (substrate reduction therapy) GSL accumulation, and the pathology associated with the lysosomal storage of GSLs, may be prevented. The two compounds are N- butyldeoxynojirimycin (NB-DNJ) and N-butyldeoxygalactonojirimycin (NB-DGJ), a glucose galactose analogue respectively. NB-DNJ has recently approved for clinical use in type 1 Gaucher disease, a lysosomal storage disorder that lacks CNS involvement.
The student will be involved in one or more aspects of the following research projects:
1. NB-DNJ will be evaluated in authentic murine models of glycosphingolipidoses, including a model of Tay-Sachs disease and a model of Sandhoff disease in combination with other experimental therapies.
2. We are studying, at a cell biological level, the changes in lipid and protein trafficking in cells that store GSLs. We aim to understand how cellular dysfunction arises in peripheral cells and neurons, in response to storage.
3. Characterization and functional studies of the enzyme(s) involved in glycolipid biosynthesis and the mechanism of action of inhibitory compounds.
References:
Jeyakumar, M., Thomas, R., Eliott-Smith, E., van der Spoel, A., d'Azzo, A., Perry, V.H., Butters, T.D., Dwek, RA. and Platt, F.M. (2003) Central nervous system inflammation is a hallmark of pathogenesis in mouse models of GM1 and GM2 gangliosidosis. Brain 126, 974-987
Sillence, D and Platt F.M. (2003) Storage diseases: new insights into Sphingolipid functions. Trends Cell Biol. 13, 195-203
Dwek, R.A., Butters, T.D., Platt, F. M. and Zitzmann, N. (2002) Targetting glycosylation as a therapeutic approach. Nature Drug Discovery 1, 65-75
Jeyakumar, M., Smith, D., Eliott-Smith, E., Cortina-Borja, M., Reinkensmeier, G., Butters, T.D., Lemm, T., Sandhoff, K., Perry, V.H., Dwek, R.A. and Platt, F.M. (2002) An inducible model of late onset Tay-Sachs disease. Neurobiology of disease 10, 201-210
Sillence, D., Puri, v., Marks, D.L., Butters, T.D., Dwek, R.A., Pagano, R.E. and Platt, F.M. (2002) Glucosylceramide modulates membrane traffic along the endocytic pathway. J. Lipid Research 43, 1837-1845
Mellor, H. R., Nolan, J., Pickerig, L., Wormald, M. R., Platt, F.M., Dwek, R.A., Fleet, G.W. and Butters, T.D. (2002) Preparation, biochemical characterisation and biological properties of radiolabelled N-alkylated deoxynojirimycins. Biochem. J. 366, 225-233
Cox, T.M., Lachmann, R.H., Hollak, C.E.M., Aerts, J.M.F.G., van Weely, S., Hrebicek, M., Platt, F.M., Butters, T.D., Dwek, R.A., Moyses, C., Gow, I.R., Elstein, D. and Zimran, A. (2000) Substrate reduction using N-butyldeoxynojirimycin (OGT 918): Clinical trial of a novel oral therapy for Gaucher's disease. Lancet 355, 1481-1485
Platt, F.M., Neises, G.R., Reinkensmeier, G., Townsend, M.J., Perry, V.H., Proia, R.L., Winchester, B., Dwek, R.A. and Butters, T.D. (1997) Prevention of lysosomal storage in Tay-Sachs mice treated with N-butyldeoxynojirimycin. Science 276, 428-431
