November 28
PROGRAM

03

Glycoscience : diversity and integration

Targeting glycosphingolipids forhuman therapy
Fran Platt, PhD FMedSci
Professor of Biochemistry and Pharmacology
Department of Pharmacology, University of Oxford, UK

Fran Platt
ProfileProfessor Fran Platt received a BSc degree
in Zoology from Imperial College, University of London and a PhD in Animal Physiology from the University of Bath, UK. She
was a post-doctoral fellow at Washington
University Medical School (St. Louis, USA)and returned to the UK in 1989 to The Glycobiology Institute, Department of Biochemistry, University of Oxford. She wasawarded a Lister Institute Senior ResearchFellowship in 1996. In 2006 she moved tothe Department of Pharmacology, University of Oxford.
Her research interests are in glycosphingolipids (GSL) and in particular glycosphingolipid (GSL) lysosomal storage diseases.
She and her colleagues (Terry Butters andRaymond Dwek) pioneered a novel approach to treat these inherited metabolic
diseases (substrate reduction therapy, SRT)
that has led directly to the development ofan approved drug (miglustat) for treatingtype 1 Gaucher disease and Niemann-Pickdisease type C.
She was awarded The Alan Gordon Memorial award from the UK Gaucher association and the Horst-Bickel Award in recognition of her role in developing substrate
reduction therapy for lysosomal disorders.
Prof. Platt has presented plenary talks at
multiple scientific and clinical meetingsand is currently an Editor for the Journalof Biological Chemistry and serves on theadvisory board of multiple lysosomal storage disease charities (UK and USA). She
has published over 130 papers in peerreviewed journals and co-edited the bookLysosomal Disorders of the Brain with
Steve Walkley.
She was elected Fellow of the Academy ofMedical Sciences in 2011.

Our understanding of the functionalroles played by glycosphingolipids (GSLs)
remains incomplete 1). However, whenthese molecules cannot be degraded fullyin the lysosome severe diseases result,termed GSL lysosomal storage disorders 2)(Figure 1). The majority of these diseases
result from inherited defects in the genesthat encode lysosomal enzymes involvedin GSL catabolism.
While studying inhibitors of N-glycan
processing, determining how they disrupt the life cycle of HIV 3) we made theserendipitous discovery that the drug wewere studying, N-butyldeoxynojirmicin/
miglustat, had a novel and very unexpected enzyme target, glucosylceramidesynthase 4) (Figure 2). This drug could
therefore be used to pharmacologicallyinhibit the biosynthesis of GSLs to probe
their physiological functions, but also had
the potential to treat GSL lysosomal storage diseases. We therefore tested whether

this orally available drug would show
efficacy in mouse models of Tay-Sachs andSandhoff disease. It was found that thedrug delayed disease progression, reduced
neuroinflammation and prolonged lifeexpectancy 5)6). Clinical collaborators anda commercial partner tested this drug intype 1 Gaucher disease patients and efficacy was demonstrated 7). The drug wasapproved by the EMEA in 2002 and by theFDA in 2003. We called this pharmacological approach substrate reduction therapy(SRT). The drug reduces the number of
GSL molecules synthesised by cells so
fewer require degrading in the lysosome,allowing the rate of biosynthesis to better
match the impaired rate of catabolism.
As the drug crosses the blood-brain barrier it also has the potential to treat CNS
manifestations of these disorders. It wasrecently approved by the EMEA for treating Niemann-Pick disease type C (NPC),
following efficacy being demonstrated in
an international clinical trial 8).

L-Serine, Palmitoyl-Coenzyme ACeramide
UDP-Glucose

O

HOHCCH

HN CC

CH3

CH3OH

UDP-Glucose: N-acylsphingosine
glucosyltransferase

UDP

Glucosylceramide

OHHOHOO
OH

O

HCCH

HNCOC

Miglustat
CH3CH3OH

Lactosylceramide
Ganglio- series

Lacto(neo)- series

Globo- series

Figure 2. Glycosphingolipid biosynthesis highlighting the step in the pathway inhibited by miglustatHaving developed miglustat as a therapeutic agent we have now turned our attention
to investigating pathogenic mechanisms
in lysosomal disorders to identify novel
clinical intervention points. For example,a major current focus of the laboratory
is Niemann-Pick disease type C (NPC)
disease, a disorder involving the storage of myltiple classes of lipids including
GSLs. We have discovered that this dis-ease involves the primary storage of theceramide degradation product sphingosine 9). Sphingosine storage in turn causes
dysregulation of acidic storage calcium,preventing the fusion of late endosomeswith lysosomes, explaining the cellular
hallmarks of this disorder and explaining why all GSL species are stored in thisdisease 9)10). Furthermore, elevating cytosolic calcium compensated for the novel

calcium defect in NPC disease and wasof therapeutic benefit in a mouse modelof NPC disease 9). Very recently, we havemade a mechanistic link between the cellular pathway affected in NPC disease andmore common human disorders suggesting SRT targeting GSLs may have utility
beyond lysosomal storage diseases.

References

Figure 1. Electron microscopy showing the ultrastructureof lipid storage bodies in Tay-Sachs disease cells.

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the 20th Anniversary of the Mizutani Foundation for Glycoscience1) 	Lingwood, C.A. Glycosphingolipid functions. Cold Spring Harbor perspecAcad Sci USA 96, 6388-6393 (1999).
tives in biology 3(2011).
7) 	Cox, T., et al. Novel oral treatment of Gaucher’s disease with N-butylde2) 	Cox, T.M. & Cachon Gonzalez, M.B. The Cellular Pathology of Lysosomal
oxynojirimycin (OGT 918) to decrease substrate biosynthesis. Lancet 355,Diseases. J Pathol (2011).
1481-1485 (2000).
3) 	Fischer, P.B., et al. The alpha-glucosidase inhibitor N-butyldeoxynojirimycin 8) 	Patterson, M.C., Vecchio, D., Prady, H., Abel, L. & Wraith, J.E. Miglustat for
inhibits human immunodeficiency virus entry at the level of post-CD4 bindtreatment of Niemann-Pick C disease: a randomised controlled study. Lancet
ing. J Virol 69, 5791-5797 (1995).
neurology 6, 765-772 (2007).
4) 	Platt, F.M., Neises, G.R., Dwek, R.A. & Butters, T.D. N-butyldeoxynojirimy- 9) 	Lloyd-Evans, E., et al. Niemann-Pick disease type C1 is a sphingosine storcin is a novel inhibitor of glycolipid biosynthesis. J Biol Chem 269, 8362-8365
age disease that causes deregulation of lysosomal calcium. Nat Med 14, 1247(1994).
1255 (2008).
5) 	Platt, F.M., et al. Prevention of lysosomal storage in Tay-Sachs mice treated 10)	Morgan, A.J., Platt, F.M., Lloyd-Evans, E. & Galione, A. Molecular mechawith N-butyldeoxynojirimycin. Science 276, 428-431 (1997).
nisms of endolysosomal Ca2+ signalling in health and disease. Biochem J6) 	Jeyakumar, M., et al. Delayed symptom onset and increased life expectancy
439, 349-374 (2011).
in Sandhoff disease mice treated with N-butyldeoxynojirimycin. Proc NatlCommemorative Symposium

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