Metabolic Medicine

Research

Professor Cox’s group explores the molecular pathogenesis of lysosomal diseases with particular emphasis on the development of definitive treatment. With Dr Deegan, Clinical Director of the National Centre for the treatment and diagnosis of Lysosomal diseases, several clinical trials of substrate reducing drugs, pharmacological chaperones and innovative enzyme therapies are underway, particularly for Gaucher’s disease and Fabry disease.  Dr Marchesan conducts studies of the molecular targeting and delivery of lysosomal proteins to their sites of action.

With Dr Pavlova, promising experimental studies are underway to investigate the causation and treatment of B-cell proliferation and myelomatosis – now a leading cause of death in Gaucher’s disease. She has been awarded a Gaucher Generation Grant and independent support from Genzyme-Sanofi.

The group has secured a 4-year Stratified Medicine award from the Medical Research Council: “GAUCHERITE”.  The aim is to guide therapy by predicting long-term risk in Gaucher patients using clinical data, imaging and biomarkers to ensure optimal intervention before irreversible injury is established: by securing long-term data from this diverse national cohort, we will investigate hitherto unknown aspects of pathogenesis.

Overall the laboratory has been central to the formation of an International Tay-Sachs disease Gene Therapy Consortium to translate successful gene therapy first conducted in experimental models into a viable therapy in man.  With Dr Begoña Cachón-González, Prof Cox has secured 5 years funding (DPFS-DCS award) from the Medical Research Council to develop clinical gene therapy in the UK.

In collaboration with colleagues, and a joint award at the Weizmann Institute of Science, the group is investigating necroptosis as a potential cause of oligodendrocyte loss and demyelination and predict that blocking this cell-death programme will benefit Krabbe disease and another sphingolipidosis – diseases in which there is a compelling unmet medical need.

Cachón-González MB, Wang SZ, Ziegler R, Cheng SH, Cox TM. (2014). Reversibility of neuropathology in Tay-Sachs related diseases. Human Molecular Genetics 2014; 23: 730-748.   

Vitner EB, Salomon R, Farfel-Becker T, Meshcheriakova A, Ali M, Klein A, Shinder V, Cox TM, Futerman AH.  RIP3 as a novel therapeutic target for Gaucher disease. Nature Medicine 2014; 20: 204-208.

Pavlova EV, Wang S, Archer J, Dekker N,  Aerts JMFG, Karlsson S, Cox TM. B-cell lymphoma and myeloma in murine Gaucher disease. Journal of Pathology. 2013; 231: 88-97.

 Jeyakumar M, Williams I, Smith DA, Cox TM, Platt FM.  Critical role of iron in the pathogenesis of the murine gangliosidoses.  Neurobiol Dis 2009; 34:406–16.

 Griffiths WJH, Mayr R, McFarlane I, Hermann H, Halsall DJ, Zoller H, Cox TM.  Clinical presentation and molecular pathophysiology of autosomal dominant hemochromatosis caused by a novel ferroportin mutation.  Hepatology 2010; 51:788-95.

 Cox TM. Eliglustat tartrate, an orally active glucocerebroside synthase inhibitor for the potential treatment of Gaucher disease and other lysosomal storage diseases.

Curr Opin Invest Drugs 2010; 11:1169-81.

 Roos HI, Roos JCP, Cox TM.  Orphan drug pricing may merit a competition law investigation.  Brit Med J 2010; 341:1084-6.

 Pavlova EV, Deegan, PB, Tindall J, McFarlane I, Mehta A, Hughes D, Wraith JE, Cox TM.  Potential Biomarkers of Osteonecrosis in Gaucher Disease.  Blood Cells Mol and Dis 2011; 46:27-33.

 Deegan PB, Pavlova EV, Tindall J, Stein P, Bearcroft P, Mehta A, Hughes D, Wraith JE, Cox TM. Osseous Manifestations of Adult Gaucher Disease in the Era of Enzyme Replacement Therapy. Medicine (Baltimore) 2011; 90:52-60.

Legend

Structural implications of the newly identified mutation in the human beta hexosaminidase subunit responsible for late-onset Sandhoff disease.