We seek to understand the molecular causation of sphingolipid diseases and to improve their outcome – conducting therapeutic research principally in the field of lysosomal disorders – with special reference to those which affect the brain. As an Internist and Metabolic Physician, Professor Tim Cox, with Drs Patrick Deegan, William Griffiths and Chong Yew Tan has clinical interests in the disorders of fructose and iron metabolism, porphyria and lipid diseases – as well as sundry inborn errors of metabolism, such as alkaptonuria.
The laboratory group is closely integrated with clinical practice at Addenbrooke’s Hospital where there is are National Centres for the diagnosis and treatment of lysosomal diseases and for hepatology (Liver Transplantation), to which patients with difficult-to-manage metabolic conditions are referred. The group works closely with paediatric neurologists, including Dr Alasdair Parker and Dr Anna Maw, who have an interest in paediatric neuro-metabolic conditions.
Our main goal for treatment is to develop gene therapy for serious neurodegenerative disorders of the lysosome, including Tay-Sachs and Sandhoff diseases; Dr Begoña Cachón, with Professor Cox, are at the centre of a Consortium to develop a clinical vector for gene therapy trials for these devastating neurological disorders. Other studies relate to the inflammatory features and possible causes of cell death in the white matter disorder, Krabbe disease – also a sphingolipidosis due to deficiency of a lysosomal enzyme.
The molecular causation of lymphoproliferation with B cell lymphoma and multiple myeloma which complicates Gaucher disease is unknown but Dr Pavlova and colleagues are examining the relationship of this to the pathological sphingolipids in inducible models of Gaucher disease.
The clinical research group has already brought substrate reduction therapy into clinical use for Gaucher disease: and Prof Cox continues to serve as a senior investigator in international trials using newly discovered inhibitors of glycosphingolipid biosynthesis to improve the outcome for patients with these disorders. He served as Clinical Expert in relation to approval eliglustat, a first-line oral agent authorized in 2014 as Celderga for type I Gaucher disease by the European Commission. Members of the laboratory group carry out into the mode of action of substrate inhibitors and of pharmacological chaperones for patients with lysosomal diseases. We have moreover generated several authentic models of lysosomal disorders, including an informative living system with inducible and reversible neurological disease: this will allow refined therapeutic exploration and inform the experimental study of molecular pathogenesis.
The group is now funded by the Medical Research Council; The National Institute for Health Research; The Children’s Medical Charity, SPARKS; by an investigator-sponsored study with Genzyme (a Sanofi company) – there is also a UK collaborative award with The Weizmann Institute of Science, Rehovot.
MRC Biological Catalyst DPFS-DCS award (PI TM Cox with Co-PI MB Cachon-Gonzalez) Gene Therapy for Tay-Sachs and Sandhoff diseases (1/10/13-31/3/18). £2,804,000.
MRC Stratified Medicine Consortium award Predictive measurements to stratify clinical outcomes in children and adults with Gaucher disease and responses to specific therapies (GAUCHERITE consortium: TM Cox Lead applicant; Co-PI FM Platt (Oxford). £3,740,000. 1/10/2013-30/9/2017