Institute of Child Health
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- Developmental Biology and Cancer
- Developmental Neurosciences
- Genetics and Genomic Medicine
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Centre for Translational Omics
Omics studies (genomics, proteomics, metabolomics, lipidomics, glycomics) have come of age and are beginning to be applied in clinical practice. We have brought together a group of experts in developing and applying these technologies in the Centre for Translational Omics. The GOSgene rare disease gene discovery team, ICH Proteomics and UCL Genomics, have been integrating into the section to provide a core of interconnected expertise in omics technologies, data generation and project design. This unique and highly interdisciplinary environment will create opportunities for collaborating researchers and clinicians at UCL and its clinical partners (e.g. GOSH, UCLH, RFH), with the emphasis on translating the promise offered by these exciting approaches directly into clinical benefit.
Telephone Number:0207 905 2266
Mike Hubank directs the UCL Genomics lab, now integrated into the Centre for Translational Omics. The field of genomics has expanded dramatically in recent years, creating new opportunities for research and clinical translation. Application specialists within the Genomics team use their expertise to design, run and interpret genomics experiments in a wide variety of clinical and biological contexts. This is a highly interdisciplinary process involving collaboration with research groups across the clinical spectrum.
Genomics requires investment in advanced technologies. UCL Genomics operates robotic platforms for automating sample preparation, and high throughput sequencing on the latest platforms, including Illumina NextSeq 500, Hiseq 2500 and Miseq. UCL Genomics has been engaged in collaborative research since the birth of the field in 2000, and our combination of expertise, experience and analytical skills is leading to innovation in Genomic Medicine at UCL. We believe that combining genomics with other omics approaches will result in higher resolution understanding of disease, leading to better monitoring, and targeted, personalized treatment.
Genomic medicine is fundamental to many exciting research projects at UCL, including:
Hypertrophic Cardiomyopathy: Collaborators, Prof Perry Elliot and Prof Bill McKenna. Supported by a CBRC Specialist Biomedical Research Centre Collaborative Research grant we constructed one of the first targeted gene panels to be used in the UK to simultaneously screen 40 candidate genes in hundreds of patients to identify causative mutations (Lopes, Zekavati et al 2013). This work was a fore-runner for the generation of comparable panels for other disorders (e.g. immunodeficiencies) which, thanks to liaison between our lab, the GOSH clinics and the NE Thames regional genetics lab (under Prof Nick Lench), are now in clinical practice.
Antigen Receptor Repertoire: Collaborators, Prof Robin Callard and Prof Nigel Klein. We obtained pump prime funding (NHS Innovations) to pilot a method developed at UCL Genomics for simultaneously detecting personal variants in all antigen receptors following VDJ rearrangement (TCRα, Β, γ and δ, plus Ig kappa and lambda.) This has potential applications in monitoring of immune repertoire during disease progression, treatment, and immunization.
Pathogen Diagnostics Collaborators, EU-FP7 PATHSEEK consortium (http://www.ucl.ac.uk/pathseek), led by Dr Judy Breuer (UCL). We aim to improve clinical diagnosis and patient management by the application of high throughput sequencing to samples from patients with suspected infectious disease. In collaboration with Prof Breuer and Dr Vincent Plagnol, we have also pioneered a method for deep-sequencing of RNA to successfully identify causative pathogenic viruses in patients at GOSH.
Cancer Diagnostics and Monitoring: Collaborators include Profs John Anderson, Tariq Enver, Darren Hargrave, Tom Jacques, Kathy Pritchard-Jones, Jonathan Ham, Tim Forshew, Nick Goulden, Louis Chessler (ICR). We applied genomics methods to identify somatic mosaic p53 mutations responsible for multiple tumours in a patient. We are also working on high resolution tracking of leukemic clones, studying the diagnostic potential of circulating tumour DNA, have applied exon arrays to examine the biology of medulloblastoma (Menghi et al. 2011) and we are working to develop genomics based method for the accurate detection of minimal residual disease in patients with acute lymphoblastic leukaemia.
Gene Discovery: Collaborators include Prof Robert Kleta. We have been involved in several high throughput sequencing and genotyping projects aimed at gene discovery, notably identifying genes responsible for rare kidney disorders (Stanescu et al. 2011, Bockenhauer et al. 2009).
Gene and Cell Therapy: Collaborators include Dr Steve Howe, Profs Adrian Thrasher, Jane Sowden and Robin Ali. When a child undergoing gene therapy at GOSH fell ill with leukemia, we collaborated with to carry out a detailed and integrated genomic characterisation of the tumour which uncovered the molecular mechanisms which both cause the tumour and drove its proliferation (Howe et al. 2009). We also collaborated on a project led by to analyse genetically modified photoreceptor precursor cells to determine their genomic “fingerprint”, which demonstrated the molecular pathways underlying their cellular function in stem cell transplant experiments (Lakowski et al. 2011, Gonzalez-Cordero et al. 2013).
UCL Genomics also provided genomic profiling for two popular television science programmes (RTE Blood of the Irish and BBC2 Prehistoric Autopsy; Neanderthal).
Grants (Last 5 years and current)
|2012 - 2015||GOSHCC £201,381 Development of High Throughput Sequencing for MRD Analysis in ALL. Hubank Goulden|
|2012 - 2013||National Health Service Innovations PoC £49,690 A capture and sequencing method for rapid analysis of the T cell antigen receptor repertoire. Hubank, Callard, Klein|
|2009 - 2011||NIHR Biomedical Research Centre £155,801 Genotype, clinical phenotype and prognosis in hypertrophic cardiomyopathy caused by sarcomeric gene mutations. Elliot, Hubank, Syrris|
|2009 - 2010||Research into Childhood Cancer £62,337 Molecular characterisation of histological risk groups in the SIOP Wilms tumour 2001 trial. Hubank, Pritchard-Jones|
|2009||UCL Platform Technologies CIF £240,000 Provision of a Roche GS-FLX ultradeep sequencing facility for UCL. Hubank|
|2008 - 2011||NIHR Biomedical Research Centre £276,000 Illumina Beadstation Genetic Analysis Centre. Hubank|
|2006 - 2010||BBSRC £644,069 Modelling gene networks by non-linear analysis of microarray data. BB/E008488/1 Hubank|
|2012 - 2015||EU-FP7 € 5,887,033 Automated Next Generation Sequencing for Diagnostic Microbiology Breuer, Hubank, Others|
|2009 - 2013||EU-FP7 € 5,368,088 Antibiotic administration and the emergence and persistence of antibiotic-resistant bacteria in humans Wilson, Others, Hubank|
Telephone Number: 0207 679 3531
Gissen group consists of 4 postdoctoral fellows: Drs Maelle Lorvellec, Daniel Little, Joanna Hanley and Blerida Banushi; 2 research technicians: Anna Straatman-Iwanowska and Kunbi Mosaku; Microsurgery Assistant Asllan Gjinovci and a PhD student Clare Rogerson. We are also joined by visiting scientists: Dr Michael Devine (Academic Clinical Lecturer in Neurology at Imperial College, London) and Dr Danai Bem (Postdoctoral Research Fellow at the University of Birmingham with Professor Steve Watson). Maissa Mhibik is the visiting Masters student from Paris 13 University. The following PhD students are co-supervised by Prof Gissen: Anne-Marie Lyne, Emma Reid and Dr Julien Baruteau.
Our UCL collaborators are: Professors Adrian Thrasher, Simon Heales and Peter Clayton, Mr Paolo De Coppi, Drs Kevin Mills, Philippa Mills and Dr Manju Kurian (all at the UCL Institute of Child Health), Dr Simon Waddington (UCL Institute for Women’s Health), Dr Laurent Bozec (Biomaterials and Tissue Engineering, UCL Eastman Dental Institute), Professor Mark Lythgoe (Centre for Advanced Biomedical Imaging), Professor Alexander Seifalian (UCL Centre for Nanotechnology & Regenerative Medicine), Professor Mark Girolami (Department of Statistical Science).
Our external collaborators include Professors Steve Watson and Deirdre Kelly (University of Birmingham), Professor Eamonn Maher and Dr Ludovic Vallier (University of Cambridge), Dr Paul Fairchild (University of Oxford), Professor Frederic Lemaigre (de Duve Institute and Université Catholique de Louvain), Professor Torbjorn Lundstedt (University of Uppsala and Acureomics, Sweden).
ARC has an incidence of approximately 1 in 100,000 births. Mislocalisation of apical membrane proteins and absence of platelet alpha granules are the histological hallmarks of this disease. VPS33B is a homologue of yeast Vps33, which is one of the 6 proteins that forms the Homotypic Protein Sorting (HOPS) complex, involved in membrane tethering and fusion, specifically of late endosomes to lysosomes. VIPAR has distant homology with another HOPS complex component protein Vps16.
Two homologues of yeast Vps33 (VPS33A and VPS33B) are present in the multicellular organisms. It appears that VPS33A homologue participates in HOPS, whilst VPS33B forms a complex with VIPAR and functions in a different trafficking pathway to HOPS. The interaction of the VPS33B-VIPAR complex with RAB11a suggests its function in a membrane protein recycling pathway.
Phenotype of the patients, drosophila mutants and knockdown cells and zebrafish larvae suggest that VPS33B-VIPAR complex is involved in a number of different biological processes such as regulation of epithelial polarity, biogenesis of platelet alpha granules and fusion of phagosomes and lysosomes in the macrophages. Further investigation of the VPS33B and VIPAR interactors and vesicular cargo molecules will define the pathway that these proteins are involved in.
Cell lines with the VIPAR and VPS33B knockdown have reduced expression of E-cadherin, which is due to the transcriptional down regulation. Studies of the morphology of the knockdown cells showed that they have abnormally formed adherence and tight junctions. The cells lose the ability to form a monolayer and, unlike the wild type cells, cannot form tubules when grown in collagen gels. There also appears to be a loss of contact inhibition of growth as three times more knockdown cells than wild type cells were harvested when grown on plastic flasks. Abnormal expression of E-Cadherin was also seen in the morpholino knockdown zebrafish larvae and ARC patients’ liver thus suggesting a role of VPS33B-VIPAR in intracellular signalling which leads to stunted development of bile ducts. Our current investigation of the VPS33B-VIPAR involvement in the regulation of the intracellular signalling proteins utilise the Vps33b mouse knockout models.
Use of disease models for development of treatments in childhood inherited metabolic disorders
A number of collaborative projects in the lab utilise the knowledge of human genetics and cell biology in order to use disease models for treatment developments. Such projects include use of patient derived induced Pluripotent Stem cells (iPSc) for differentiation and drug screening, development of iPSc derived models of metabolic liver disease and development of gene therapy in several childhood inherited metabolic disorders.
The main interests of the group are understanding of the VPS33B/VIPAR intracellular trafficking pathway and using cell and animal models for developing treatments for childhood inherited metabolic disorders.
Understanding of the VPS33B/VIPAR intracellular trafficking pathway
We discovered that the defects in one of the two proteins: VPS33B and VIPAR result in a multisystem autosomal recessive disorder: Arthrogryposis, Renal dysfunction and Cholestasis syndrome (ARC).
Grants (last 5 years/current)
|Our group is funded by a number of different grant giving bodies including: Wellcome Trust, European Research Council, MRC, Action Medical Research, Children's Liver Disease Foundation, Great Ormond Street Hospital Charity, Actelion Pharmaceuticals, The Innovative Medicines Initiative, UCL Impact Studentships|
Telephone number: 0207 905 2628
Our mission is to discover the molecular and metabolic basis of inherited disorders, particularly those affecting the brain and/or liver, and thereby to find new treatments for these disorders. Of our 30,000 genes, 4,000 code for enzymes and transporters. Enzymes convert one chemical (“metabolite”) to another and transporters move chemicals between cells and organelles. When an enzyme or transporter doesn’t work properly we call this an “inborn error of metabolism”. Inborn errors can present in many different ways. Those affecting the brain can cause epileptic fits, movement disorders (like Parkinson’s disease or ataxia), paralysis and psychiatric symptoms such as autism. Those affecting the liver can produce liver failure or cirrhosis. Identification of a “new” inborn error as the cause of neurological disease or liver disease has traditionally relied on the development of new, more sensitive, more specific and more accurate techniques for the analysis of metabolites or enzymes. Mass spectrometry (MS) has played a very major part in these developments and, with a major contribution from Dr Kevin Mills, we have gradually built up from a single gas chromatograph – mass spectrometer to a state-of-the-art MS facility, run by Kevin, with capabilities for measuring a wide range of metabolites (“metabolomics”), lipids (”lipidomics”), proteins (“proteomics”) and sugar chains attached to proteins (“glycomics”). The identification of specific abnormal metabolites/lipids/ proteins / glycans has led to the development of new tests for enzymes and transporters and to analysis of candidate genes. This aspect of our work has been led by Dr Philippa Mills.
More recently “new” disorders have been identified by analysis of the coding regions of panels of genes or all 30,000 genes - an “exome” analysis. In this work we have collaborated closely with GOSgene, and Prof Nick Lench and his colleagues in the DNA diagnostic laboratory. The identification of a potentially faulty gene by the DNA panel or exome analysis has led to targeted measurements of metabolites and enzymes to confirm that the gene really is faulty, again relying heavily on the skills of Kevin and Philippa.
We have also commenced an analysis of children with a susceptibility to a low blood sugar – “ketotic hypoglycaemia” - by whole genome sequencing which looks not just at the DNA that codes for proteins but also the regions that regulate gene expression. Again, we will need analysis of metabolites and enzymes to confirm we have found the DNA abnormality that is responsible for the child’s metabolic disorder.
The detection of the known inborn errors of metabolism and of “new” disorders and the development of new treatments will continue to be heavily dependent on state-of-the-art methods for the analysis of metabolites (“metabolomics, lipidomics”), proteins (“proteomics”) glycans (“glycomics”) and DNA (“genomics”). Thus, it is very exciting to be in a unit that is constantly seeking to improve what these platforms can offer.
We have made significant contributions to the elucidation of the following inborn errors and their treatment (the numbers in brackets are the reference numbers in the Online Mendelian Inheritance in Man [OMIM] database, http://www.ncbi.nlm.nih.gov/omim)
Disorders of bile acid synthesis - some treatable by bile acid replacement therapy (607764, 604741, 213700, 604489, 261515, 603711)
Peroxisomal disorders (excluding disorders already mentioned) – biogenesis disorders (e.g. 603360), and disorders of plasmalogen synthesis (602744)
Disorders of monoamine neurotransmitter synthesis causing infantile Parkinsonism - treatable in some cases (608643, 191290)
Disorders of fatty acid oxidation – detectable by newborn screening with treatment available to prevent brain damage (201450) or as cause of hyperisulinism treatable with diazoxide (609975)
Disorders of cholesterol synthesis causing developmental delay and malformations (270400, 602398, 302960, 215140)
Disorders leading to phytosterol accumulation - both genetic (210520) and as a consequence of parenteral nutrition, the latter leading to severe liver disease and treatable by reduction of phytosterol intake.
Congenital disorders of glycosylation (212065, 608104, 611908)
Disorders affecting vitamin B6 metabolism causing B6-responsive epilepsy (610090, 107323)
Disorders of manganese transport causing dystonia / Parkinsonism and chronic liver disease (611146) - treatable with disodium calcium edetate and iron supplementation
Disorders of intermediary metabolism causing movement disorders e.g. pyruvate dehydrogenase E2 deficiency (245348) treatable with a ketogenic diet and hydroxyisobutyryl-CoA hydrolase deficiency (610690)
Grants (last 5 years/current)
Great Ormond Street Children’s Charity
|2010 - 2012||W1228 Metabolic Research. £118,052|
|2011 - 2012||W1022 Vitamin B6 metabolism in neonates and the effect of feeding method. £86,442|
|2012 - 2014||W1216 Identification of children whose epilepsy can be controlled better by vitamin B6 than anti-epileptic drugs. £53,386|
|2012 - 2015||W1254 Inborn Errors of Metabolism / Other Novel Therapeutic Interventions. /3197,085|
Donation from Parents of a Child with a Metabolic Disorder
|2010 - 2011||Measurement of S2-carboxylpropylcysteamine in urine and use in treatment of 3-hydroxyisobutyryl-CoA hydrolase deficiency. £31,000|
Industry Sponsored Investigator Led Project
|2012 - 2015||Actelion UK Ltd. Tests for diagnosis and monitoring of Niemann-Pick C disease. £72,500|
NIHR Biomedical Research Centre
|2009 - 2012||Is pyridox(am)ine phosphate oxidase deficiency a common cause of epilepsy, infertility, miscarriage and premature birth? BRC Senior Postdoctoral Personal Fellowship for Dr P. Mills. £104,612|
|2012 - 2015||Innovative medicine initiative EU Consortium – Stem cells for biological assays of novel drugs and predictive toxicology (StemBANcc). 850,000 Euros|
|2013 - 2016||European Union SME Targetive collaborative. Health and the understanding of metabolism, aging and nutrition (HUMAN) project. 613,000 Euros|
Action Medical Research
|2012 - 2015||Investigation of manganese metabolism and treatment development for neurological childhood disorders associated with manganese accumulation using a zebrafish gene knockout model. Research Training Fellowship for Dr. Karin Tuschl. £200,000|
Telephone Number: 0207 813 8321
Simon Heales holds the UCL Chair of Clinical Chemistry and is the head of Chemical Pathology at GOSH and the Neurometabolic Unit based at the National Hospital, Queen Square. These laboratories provide highly specialised diagnostic and monitoring services for a wide range of conditions including disorders affecting mitochondrial, lysosomal, glycogen and neurotransmitter metabolism. The GOSH lab also hosts the largest newborn screening laboratory in the UK. Underpinning these activities is an active research (basic and translational) research programme. Close links exist with the mass spectrometry group (Dr Kevin Mills), mitochondrial group (Dr Shamima Rahman) and neurotransmitter/vitamin groups (Dr Manju Kurian, Dr Phillipa Mills, Dr Manju Kurian and Prof Paul Gissen).
Current active research projects include :
Elucidating the mechanism of the ketogenic diet with a particular focus on medium chain fatty acids and mitochondrial function.
The study of lysosomal metabolism and the potential link between Gaucher disease and Parkinson’s disease.
Oxidative stress and the effects upon brain cofactor/vitamin availability.
The potential role of alterations in lysosomal/mitochondrial metabolism and dopamine metabolism.
Biomarker discovery in lysosomal and neurodegenerative disorders
Grants (Last 5 years & current)
|Jan 2013 – December 2018||Vitaflo, industrial collaboration awards, for 2 PhD students. Elucidation of the mechanisms responsible for the ketogenic diet. £140,000.|
|Jan 2010 – Dec 2013||Genzyme, industrial collaboration, for research technician. Development of dried blood spot assays for lysosomal storge disorders. £200,000|
|October 2010 – September 2013||CHRAT studentship. Elucidation of the mechanisms responsible for the loss of 5-methyltetrahydrofolate from the central nervous system. £70,000|
|Jan 2014 – December 2016||UCL Impact studentship (with Genzyme). Gene therapy for Fabry disease. £70,000|
|Jan 2012 – Dec 2014||Innovative medicine initiative EU Consortium – Stem cells for biological assays of novel drugs and predictive toxicology (StemBANcc). 850,000 Euro|
|Jan 2014 – December 2017||Training in neurodegeneration and neurorepair. EU consortium. 500,000 Euro|
Telephone Number: 0207 905 2873
Kevin Mills heads the Biological Mass Spectrometry at the UCL Institute of Child Health which studies the elucidation of disease mechanisms in rare and neurological diseases. This department serves the entire UCL, contains in excess of £5 million of cutting edge technology and is one of the biggest and sophisticated mass spectrometry facilities in the country. The mass spectral research group is composed of approximately 20 full time researchers and is unique in that it incorporates proteomics including tissue imaging (ability to ‘omic’ profile tissue sections on microscope slides), metabolomics, lipidomics and also has the ability to translate any biomarker discovered into a test to NHS / Industry accredited standards. The Unit also includes the NIHR GOSomics facility run by Dr Wendy Heywood, the UCL Proteomics Platform and works very closely with the Leonard Wolfson Experimental Neurology Centre at Queen’s Square. Our aim is to provide the link between research, diagnosis and translation of new tests into the portfolio of tests for the NHS and Industry.
Kevin’s main interest is understanding the disease mechanisms underlying rare inborn errors of metabolism. His group’s focus is on patient-driven, translational research which aims to establish rapid, sensitive methods to study, diagnose and monitor the treatment of patients from GOSH and the National Hospital for Neurology. His laboratory is unique in that it can develop any diagnostic marker found in the ‘omic’ wings of the facility into rapid, multiplexed, diagnostic medical tests in the targeted mass spectrometry section. His group was responsible for the development of a new, quicker and gold standard test for the diagnosis of Fabry disease. This assay is used today both nationally and internationally for screening millions of patients for Fabry disease.
Kevin is a senior lecturer at UCL and an honorary clinical scientist at Great Ormond Street Hospital where he works very closely with the inborn errors of metabolism unit (Professor Paul Gissen, Dr Stephanie Grunewald, Professor Peter Clayton, Dr Philippa Mills), Dermatology (Professor John Harper / Dr Victoria Kinsler), Professors Simon Heales (Chemical pathology) and Neil Sebire (histopathology department). However, he also works very closely on large biomarker projects in neurodegenerative and cardiovascular diseases with Professors Nic Fox/John Hardy (Institute of Neurology) and Professor Perry Elliott (The Heart Hospital).
Grants (Last 5 years & current)
|2014-2017||Glycosphingolipid analyses in ERT trial for Fabry Disease £83,600|
|2013-2016||Mass Spectrometry Equipment grant: Lipidomic, metabolomics and high throughput drug screening capability SLMS £607,000|
|2013-2015||Project Title: Development of novel protein biomarkers for the prediction of response to treatment in childhood arthritis, within the CHARMS study. GOSH UCL BRC Industry Collaboration Grants £53,000|
|2013-2015||Project Title: The development of a rapid blood spot screening test for the diagnosis of lysosomal storage diseases. GOSH UCL BRC Industry Collaboration Grants £50,031|
|2013-2018||Analysis of lysosmal storage products in biological fluids, Sanofi (Genzyme), £83,600|
|2013-2018||Health and the Understanding of Metabolism, Aging and Nutrition (Human)- European Union SME-Targeted Collaborative Project £514,920|
|2012-2014||Actelion Pharmaceuticals -Niemann-Pick C: Screening Tests and Markers of disease activity £72,500|
|2012 -2017||Innovative medicine initiative EU Consortium – Stem cells for biological assays of novel drugs and predictive toxicology (StemBANcc) £1.63 million|
|2012||UCLB, startup costs for technology transfer for Down syndrome screening (IF to MS platforms), £8,500|
|2012-2015||Medical Research Council Project Grant MR/J003794/1. Folate metabolism and development of neural tube defects. £757,565:|
|2011-2014||Foundation for the study of infant deaths (FSID) Proteomic identification of infection-related sudden unexpected infant death £100K|
|2010-2013||Parkinson’s UK Understanding pathological spread in Parkinson’s Disease £319,334.22|
|2011-2012||SPARKS ‘Prevention of neural tube defects by inositol PONTI’ £67,111|
|2010-2015||Equipment grant (Velos orbitrap MS and Xevo-TQS tandem mass spectrometer) £734,000|
|2010 - 2015||Cancer Research UK ‘Identification of protein (including cytokine, chemokine and growth factor) serum biomarkers for the early detection of pancreatic cancer’ £185K|
|2010 - 2013||Wellcome Trust. ‘Studies into the molecular causes of Crohn's disease and Ulcerative Colitis’ £935,000|
|2010||UCL CIF3 Equipment Grant: Electrospray Triple Quadruple Mass Spectrometer / Velos Orbitrap proteomics mass spectrometer £738,000|
|2008-2013||Genzyme Corporation. ‘Analysis of glycosphingolipids in patients undergoing enzyme replacement therapy’. £123K|
|2009-2012||Wellcome Trust. Fasting & protein sensitive hyperinsulinaemic hypoglycaemia due to SCHAD mutations: understanding novel mechanisms of fatty acids & amino acid induced insulin secretion. £173,081|
|2006-2009||Wellcome Trust. Pyridoxal phosphate and epilepsy £209,788|
|2008-2011||CHRAT, University College London. PhD student (A metabolomic and proteomic study of oxidative stress during stroke) £100,000|
Telephone number: 0207 905 2108
The aim of our research is to improve diagnosis and treatment for children with inherited metabolic disorders, primarily focusing on those disorders that cause neurological disease. The majority of these disorders occur because enzymes which convert metabolites into others or proteins that transport these chemicals around the body are missing or not working properly. Often this can lead to a build-up of metabolites in the body that are toxic to us. Sometimes it can cause a shortage of metabolites that are essential for our bodies to work efficiently. We use our knowledge of the metabolic biochemical pathways in parallel with next generation sequencing methodologies to facilitate identification of candidate genes in patients, mutations in which are then investigated further in model systems. Greater understanding of metabolic disorders will enable identification of more effective treatments for these life-threatening diseases. Characterisation of the biochemical and genetic basis of several metabolic disorders has enabled us to develop translational diagnostic tests that allow clinicians to diagnose patients more rapidly, facilitate better monitoring of treatment and enable pre-natal diagnosis. Many metabolic disorders are eminently treatable and if treated promptly can hopefully limit any irreversible damage that may occur. We collaborate closely with Prof. Peter Clayton and Prof. Paul Gissen at UCL Institute of Child Health and have close links with the paediatric neurology and metabolic teams at Great Ormond Street Hospital (GOSH) whilst working alongside the Chemical Pathology Department and the Clinical Genetics Service at GOSH to develop translational tests for patient diagnosis.
- Defining the genetic and biochemical basis of two of the vitamin B6-responsive epilepsies; pyridox(am)ine 5’-phosphate oxidase (PNPO) deficiency and pyridoxine-dependent epilepsy due to mutations in ALDH7A1 (PDE). Children with vitamin B6-dependent epilepsy disorders cannot control the amount of the active form of vitamin B6 (PLP) in their brain cells and have epileptic fits that do not respond to antiepileptic drugs but stop immediately if they are given large doses of vitamin B6. However, for a large number of patients whose epilepsy has showed some response to vitamin B6 treatment the cause of their epilepsy remains undetermined. Our investigation of these patients continues; hopefully we will be able to determine the pathophysiology of the epilepsy in these undiagnosed patients in the not too distant future.
Unfortunately, whilst B6-treatment of patients with PDE or PNPO deficiency is able to stop the seizures that they experience, the long term prognosis is wide. We are therefore also trying to understand the mechanism of how the cell regulates the availability of B6 in the cell and how the cell supplies sufficient PLP to the B6-dependent enzymes that require it so that we can ultimately provide better treatments for patients with B6-dependent epilepsy. Induced pluripotent stem cells (iPSCs) hold tremendous potential as tools to uncover pathophysiology of disease by creating relevant cell models. A collaborative project with Prof. Paul Gissen is investigating whether neurons differentiated from iPSCs derived from patients with B6-dependent/responsive epilepsy will recapitulate the in vivo phenotypes and will open new possibilities for the investigation of how the cell regulates the concentration of PLP and most importantly, will enable personalised medicine for patients with vitamin B6-dependent epilepsies.
- Identification of a new disease of abnormal manganese storage in liver and brain which causes liver damage and a parkinsonian-like movement disorder; caused by mutations in SLC30A10. Using yeast expression studies we have been able to demonstrate that in humans this solute carrier is involved in the transport of manganese. Currently we are establishing zebrafish models of manganese toxicity, in collaboration with Prof. Steve Wilson (UCL), in order to understand the pathways that lead to neurodegeneration and to identify effective treatments to prevent brain and liver disease in patients with acquired and inherited disorders of manganese accumulation. The approach that will be used to study the mechanisms of manganese toxicity will be transferable to any single gene disorder and will therefore facilitate our investigation of the basis of many other inborn errors of metabolism and enable treatment development.
Other areas of research include i) the congenital disorders of glycosylation for which we have been instrumental in the identification of three new inborn errors of glycosylation (MAN1B1 deficiency, Cog8 deficiency and Cog1 deficiency) including implementing a novel mass spectrometry based methods for the diagnosis of patients with congenital disorders of glycosylation Type II and ii) the discovery of a new inborn error of bile acid metabolism (Bile acid-CoA ligase deficiency).
Grants (last 5 years/current)
|Oct 2013||Development of a Liver Directed Gene Therapy for Patients with a rare Inherited Disorder of Protein Metabolism: Citrullinemia type I. Clinical Fellowship for Dr. Julien Baruteau – Secondary supervisor. £200,000|
|Sept 2013||Health and the understanding of metabolism, aging and nutrition (HUMAN) European Union SME Targetive collaborative project – Co-applicant 613,000 Euros|
|Dec 2012||Niemann-Pick C: Screening Tests and Markers of Disease Activity. Actelion – Co-applicant. £72,500.|
|Sept 2012||Investigation of manganese metabolism and treatment development for neurological childhood disorders associated with manganese accumulation using a zebrafish gene knockout model. Clinical Fellowship for Dr. Karin Tuschl – Primary supervisor. £200,000|
|Sept 2012||GOSH CC Leadership award. Inborn errors of metabolism, epilepsy, movement disorders. Personal salary for 9 months. PI. £43,494.|
|Nov 2012||Investigation of cellular and molecular pathology of neurometabolic disorders. UCL IMPACT award / GOSH CC (Metabolic Fund) – PI. £65,070.|
|May 2012||Innovative medicine initiative EU Consortium – Stem cells for biological assays of novel drugs and predictive toxicology (StemBANcc) - Co-applicant. 850,000 Euros|
|July 2011||Identification of children whose epilepsy can be controlled better by vitamin B6 than anti-epileptic drugs. GOSHCC Neuroscience grant - Co-applicant. £54,000.|
|Feb 2011||Vitamin B6 metabolism in neonates and effect of feeding method. GOSHCC - Co-applicant. £86,000.|
|June 2010||Measurement of S2-carboxylpropylcysteamine in urine and use in treatment of 3-hydroxyisobutyryl-CoA hydrolase deficiency. Co-applicant. £31,000.|
|March 2010||Investigation of genetic factors involved in manganese homeostasis. Academic training fellowship for Karin Tuschl. NIHR Biomedical Research Centre including £3,000 for consumables.|
|June 2009||Is pyridox(am)ine phosphate oxidase deficiency a common cause of epilepsy, infertility, miscarriage and premature birth? BRC Senior Postdoctoral personal fellowship post, NIHR. £104,612.|
|March 2009||Do inborn errors of Vitamin B6 metabolism cause autism and the neurological complications of coeliac disease? Fellowship for Dr. Emma Footitt (PhD Studentship). GOSH special trustees. £120,000.|
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