Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

The Oxford Rare Disease Initiative is a network of more than 250 researchers and clinicians from the University of Oxford and the Oxford University Hospitals Trust. Together the researchers and clinicians work on over 350 rare diseases, from a wide range of disease areas.

If you would like more information about our research please contact us at OxfordRareDiseases@medsci.ox.ac.uk

Examples of our research:

 Professor Dame Kay Davies

Professor Dame Kay DaviesDr Lee’s Professor of Anatomy
Associate Head, Medical Sciences Division
Founder Member, Oxford Centre for Translational Neuromuscular Science
Chair, Oxford Rare Disease Initiative
Department of Physiology, Anatomy and Genetics
 
Professor Dame Kay Davies is the Dr Lee's Professor of Anatomy in the Department of Physiology, Anatomy and Genetics and Director of the MRC Functional Genomics Unit at the University of Oxford.  She has worked on the molecular analysis and development of treatment for Duchenne muscular dystrophy (DMD) for more than 25 years.  She is co-founder of a company to deliver utrophin modulation to the clinic for DMD which currently has a drug in Phase 1 trials. She has published more than 400 papers and won numerous awards for her work.  She is a founding fellow of the UK Academy of Medical Sciences and was elected a Fellow of the Royal Society in 2003.  She has been a Governor of the Wellcome Trust since 2008 and became Deputy Chairman in October, 2013.  She was made Dame Commander of the British Empire for services to science in 2008.

Professor Matthew Wood

Professor Matthew WoodProfessor of Neuroscience
Department of Physiology, Anatomy and Genetics
 
Professor Matthew Wood graduated in Medicine from the University of Cape Town, working in clinical neuroscience before gaining a doctorate in Physiological Sciences from the University of Oxford.  He is currently Professor of Neuroscience at the University of Oxford and Fellow and Tutor in Medicine at Somerville College, Oxford. The main focus of research in his laboratory is the study of RNA biology and the development of RNA-based therapy for degenerative disorders of the nervous system and muscle.
 
He is currently co-PI of the International MDEX Consortium, a leading international translational medicine network, which is developing RNA-based therapies for neuromuscular diseases such as Duchenne muscular dystrophy.
 
He is also an investigator of the Oxford Parkinson’s Disease Centre (opdc.medsci.ox.ac.uk) and the Oxford Stem Cell Institute (www.stemcells.ox.ac.uk) and is co-leading a large EU IMI initiative to investigate and develop new methods for drug delivery to the brain. 

Professor Frances Platt

Professor Frances PlattProfessor of Biochemistry and Pharmacology
Department of Pharmacology
 
Our primary interest is in glycosphingolipid lysosomal storage diseases, both in terms of pathophysiology and treatment. For examples, our research led to the development of miglustat for the treatment of glycosphingolipid storage diseases. We currently work on several lysosomal disorders including Gaucher, Tay-Sachs, Sandhoff, Fabry and a major focus on Niemann-Pick type C disease. In addition we are discovering links between rare lysosomal disorders and more common human diseases. These studies shed light on fundamental cell biology relating to the lysosome and identify shared clinical intervention points between rare and common diseases. Our current activities focus in four main areas of research:
  • Lysosomal storage disorders, pathogenesis and therapy
  • The effects of lysosomal storage on the immune system
  • Development of biomarkers for monitoring storage disease patients
  • Lysosomal dysfunction in more common diseases

Professor Kevin Talbot

Professor Kevin TalbotProfessor of Motor Neuron Biology
Nuffield Department of Clinical Neurosciences
 
Kevin Talbot is Professor of Motor Neuron Biology at the University of Oxford in the Nuffield Department of Clinical Neurosciences. He directs the Oxford MND Care and Research Centre at the John Radcliffe Hospital which is an internationally recognised centre for diagnosis, management and research into amyotrophic lateral sclerosis and other motor neuron diseases.
 
His research aims to identify the earliest pathological pathways in motor neuron degeneration to define the best targets for drug therapy. Development of novel models of ALS, based on mutations in the genes TDP-43 and FUS is coupled with a complementary program of primary motor neuron cultures derived from induced pluripotent stem cells. The Oxford Centre has a large biomarker program using brain imaging and biochemical analysis. The two programs are complementary and together have the potential to reveal the early events in the development of motor neuron degeneration.

Professor Angela Vincent

Professor Angela VincentProfessor of Neuroimmunology
Nuffield Department of Clinical Neurosciences
 
The Vincent Neuroimmunology group has worked on autoimmune forms of rare neurological diseases since they came to oxford in 1988. Originally, defining new antibodies to targets at the neuromuscular junction that caused myasthenia gravis, the Lambert Eaton myasthenic syndrome and neuromyotonia, much of their recent work has been to define antibodies to central nervous system proteins, such as the potassium channel associated proteins LGI1 and CASPR2, and Glycine receptors, in patients with very rare but severe and treatable disorders. They have also recently demonstrated the importance of antibodies to myelin-oligodrendocyte glycoprotein MOG in patients with acute onset of optic neuritis or spinal cord demyelination. The group also has a particular interest in the possible role of these or other antibodies in patients with psychiatric disorders or seizures and in healthy mothers whose children develop developmental disorders such as autism or schizophrenia which might be caused by placental transfer of maternal antibodies during development. These and other antibodies, discovered by major centres in USA and Spain, are measured routinely for patient diagnosis so that the clinical features and treatment responses can be accurately described.

Professor Hugh Watkins

Professor Hugh WatkinsProfessor of Cardiovascular Medicine
Radcliffe Department of Medicine
 
Hugh Watkins has made a series of contributions to the understanding of the genetic basis of inherited cardiac diseases, and has used these advances to pioneer new approaches to diagnosis and therapy with substantial impact on human health. His work on hypertrophic cardiomyopathy, the most common and clinically important Mendelian cardiac disorder, provided a paradigm for the field and has changed practice worldwide. HCM is a major clinical problem as it affects 1 in 500 of the population and is the commonest cause of sudden death in young adults. Building on the discovery that this previously ‘idiopathic’ heart muscle disorder is caused by mutations in diverse myofilament proteins he recognised the potential impact this could have and went on to develop direct genetic testing and to show its clinical utility for identifying individuals at risk. Indeed genetic testing is now considered the first line approach for managing families affected by this disorder, with a Class I indication in new European guidelines. In functional studies his group demonstrated that the mutant myofilament proteins increase calcium-sensitivity and the energy cost of force production. These findings highlighted novel aspects of muscle physiology and cardiac energetics, opening the way to new approaches to therapy which are now undergoing clinical trial.

Professor Peter Robbins

Professor Peter RobbinsProfessor of Physiology and Head of Department
Department of Physiology, Anatomy and Genetics
 
Peter Robbins studied medicine at the University of Oxford. He gained a DPhil in Physiology in 1981 and qualified in Clinical Medicine in 1984. He joined the academic staff of the Department of Physiology, Anatomy & Genetics in 1985 (which at the time was the University Laboratory of Physiology), where he has remained ever since. He became Head of Department in 2011. His particular interest is in integrated systems responses of humans, particularly in relation to hypoxia and, more recently, their variations with iron status. Iron and oxygen are intimately linked at molecular, cellular and integrative levels. Peter Robbins’ interests in rare diseases relate to those that affect hypoxia signalling pathways. Such diseases tend to be first diagnosed through an elevated haemoglobin concentration – arising through excessive erythrocytosis – that is detected on routine blood testing. Thus, these diseases are all associated with upregulation of the hypoxia-sensing pathways. While no diseases that downregulate these pathways are known, he has shown that a high-altitude population, the Tibetans, has undergone natural selection in favour of a reduction in sensitivity of these pathways. Erythrocytosis may be congenital or acquired. It may be primary, where the intrinsic defect is in the bone marrow, or secondary, where the erythrocytosis is driven through increased levels of the hormone, erythropoietin (EPO). Diseases relating to hypoxia signalling are typically associated with EPO levels that are inappropriately normal or high, and are thus classed as secondary. Although a patient’s initial presentation is often through an abnormally elevated haemoglobin, hypoxia sensing pathways impinge on many systems. For example, patients with certain defects run a very high risk of thrombotic events as early adults. We have particularly studied patients with Chuvash Polycythemia, which is a recessive disorder resulting in hypomorphic alleles for the von Hippel Lindau tumour suppressor protein, VHL. Their hypomorphic nature slows the degradation of the transcription factor, hypoxia inducible factor (HIF). We have demonstrated that these patients are abnormally sensitive to acute hypoxia, with very marked increases arising in pulmonary ventilation and pulmonary arterial pressure with acute hypoxia. We have also shown their skeletal muscle metabolism is abnormally glycolytic, with excessive lactic acid production and acidosis which significantly limits exercise capacity. More recently, we have been working in concert with a number of clinicians in the UK and Europe who hold registries of patients with undiagnosed forms of secondary erythrocytosis to increase our abilities to provide a molecular diagnosis. In the summary paper for the WGS500 consortium, we report a new mutation in BPGM that was detected through whole genome sequencing. In collaboration with investigators in the Nuffield Department of Medicine and in the Wellcome Trust Centre for Human Genetics, we are now working on improving the diagnostic pathway using an ultra-high multiplex PCR method to allow rapid and high-throughput sequencing of candidate genes in a custom-designed panel.

Professor Georg Hollander

Georg HollanderAction Research Professor of Paediatrics
Radcliffe Department of Medicine
Weatherall Institute of Molecular Medicine
 
The thymus provides the physiological microenvironment for the development of T lymphocytes and is therefore crucial for the immune system's ability to distinguish between vital self and injurious non-self. Essential for this competence are thymic epithelial cells (TEC), which classify into separate cortical (c) and medullary (m) lineages with specific molecular, structural and functional characteristics. cTEC attract blood-borne precursor cells, commit them to a T cell fate and foster their differentiation to a developmental stage at which individual immature T cells (designated thymocytes) express the T cell antigen receptor (TCR). Because the TCR specificity is generated pseudo-randomly during thymocyte development, its utility for a given individual will need to be assessed. cTEC positively select thymocytes that express a TCR with intermediate affinity for the peptide/MHC complexes and thus ensure their further survival and maturation. In contrast, mTEC - in collaboration with dendritic and other hematopoietic cells situated in the thymic medulla - mediate negative selection through apoptosis, thus removing thymocytes that recognize self-antigens with high affinity. The selection of thymocytes by both cTEC and mTEC depends on their collective ability to promiscuously express transcripts encoding almost all ubiquitously and tissue-restricted proteins thus enabling these cells to instruct a functional yet self-tolerant T cell repertoire.
 
Primary disorders affecting the differentiation and function of TEC are very rare (with the notable exception of the 22q11 deletion syndrome (22q11DS), which has an estimated incidence of one in 4000 births and a wide phenotypic spectrum that results only in 1% of all affected individuals in athymia). A few genetic disorders have been identified for other forms of thymic stromal defects resulting in a lack of regular TEC development and function. However, the precise molecular causes for at least a third of all clinical presentations of severe congenital thymus stromal defects, presenting typically as severe thymus hypoplasia or athymia with a decreased formation or complete absence of T cells, respectively, remain presently unknown. The Laboratory for Developmental Immunology (Weatherall Institute for Molecular Medicine and Department of Paediatrics) focuses its research on the genetic circuits and epigenetic influences that control regular TEC differentiation and function in humans and experimental animal models. For the work on human thymus developmental defects, we have established an exclusive cohort of severe T cell deficient patients in which all known molecular causes of T and thymic epithelial cell deficiencies have been excluded. This cohort provides a unique opportunity to identify the molecular cause of novel TEC defects (as “experiments of nature”) and gain, with the help of experimental model systems, a mechanistic insight into the genetic control of thymus organogenesis and function.

Professor Vincenzo Cerundolo

Professor Vincenzo CerundoloProfessor of Immunology
Radcliffe Department of Medicine
MRC Human Immunology Unit
 
Vincenzo Cerundolo’s group is currently undertaking a series of experiments aimed at measuring the frequency of 21-hydroxylase specific T cells in a large cohort of patients with Addison’s disease with the aim of identifying, using overlapping 18aa peptides spanning the full length of 21-hydroxylase, immunodominant CD8+ and CD4+ T cell responses in Addison’s patients both ex-vivo and after in-vitro culture of peripheral blood lymphocytes. The group subsequently hopes to extend these results by assessing the potential of 21-OH specific T cell responses to be used against tumours derived from adrenal cortex, including adrenocortical carcinoma (ACC).
 
The results obtained should prove to be very informative to assess the potential diagnostic and therapeutic value of eliciting 21-OH specific T cell responses in patients with adrenal cortex cancer. These findings may pave the way towards the development of 21-OH vaccines to be used in phase I clinical trials in patients with adrenal cortex cancer in the presence or absence of immune check point inhibitors.

Professor Douglas Higgs

Professor Douglas HiggsProfessor of Molecular Haematology
Radcliffe Department of Medicine
MRC Weatherall Institute of Molecular Medicine
 
Rare Disorders of Red Blood Cells
Red blood cells are required to transport oxygen to the tissues. They do this via the specialised red cell pigment haemoglobin which is composed of two subunits called alpha globin and beta globin. Understanding the molecular basis for both common and rare disorders of the red cell lies at the heart of our research. These diseases may perturb the formation and maturation of red cell precursors in the bone marrow (e.g. Congenital Dyserythropoetic Anaemia, Diamond Blackfan Anaemia) or synthesis of the globin chains (causing thalassaemia). Alternatively, they may result from defects in the red cell membrane or abnormalities of the energy supply to the red cell, both of which cause premature destruction of the red cell (called haemolytic anaemia). Understanding the mechanisms underlying these rare diseases enables us to provide accurate diagnosis and improved treatment for many affected families. In addition, these rare diseases have illustrated many of the general principles by which human genetic diseases arise. In particular we have identified mutations involving the key cis-elements regulating gene expression (Promoters, enhancers, silencers and boundary elements). In addition we have identified mutations in trans-acting mutations in important classes of proteins that regulate gene expression (e.g. GATA1, TFIIH) including the first example of mutations in a protein (called ATRX) which controls how DNA is packaged into chromatin in the cell’s nucleus. Mutations in this class of protein are now recognized as a common cause of human disease. We identify patients with rare diseases via the Oxford Haematology Clinic for Red Cell disorders and are grateful for the help of our patients in this research. By studying rare families with inherited diseases we have shown that the principles learnt from such studies also reveal how similar mutations, acquired during life can cause or contribute to very common human diseases including cancer.

Professor Ashley Grossman

Professor Ashley GrossmanProfessor of Endocrinology
Radcliffe Department of Medicine
Oxford Centre for Diabetes, Endocrinology & Metabolism
 
I am Head of the Department of Endocrinology at the Oxford Centre for Diabetes, Endocrinology and Metabolism, having formerly worked at Barts and the London School of Medicine for many years, and am a fellow of Green-Templeton college. In 2014 I was awarded the Geoffrey Harris prize in neuroendocrinology from the European Society of Endocrinology. The main research interests of my Department are in the general area of endocrine oncology, on the epidemiology, diagnosis and management of complex tumours of the hypothalamus and pituitary, and of neuroendocrine and adrenal tumours. While each individually are rare tumours, when summed they represent a considerable burden of human disease.
 
In terms of laboratory research, in collaboration with the department of neuropathology we have been exploring the molecular pathogenesis of the principal hypothalamic tumour, the craniopharyngioma, and growth-hormone secreting tumours – somatotroph tumours - causing the syndrome of gigantism in children and acromegaly in adults. For craniopharyngiomas, we have established that somatic mutations of β-catenin represent the dominant oncogenic transformation in the more common adamantinomatous craniopharyngioma, while the signalling kinase BRAF is mutated in the rare papillary craniopharyngioma: this latter change may represent a novel ‘druggable’ target. For somatotroph tumours, we are currently carrying out a whole-exome sequencing study to identify key oncogenes and tumour suppressor genes not so far identified in germline disease. This too should allow for the introduction of novel therapeutic strategies.
 
Malignant phaeochromocytomas are very rare but rarely treatable in an effective manner. In cell line studies we have shown that combinations of targeted agents against key signaling pathways have a synergistic effect in controlling cell growth, and we are currently extending this work to other types of neuroendocrine tumour.

On this page