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Research undertaken by Professor Frances Ashcroft at the University of Oxford and her collaborators at the University of Exeter has led to several hundred neonatal diabetes (ND) patients worldwide being able to switch from daily insulin injections to oral sulphonylurea tablet therapy since 2008. ND is a rare but potentially devastating monogenic form of diabetes affecting about 1 in 150,000 live births. Sufferers were previously assumed to have type 1 diabetes and thus were treated with insulin injections; sulphonylurea treatment has transformed their quality of life and led to marked health improvements. It has also ameliorated the mental and motor developmental delay that affects about a fifth of ND patients.
The diagnosis and treatment of patients with Maturity Onset Diabetes of the Young (MODY) has been revolutionised by the research of Professors Andrew Hattersley (FRS) and Sian Ellard at Exeter. Prior to this research, up to 90% of patients with MODY were misdiagnosed as having type 1 or type 2 diabetes. To address this, the team developed new tests and integrated these into routine diagnosis. They showed that patients could be stratified to achieve delivery of the most appropriate therapy and, as a result, as many as 15000 patients worldwide have now gained a better quality of life.
Long-standing research led by Prof. O'Rahilly (Department of Clinical Biochemistry) into the genetic and biochemical basis of severe insulin resistance syndromes, has led to improvements in diagnosis and care of patients internationally. These advances have facilitated revision of existing clinical classifications and implementation of novel diagnostic and management algorithms for these conditions. The clinical applicability of this research was recognised in 2011 by the Department of Health-England who have commissioned a national severe insulin resistance service in Cambridge, with support totalling ~£450,000 per annum.
The University of Oxford's United Kingdom Prospective Diabetes Study (UKPDS) was a landmark 30-year clinical trial, reported in over 80 academic research papers between 1983 and 2008. It showed beyond doubt that diabetic complications, previously thought to be inevitable consequences of the condition, could be delayed or prevented by improved treatment from the time of diagnosis. These findings have had a profound influence on the management of type 2 diabetes, clinical guidelines, and standards of care, and have reduced diabetes-related complications worldwide, lowering the incidence of blindness, kidney failure, amputation, heart attack and stroke.
Research conducted at King's College London into the mechanisms underlying hypoglycaemia unawareness in type 1 diabetes mellitus (T1DM) and novel technology for reducing the risk of hypoglycaemia has led directly to innovative changes in the management of diabetes. These include UK and worldwide development and dissemination of the government-recommended `Dose Adjustment for Normal Eating' (DAFNE) programme and on-going development of continuous subcutaneous insulin infusion (pump) therapy, now used by over 18,500 people with T1DM in the UK.
Research led by Pardhan has enhanced the healthcare offered to diabetic patients of South Asian origin in the UK and overseas (Pakistan, East Africa). Prevalence of diabetes within this ethnic group is six times higher than in Caucasians. Our research into this group, which demonstrated an increased risk of sight-threatening eye disease and poor engagement with screening/treatment regimes, has impacted upon both patients and healthcare practitioners. Ophthalmologists, general practitioners and other clinicians have used our findings to target various physiological and cultural factors that influence diabetic control and eye health in the South Asian population.
Our research also provided the underpinning data that informed reports commissioned by the Royal National Institute of Blind People (RNIB). These reports demonstrate the increased prevalence of eye problems in patients of South Asian origin, and highlight the barriers that affect patients' access to primary and secondary eye-care across the UK. The reports evaluate the effectiveness of current management, and suggest strategies to improve the eye health of this group of patients.
These reports have led directly to the creation of dedicated community-based eye-care programmes. Funded by the Royal National Institute of Blind People (£400,000) and Innovation, Excellence and Strategic Development Fund (Department of Health), the programmes are designed to reduce diabetic-related complications through improved self care by patients in Bradford and Glasgow, regions that have significant Asian diabetic populations.
Understanding and finding treatments for rare disease represents a major challenge across medicine. We have shown this is possible for rare muscle channelopathies and our work has directly benefited the lives of patients. Our 15 year basic research programme has elucidated the genetic architecture and identified new disease mechanisms for these disabling muscle conditions. We also determined the true disease frequency through the only UK epidemiology study. We translated fundamental research into new DNA-based diagnostic testing and electrophysiological diagnostics for rapid and reliable diagnosis. Our research led directly to our centre being commissioned by the NHS (£6m) as the only UK centre for diagnosis and management and we established the UK NHS national genetics channelopathy reference laboratory. We have built the world's largest genetically stratified patient cohorts which allowed us to lead the first international randomised controlled trial. This trial showed clear efficacy of a reprofiled mexiletine. This led to a successful European orphan product status application for this indication and national treatment guidelines.
Congenital myasthenic syndromes (CMS) are inherited neuromuscular disorders caused by defects at neuromuscular junctions, which are often a result of acetylcholine receptor gene mutations. A subset of CMS patients (around 14% in the US and Europe) have limb-girdle myasthenia (LGM). This disease can be highly disabling with symptoms including increasing weakness of skeletal muscles. As a result of collaborative work between Newcastle and Oxford, it was determined that many LGM patients have a mutation of the Dok-7 gene (unrelated to the acetylholine receptor), and do not, therefore, respond to standard CMS treatments. Since then, a number of additional mutations have been discovered, and genetic testing is now available for the majority of known LGM-causative genes. Crucially, Dok-7 patients, and those with other non-receptor related mutations, can now be diagnosed accurately and treated effectively, with ephedrine and salbutamol (in the US, albuterol). This significantly improves these patients' quality of life by enabling them to walk and breathe unassisted.
Ataxia telangiectasia (A-T) is an inherited disease affecting multiple systems in the body, causing severe disability and death. Work led by Professor Malcolm Taylor at the University of Birmingham has been central to the biological and clinical understanding of this disease, from the identification of the gene responsible to the clarification of related conditions with different underlying causes. As a result of this work, within the 2008-13 period, his laboratory has been designated the national laboratory for clinical diagnosis of A-T — a service also offered internationally — and has also changed national screening policy for breast cancer, following his confirmation of the increased risks of A-T patients and those who carry a single copy of the gene for this type of tumour. Furthermore, he has contributed in a major way to patient support for this condition.
Research conducted by Professor Tim Goodship and co-workers at Newcastle has had a profound effect on the prognosis for patients with atypical haemolytic uraemic syndrome (aHUS). By engaging in research on the genetic factors underlying the disease they developed an understanding of the molecular mechanisms responsible. Identifying that the majority of patients with aHUS have either acquired or inherited abnormalities of the regulation of complement (part of the immune system) led to the establishment of a UK national service for genetic screening and treatment with the complement inhibitor eculizumab. As eculizumab is now available to patients in England, the progression to end-stage renal failure can be prevented and patients already on dialysis will soon be successfully transplanted.