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Genetic research at King's College London (KCL) has had significant impact on the current and future care of people with motor neurone disease (MND). KCL researchers discovered several MND-causing genes, which have been taken up by diagnostic and research laboratories throughout the world. This has improved early diagnosis and predictive gene testing in high-risk families and enabled children to be born free of MND by pre-implantation genetic diagnosis. Research laboratories in academia and industry have used mutant genes in cellular and animal models to identify fundamental disease mechanisms and disease-critical pathways to advance drug discovery for this fatal disease.
Limb-girdle muscular dystrophy type 2A is a rare (about six cases per million individuals) and incurable muscular disorder with a genetic basis. Although diagnosis is a multi-step process, which includes symptom assessment and histopathology of affected muscle, it invariably involves measurement of the amount of protein calpain 3 in muscle biopsy samples. This is performed in diagnostic laboratories worldwide using the two monoclonal antibodies CALP-12A2 and CALP-2C4, which were developed by researchers at Newcastle University in the late 1990s. In 2009 Newcastle University signed a licensing agreement with the international bioscience company Leica Biosystems that currently sells the antibodies to institutions worldwide.
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.
Research at the UCL School of Pharmacy has positively influenced healthcare in startle disease/hyperekplexia, a rare disease that affects humans and several animal species, including dogs, horses and cattle. The identification and functional characterisation of mutations in genes involved in human startle disease by researchers at the School has improved genetic diagnostics and patient care. Our research on startle disease in cattle and dogs has also led to new non- invasive diagnostic tests that have alleviated animal suffering and reduced negative economic impacts on farmers. Overall, our findings have been translated into tangible benefits for the human and animal populations affected by this disease and have changed the way in which the disease is diagnosed and treated. We have also significantly increased the awareness of this rare disorder by communicating with academics, healthcare and veterinary professionals, and the general public.
King's College London (KCL) has developed a generic test format which is being used to cheaply and easily detect a large number of single-gene disorders and chromosomal abnormalities in in vitro fertilised embryos — a highly significant impact. The test resulted from KCL's research to develop new strategies for preimplantation genetic diagnosis (PGD), which involved developing a small number of DNA probes targeted around a known area of genetic risk to identify mutations as well as methods to detect chromosomal translocations. Because the approach is cheap and easy to apply, it is being used by IVF clinics worldwide as well as by the NHS. The KCL/Guy's and St Thomas' Centre for PGD was licensed in 2008 by the UK Human Fertilisation and Embryo Authority to analyse over 50 genetic conditions affecting single genes and carries out more than half of all the UK's PGD testing. Embryos can now be tested using these techniques for virtually any inherited genetic disease prior to implantation with a 98% success rate, thus reducing the need for later prenatal diagnosis and termination of an affected foetus.
Professor Dickson's research group at Royal Holloway has pioneered the enabling technologies for the development of genetic therapies for the incurable disease Duchenne Muscular Dystrophy (DMD). Dickson's group has, (i) cloned replacement copies of the normal DMD gene, (ii) identified a natural substitute for the defective gene, and (iii) demonstrated that synthetic DNA can be used to correct the defective gene. The work has created impact on health and welfare through the development and clinical trials of a series of investigational medicinal products for this hitherto incurable disease, several clinical trials, and impact on commerce through industrial investment and licensed patents.
Acute promyelocytic leukaemia (APL) is of interest because it is the first cancer that can be cured with drugs that target a unique molecular abnormality. KCL research has developed accurate molecular techniques which are essential to diagnose the disease, guide treatment, and monitor for relapse. Sub-microscopic levels of leukaemic cells remaining in the patient's bone marrow after treatment (referred to as `minimal residual disease') give an early warning of re-occurrence of the disease. Our laboratory has developed sensitive tests for these cells, allowing treatment to be tailored to individual patient needs. This has had a major impact on APL diagnosis and monitoring and has been incorporated in national and international disease-treatment guidelines.
Research at the UCL Institute of Ophthalmology over the last 20 years has resulted in the identification of a large number of novel genes that cause inherited retinal disease. These genes have been incorporated into diagnostic tests, which have allowed molecular diagnosis, improved genetic counselling including pre-natal/pre-implantation diagnosis, better information about prognosis and have informed decisions about which diseases should be prioritised for clinical trials of novel treatments. The identification of these genes has greatly improved understanding of disease mechanisms, an essential prerequisite for developing new treatment approaches such as gene therapy.
Very considerable changes worldwide, in the management of patients with chronic obstructive pulmonary disease (COPD) admitted with acute ventilatory failure, have been a major impact of the research of the King's College London (KCL) Clinical Respiratory Physiology Group. Previously, invasive ventilation to treat such COPD patients was associated with complications which could be fatal. The KCL group conducted the first randomised controlled trial in the world of treatment by non-invasive ventilation (NIV). The trial demonstrated that NIV reduces complications and death compared to invasive ventilation. The study dramatically changed the treatment of hypercapnic flare-ups (where there is too much carbon dioxide in the blood) of acute COPD worldwide. NIV has become best and routine practice, and is advocated in national and international guidelines, benefiting many thousands of COPD patients.
Over the past decade our research findings have impacted on the diagnosis and treatment of patients with inherited cardiomyopathies. Our work on risk stratification in patients with hypertrophic cardiomyopathy forms the basis for international guidelines on the use of implantable cardioverter defibrillators. Our research in patients with arrhythmogenic right ventricular cardiomyopathy has led to the development of a new international standard for the diagnosis of disease in patients and relatives. We have contributed to national and European guidelines on genetic testing in these conditions. We have also been influential in changing national policies, service design, and provision of care for inherited heart muscle disease.