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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.
Diagnostic tests have been successfully developed for identification of the cause of erythrocytosis, particularly in patients with unexplained forms of this rare disease. A diagnostic service with worldwide reach was developed for the genetic characterisation of patients that carry mutations identified by the Queens's group. It deals with approximately 100 samples per year referred for investigation for this rare disease from the UK, Europe and further afield. Proper diagnosis helps in management of patients with erythrocytosis where the problem is not mutation in one of the familiar causative genes. A pan-European web-based database has been established to collect information on long-term outcomes to inform patient management.
Haemophilia, an inherited bleeding disease, is treated by frequent and extremely expensive infusions of recombinant versions of the missing factors. Advances in gene therapy have now been achieved at UCL, with successful treatment of Haemophilia B in 10 severely affected patients. The novel factor IX expression cassette has been patented and licensed to an industrial partner (UniQure). Savings to the NHS in excess of £1.5m have already been made and increase every month. Pre-clinical advances have also been made in Haemophilia A, and the factor VIII expression cassette has been patented and licensed to an industrial partner (BioMarin).
Impact on society (non-profit organisations) and public attitudes: The discovery of the reversibility of Rett syndrome in a mouse model for the disease has changed attitudes and awareness amongst families of sufferers and has led directly to the formation of two new charities: the Rett Syndrome Research Trust (US) and ReverseRett (UK).
Impact on health and welfare: Two new clinical interventions are being trialled with Rett syndrome patients.
Beneficiaries: Families living with Rett syndrome worldwide.
Significance and Reach: The research has given hope to thousands of families world-wide and has prompted an active philanthropic drive to fund research into a cure based on the UoE findings. The RSRT has raised $15 million since 2008. The incidence of Rett syndrome is 1 in 10,000 females. Some 16,000 individuals have Rett syndrome in the USA, and an estimated 2,400 in the UK.
Attribution: The research was carried out at UoE led by Adrian Bird. The critical underpinning paper was the UoE demonstration of reversibility (2007).
Research by Professor David Brook on inherited disorders has made a major contribution to the human genetics field. The work involved gene identification and mutation detection for genotype/phenotype correlation analysis in patients, which has led to the development of diagnostic tests for inherited conditions including myotonic dystrophy type 1 (DM1), Holt-Oram Syndrome (HOS), and campomelic dysplasia (CD). The tests have benefitted patients in the UK and throughout the rest of the world and in many cases they have been used as the definitive diagnostic measure. The assays developed have also been used in affected families for prenatal diagnosis to enable informed reproductive decisions.
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.
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 carried out by the University of Southampton into the genetic causes of diseases, and the gene mapping techniques and applications derived from this research, has benefited patients worldwide through improved prediction, diagnosis and treatment for common diseases with a complex genetic basis. A particularly striking example is age-related macular degeneration which is a common cause of blindness. Commercially, the research provides cost-effective strategies for genotyping DNA samples, and marker-based selection strategies for economically relevant animal species, such as cattle. The work underpins the development of the personal genomics industry, which specialises in individual genetic risk profiling.
King's College London (KCL) researchers have had a tremendous impact on furthering the understanding of how titin mutations lead to severe hereditary and spontaneous muscle diseases, which has ultimately improved clinical guidelines, genetic diagnosis and counselling of patients and their families. New genetic tests, driven by KCL research pinpointing how specific mutations adversely impact the normal interaction of titin with other proteins and lead to a loss of muscle function, have been adopted by public health agencies across Europe. Based on these original research insights, novel potential treatment targets continue to be discovered, and drugs aimed at these targets are currently being developed.
Research at the UCL Institute of Child Health (ICH) has led to the successful treatment of children with primary immunodeficiency diseases for whom there was little chance of "cure" by the only other possible means: haematopoietic stem cell transplantation (HSCT). Beginning in 2002, we have treated 32 patients with four different primary immunodeficiency disorders. In total we have treated 12 patients with severe combined immunodeficiency (SCID-X1), 13 patients with adenosine deaminase deficient severe combined immunodeficiency (ADA-SCID), 5 patients with chronic granulomatous disease (CGD) and 2 patients with Wiskott-Aldrich syndrome (WAS). Most of the patients have been successfully treated and are at home, off all therapy. We are now starting to develop this technology to treat a wider range of related disorders.