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Contact: Katherine Barnes
katherine.barnes@kcl.ac.uk
44-020-784-83076
King's College London

'Goldilocks' gene could determine best treatment for TB patients

Tuberculosis patients may receive treatments in the future according to what version they have of a single 'Goldilocks' gene

'Goldilocks' gene could determine best treatment for TB patients Tuberculosis patients may receive treatments in the future according to what version they have of a single 'Goldilocks' gene, says an international research team from Oxford University, King's College London, Vietnam and the USA.

This is one of the first examples in infectious disease of where an individual's genetic profile can determine which drug will work best for them the idea of personalised medicine that is gradually becoming familiar in cancer medicine.

The scientists found that people generate an immune response to tuberculosis that is 'too much', 'too little' or 'just right', according to what versions they have of the LTA4H gene.

The findings indicate that patients are likely to benefit from different drug treatments depending on their LTA4H gene profile.

Furthermore, the researchers show that steroids used as part of the standard treatment for the most severe form of tuberculosis, TB meningitis, only benefit some patients.

The results of the study, part-funded by the Wellcome Trust, are published in the journal Cell.

Tuberculosis is a major cause of death worldwide, with an estimated 9.4 million cases and 1.7 million deaths in 2009. The disease is caused by Mycobacterium tuberculosis bacteria and differs according to where the infection takes hold. Most TB affects the lungs, but around 40% of cases involve disease elsewhere. In perhaps 1% of cases, TB affects the brain. This form of the disease, TB meningitis, is the most serious. It is hard to diagnose and treat, and even with treatment it is often fatal.

The standard treatment for TB meningitis involves a range of antibiotics to try and kill the bacteria, and the steroid dexamethasone to dampen inflammation the body's response to tuberculosis infection that can be almost as much of a problem.

The new study combines work in zebrafish at the University of Washington, Seattle to identify genes and biological pathways involved in the immune response to TB, with clinical research work in collaboration with Pham Ngoc Thach Hospital, the Hospital for Tropical Diseases and the Oxford University Clinical Research Unit in Vietnam.

The scientists identified a gene in zebrafish associated with susceptibility to tuberculosis, which controlled the balance of the inflammatory response. Variations in the DNA code in this gene could alter different biological pathways, leading either to too much inflammation or too little. Both too much and too little inflammation were problems, allowing the tuberculosis bacteria to thrive and multiply.

The researchers showed that blocking the appropriate biological pathway with drugs could restore just the right level of inflammatory response.

The researchers based in Vietnam then went back to samples from a previous clinical trial in over 500 patients with TB meningitis. They showed changes at a single position in the human LTA4H gene were associated with treatment response.

Only those having LTA4H genes that led to too much inflammation benefitted from the use of the steroid dexamethasone.

There is some suggestion that the steroid could have an adverse effect for those whose LTA4H genes already lead them to have a reduced inflammatory response, though the result is not statistically significant.

'It's like a "Goldilocks" gene. Depending on what versions of the LTA4H gene you have inherited, you could see an inflammatory response to tuberculosis that is "too much", "too little", or "just right",' explains Dr Sarah Dunstan Head of Human Genetics of Oxford University Vietnam. 'You are likely to benefit most from a treatment tailored to your own genes.'

Dr Guy Thwaites of King's College London and who lead the clinical study in Vietnam on a Wellcome Trust Fellowship says: 'This is a fundamental discovery. It is now possible to think about the use of simple but rapid genetic tests to determine how people will respond to tuberculosis infection and whether they would benefit from steroids.'

'The findings could apply much more widely than just in TB meningitis, or other forms of tuberculosis,' adds Dr Thwaites. 'Since the inflammation pathways governed by the LTA4H gene are central to many infections, there could be implications for many diseases.'

'This study highlights the power of really good clinical research supported through Wellcome Trust Fellowships and linked with some of the very best scientists in the world in Vietnam and the USA, which can bring immediate benefits to patients and also point the way to develop better, more targeted drugs to treat people with tuberculosis in the future,' says Professor Jeremy Farrar who leads the Oxford University Clinical Research Unit in Vietnam. 'The idea that a patient's genes can determine what treatment they will benefit from is pretty novel outside of cancer. Nothing like this has been seen before in infectious disease. Now we need to see if we can use this to help patients with this devastating disease'

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For more information please contact:

Dr Sarah Dunstan of the Oxford University Clinical Research Unit in Vietnam on: 84-90-810-7807 or sdunstan@oucru.org

Dr Guy Thwaites of King's College London on: 07818-040689 or guy.thwaites@btinternet.com

Professor Jeremy Farrar of the Oxford University Clinical Research Unit in Vietnam on: 84-83-836-2225 or jfarrar@oucru.org

Or the University of Oxford press office on 44-1865-280530 or press.office@admin.ox.ac.uk

Notes to Editors

* The paper 'Host genotype-specific therapies can optimise the inflammatory response to mycobacterial infections' by David Tobin and colleagues is to be published in the journal Cell with the embargo of 17:00 UK time / 12:00 noon US Eastern time on Thursday 2 February 2012.

* The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. It supports the brightest minds in biomedical research and the medical humanities. The Trust's breadth of support includes public engagement, education and the application of research to improve health. It is independent of both political and commercial interests. http://www.wellcome.ac.uk

* King's College London is one of the top 30 universities in the world (2011/12 QS World University Rankings), and the fourth oldest in England. A research-led university based in the heart of London, King's has nearly 23,500 students (of whom more than 9,000 are graduate students) from nearly 140 countries, and some 6,000 employees. King's is in the second phase of a 1 billion redevelopment programme which is transforming its estate.

King's has an outstanding reputation for providing world-class teaching and cutting-edge research. In the 2008 Research Assessment Exercise for British universities, 23 departments were ranked in the top quartile of British universities; over half of our academic staff work in departments that are in the top 10 per cent in the UK in their field and can thus be classed as world leading. The College is in the top seven UK universities for research earnings and has an overall annual income of nearly 450 million.

King's has a particularly distinguished reputation in the humanities, law, the sciences (including a wide range of health areas such as psychiatry, medicine, nursing and dentistry) and social sciences including international affairs. It has played a major role in many of the advances that have shaped modern life, such as the discovery of the structure of DNA and research that led to the development of radio, television, mobile phones and radar. It is the largest centre for the education of healthcare professionals in Europe; no university has more Medical Research Council Centres.

King's College London and Guy's and St Thomas', King's College Hospital and South London and Maudsley NHS Foundation Trusts are part of King's Health Partners. King's Health Partners Academic Health Sciences Centre (AHSC) is a pioneering global collaboration between one of the world's leading research-led universities and three of London's most successful NHS Foundation Trusts, including leading teaching hospitals and comprehensive mental health services. For more information, visit: http://www.kingshealthpartners.org.

* Oxford University's Medical Sciences Division is one of the largest biomedical research centres in Europe, with over 2,500 people involved in research and more than 2,800 students. The University is rated the best in the world for medicine, and it is home to the UK's top-ranked medical school.

From the genetic and molecular basis of disease to the latest advances in neuroscience, Oxford is at the forefront of medical research. It has one of the largest clinical trial portfolios in the UK and great expertise in taking discoveries from the lab into the clinic. Partnerships with the local NHS Trusts enable patients to benefit from close links between medical research and healthcare delivery.

A great strength of Oxford medicine is its long-standing network of clinical research units in Asia and Africa, enabling world-leading research on the most pressing global health challenges such as malaria, TB, HIV/AIDS, Dengue and Influenza. Oxford is also renowned for its large-scale studies which examine the role of factors such as smoking, alcohol and diet on cancer, heart disease and other conditions.



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