'Goldilocks' gene used to find drug treatment that is 'just right' for TB patients
One of first examples of using personalised medicine for an infectious disease
Tuberculosis patients may soon receive treatments specially tailored to their DNA, an international research team from Oxford University, King's College London, Vietnam and the U.S. has revealed.
The idea of personalised medicine is already becoming familiar in the treatment of cancer. But this would be one of the first times where an individual's genetic profile can determine which drug will work best for them for an infectious disease.
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.
Goldilocks effect: A scientists checks the results of a DNA test, as research reveals that people generate an immune response to tuberculosis according to what versions they have of the LTA4H gene (file photo)
This indicates 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 per cent of cases involve disease elsewhere. In perhaps 1 per cent 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.
An X-ray of a human chest showing pulmonary tuberculosis. Most TB affects the lungs, but around 40 per cent of cases involve disease elsewhere
The new study combines work on
zebrafish at the University of Washington, 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.
scientists identified a gene in zebrafish associated with
susceptibility to tuberculosis, which controlled the balance of the
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.
'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”'
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.
Dr Sarah Dunstan, Head of Human Genetics at Oxford University Vietnam, said: '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”.'
She added: '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.
Professor Jeremy Farrar, who leads the Oxford University Clinical Research Unit in Vietnam, said: '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.'