This is one of the first examples of how an individual’s genetic profile can determine which drug will work best for them against an infectious disease – the idea of personalised medicine that is gradually becoming familiar in cancer medicine.
In a study published in the journal ‘Cell’, scientists from Oxford University, King’s College London, Vietnam and the USA found that people generate an immune response to TB that is ‘too much’, ‘too little’ or ‘just right’, according to the versions of the LTA4H gene they have. 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 TB, tuberculous meningitis, only benefit some patients. TB 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 four in ten cases involve disease elsewhere. In around one or two in every hundred cases, TB affects the brain, and this form of the disease – tuberculous meningitis – is the most serious. It is hard to diagnose and treat, and even with treatment, it is often fatal.
The standard treatment for tuberculous meningitis involves a range of antibiotics to try to kill the bacteria and the steroid dexamethasone to dampen inflammation. Inflammation, the body’s response to tuberculosis infection, can be a serious 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, part of the Wellcome Trust’s South-east Asia Programme.
The scientists identified a gene in zebrafish associated with susceptibility to TB, 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. They 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 tuberculous 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.
Dr Sarah Dunstan, Head of Human Genetics at Oxford University’s Vietnam unit explains: “It’s like a ‘Goldilocks’ gene. Depending on what versions of the LTA4H gene you have inherited, you could see an inflammatory response to TB that is ‘too much’, ‘too little’, or ‘just right’. You are likely to benefit most from a treatment tailored to your own genes.”
Dr Guy Thwaites of King’s College London, who led 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 tuberculous meningitis, or other forms of TB. Since the inflammation pathways governed by the LTA4H gene are central to many infections, there could be implications for many diseases.”
Professor Jeremy Farrar, Director of the Wellcome Trust’s Vietnam Research Programme and Oxford University Clinical Research Unit, adds: “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 TB in the future.
“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.”
Image: A photomicrograph of Mycobacterium tuberculosis. Credit: Wellcome Images.
Tobin D et al. Host genotype-specific therapies can optimise the inflammatory response to mycobacterial infections. Cell 2012 (epub ahead of print).