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Why the drugs don't work: gene fault explains multiple sclerosis treatment failure

23 July 2012
Appeared in BioNews 666

A genetic variation could explain why a previously promising class of drugs does not work as treatment for multiple sclerosis (MS), despite being used successfully in other autoimmune diseases.

The drugs, known as anti-TNFs - they inhibit the action of a chemical in the body called tumour necrosis factor (TNF) - are an established therapy for patients with inflammatory bowel disease and rheumatoid arthritis.

But a study carried out ten years ago showed that anti-TNFs can in fact worsen symptoms of MS. At the time, the reasons for this were unknown. Some experts suggested the drugs could even trigger the disease in those predisposed to the condition.

In the current study, the team from Oxford University investigated a genetic variant found in a gene already associated with a risk of developing MS.

The gene encodes TNF receptor 1 protein. Normally, this protein sits within a cell's membrane, where it senses TNF circulating outside the cell. Its activation starts a cascade that can lead to inflammation and cell death.

However, researchers found that the variant produces a shortened version of the protein, which is released outside of the cell, instead of anchoring to its membrane. It then 'mops up' TNF molecules, preventing them from signalling to cells and effectively performing the same process as anti-TNF drugs.

'Whilst [this] gene variant is linked to a modest risk of developing MS, the drug that mimics the effect of the variant has a considerably greater impact', said Professor Lars Fugger of the Nuffield Department of Clinical Neurosciences, who led the study. 'The effects of genetic variants influencing disease risk or resistance can be amplified by drugs. This has often been completely overlooked, but will be critical for using genetic findings in a medical context'.

The variant was discovered using a genome-wide association study (GWAS), published in Nature. GWAS collect data from thousands of people with a particular disease, and identify genetic variations that are more prevalent in those with the condition. Most studies of this kind discover dozens of significant variations, each increasing the chances of developing the condition by a small percentage.

Analysing the entire human genome has raised the hope that genetic abnormalities can be identified and used to refine or identify treatments for patients with certain disorders.

Professor Fugger said that the study 'shows that this is possible. It's one of the first such examples, certainly in autoimmune disease'.

Nick Rijke, director of policy and research at the MS Society, told BBC News that the study 'could help ensure that people with MS are offered the drug treatments that are most likely to work for them'.

Gene flaw 'explains why drugs failed to treat MS'
BBC News |  9 July 2012
Gene link to multiple sclerosis
Medical Xpress (Press release) |  11 July 2012
Genome study highlights risk factor for multiple sclerosis
Nature News |  9 July 2012
TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis
Nature |  8 July 2012
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