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

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'.