A landmark British study has raised the prospect of a pill that could treat brain diseases such as Alzheimer's by halting the death of neurons.
The research, performed on sick mice, is at a very early stage and it could be a decade or more before any medicine is developed.
But experts say the results are highly significant, and one predicted future generations would see the findings as a historic turning point.
The Medical Research Council (MRC) team focused on the root cause of many degenerative brain diseases, including Alzheimer's and Parkinson's – abnormally shaped proteins that stick together in clumps and fibres.
When enough misshapen protein builds up in the brain, it can trigger a reaction that results in the death of nerve cells.
Other approaches have sought to stop or limit the accumulation of the abnormal protein, whose structure is folded the wrong way. Instead, the MRC team targeted the harmful way brain cells react to misfolded proteins.
Using a drug injected into the stomachs of mice, they flipped a cellular switch from off to on to prevent neurons dying.
Five weeks after treatment, one group of mice remained free of symptoms such as memory loss, impaired reflexes or limb dragging. They also lived longer than untreated animals with the same disease.
The mice suffered serious side effects, including weight loss and raised blood sugar, and the scientists say human trials are a long way off.
But they also believe the research demonstrates in principle the possibility of developing a pill that can protect the brain from neurodegenerative disease.
The research, reported in the journal Science Translational Medicine, duplicated previous results achieved by the same team by means of genetic engineering.
As in the earlier study, a neurodegenerative disease caused by abnormal prion proteins was induced in the mice. Prion diseases, which include Creutzfeldt-Jakob Disease (CJD), are rare in humans but share the same underlying cause – misfolded proteins – as more common conditions such as Alzheimer's.
Lead scientist Prof Giovanna Mallucci, from the MRC toxicology unit at the University of Leicester, said: "Our previous study predicted this pathway could be a target for treatment to protect brain cells in neurodegenerative disease. So we administered a compound that blocks it to mice with prion disease.
"We were extremely excited when we saw the treatment stop the disease in its tracks and protect brain cells, restoring some normal behaviours and preventing memory loss in the mice.
"We're still a long way from a usable drug for humans – this compound had serious side effects. But the fact we have established that this pathway can be manipulated to protect against brain cell loss, first with genetic tools and now with a compound, means that developing drug treatments targeting this pathway for prion and other neurodegenerative diseases is now a real possibility."
The experimental drug, known as GSK2606414, is made by pharmaceutical company GlaxoSmithKline.
It targets an enzyme called PERK which plays a key role in the response of neurons to the build-up of misfolded proteins in the brain.
As part of a natural defence mechanism, the neurons react by switching off their production of new proteins. Ultimately, this leads to their death.
By blocking PERK, the new drug stops this happening, thereby allowing the cells to survive.
A key property of the compound is its ability to penetrate the "blood brain barrier" - a natural shield that prevents toxic substances entering the brain, but also acts as a major obstacle to drug treatments.
Commenting on the research, Prof Roger Morris, from the department of chemistry at King's College London, said: "This is the first convincing report that a small drug, of the type most conveniently turned into medicines, stops the progressive death of neurons in the brain as found, for instance, in Alzheimer's disease.
"True, this study has been done in mice, not man; and it is prion disease, not Alzheimer's, that has been cured. However, there is considerable evidence that the way neurons die in both diseases is similar; and lessons learned in mice from prion disease have proved accurate guides to attenuate the progress of Alzheimer's disease in patients."
He added: "This finding, I suspect, will be judged by history as a turning point in the search for medicines to control and prevent Alzheimer's disease."
Fellow expert Professor David Allsop, from the University of Lancaster, said: "Inhibiting this pathway has produced some very dramatic and highly encouraging results in mice infected with prion disease.
"The main caveats of the research, however, are that prion disease is very rare in humans, and it is not yet clear if the same approach will be viable for much more common neurodegenerative conditions like Alzheimer's disease and Parkinson's disease.
"More research is needed to determine if this approach is valid for any condition other than prion disease, and also to find ways of getting around these problematic side effects."
Dr Eric Karran, director of research at the charity Alzheimer's Research UK, said: "Targeting a mechanism relevant to a number of neurodegenerative diseases could yield a single drug with wide-reaching benefits, but this compound is still at an early stage.
"It will be important for these findings to be repeated and tested in models of other neurodegenerative diseases, including Alzheimer's disease.
"While Alzheimer's is the most common form of dementia, other diseases that cause dementia are also characterised by the abnormal buildup of proteins in the brain.
"If this process is also working overtime in these conditions too, targeting it could be a promising avenue for investigation.
"However, what is true in animals does not always hold true in people and the ultimate test for this compound will be to see whether it is safe and effective in people with these diseases."
Source: The Guardian
