Posted October 19, 2013
Guardian Web
By Alok Jha, theguardian.com
Several media outlets have hailed a development in brain research that might lead to future treatments for diseases such as Alzheimer’s and new variant Creutzfeldt-Jakob disease.
It is a bold claim, particularly because the research is at a very early stage in mice. Should we get excited?
Professor Roger Morris, an expert on prion diseases at King’s College London said: “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.”
What happens in a neurodegenerative disease?
Conditions such as Alzheimer’s, Parkinson’s and those caused by a type of protein called prion (such as CJD and Huntingdon’s disease) are all characterised by the death of brain cells and loss of function.
In all these disorders, brain cells die because mis-shapen, mis-folded proteins build up in the brain. The brain normally deals with this build-up by switching on a defence mechanisms called unfolded protein response (UPR), which prevents new proteins being made and slows down the build-up of badly-shaped ones. In people with neurodegenerative diseases, however, UPR can remain switched on for too long – while this means no more mis-folded proteins, it also prevents the formation of proteins that the brain cells need for healthy function. This can lead to the death of those cells and, over time and if the cells are not replaced, this death could affect anything from memory to movement.
What have the researchers done?
Researchers led by Giovanna Mallucci at the Medical Research Council Toxicology Unit, based at the University of Leicester have found that a chemical compound (called GSK2606414) could block some of the UPR’s functions in a mouse’s brain and stop the death of brain cells. Mice that had been infected with a prion disease developed symptoms (such as memory and movement problems) within 12 weeks, whereas those treated with the drug twice a day showed no signs of disease over the same period. Their results were published in the journal Science Translational Medicine.
Specifically, the drug was found to inhibit a part of the UPR defence mechanism called the PERK pathway. The researchers said that this pathway could form a target for future drugs to treat neurodegenerative problems.
Will this drug be useful in people?
There is a long way to go before anyone can properly answer that question. Many chemical compounds that show promise in mice do not make it far out of the lab – either because they have other side effects or their useful properties cannot be replicated in other animals.
To get into human trials after a succesful mouse study, scientists would have to first trial the drug in larger mammals and then, because this is a brain-related compound, in primates. After many years (perhaps decades) of work like this, the drug might make it to limited numbers of patients in early-stage clinical trials. There are a lot of big ifs along that path and only a tiny proportion of promising-looking drugs make it that far.
Are there likely to be side effects?
In an accompanying article in the journal, scientists not involved in the work pointed out that a deficiency in PERK causes Wollcott-Rallison syndrome in humans, which can lead to problems in the pancreas and neonatal diabetes. In addition, there could be weight loss and problems in organs such as the kidney and liver.
In their experiments, Mallucci’s team reported that the mice treated with with the GSK2606414 lost around a fifth of their body weight over a 12-week period. They also found slightly increased blood-sugar levels in the drug-treated mice. These secondary effects would need to be weeded out if this drug is to make it to human trials.
What do patient groups think?
According to Alzheimer’s Research UK, “whether this holds true in people with prion disease, or is relevant to other neurodegenerative disease such as Alzheimer’s, still remains to be investigated. But it’s an interesting proof-of-principle study and a potentially important finding.”
The Alzheimer’s Society said, “This is a promising development as it shows this biological pathway is a potential target for new treatments. However, it is important to note that this study was carried out on mice with prion disease and so it is not clear how applicable it is to humans with diseases such as Alzheimer’s. What we need now is further research into potential drugs which can target the same pathway. Whilst the ability to stop neurodegeneration in its tracks would be hugely exciting, we are still a long way from seeing a drug which is suitable for human use.”
Dr Eric Karran, director of research at the research charity, cautioned that the drug compound was 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 build-up 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.”
© 2013 Guardian Newspapers Limited.