Teaching old drugs new tricks
Research published today, funded by the MRC* and the Alzheimer’s Society’s Drug Discovery programme, has made important progress in the search for new treatments for dementia by re-purposing old drugs. Dr Louise Walker, Research Communications Officer at the Alzheimer’s Society, spoke to the scientist who led the research, Professor Giovanna Mallucci at the MRC Toxicology Unit, to find out more.
Alzheimer’s disease and other degenerative brain diseases are characterised by the presence of misfolded proteins in the brain. These proteins are thought to have toxic effects on brain cells, but exactly how they contribute to dementia still remains a mystery.
To find answers, Professor Giovanna Mallucci has been investigating a process that happens in cells called the ‘unfolded protein response’. “This is a natural part of the cell’s defences that detects when proteins are misfolded, which causes them to malfunction and build up, ‘blocking’ the system,” she says. “The response suspends much protein-making activity in the cell while it fixes the problem. If it can’t be fixed, the cell will die.”
Research has shown that elements of the unfolded protein response are highly activated in the brains of people with Alzheimer’s and Parkinson’s as well as in frontotemporal dementia. In mice with neurodegenerative disorders, the over-activation of this response leads to memory problems and eventually brain cell death.
Blocking the response in mice protects them from brain degeneration, leading Giovanna’s team to try to do the same in people. “If we can find a way to block this response with drugs, then we might be able to develop a treatment that works for people with all these different conditions.”
An innovative approach to drug discovery
Giovanna’s research first hit the headlines back in 2013, when her group discovered a chemical that could switch off a particular branch of the unfolded protein response in mice that had prion disease. Prions are toxic misfolded proteins that are the cause of Creutzfeldt-Jakob disease (CJD) and are a useful model in which to study neurodegeneration.
“The chemical we gave to our mice was able to prevent the prions from killing brain cells by targeting this response. This was incredibly exciting because it was the first time this had ever been seen: the mice were cured of a lethal degenerative brain disease,” explains Giovanna.
Dementia research experts responded positively to the news, saying that it could well be a ‘turning point’ in our search for effective treatments. But they were cautious too. The research was initially only in mice with prion disease, so there remained many questions about whether it would work in a similar way in people or in other neurodegenerative conditions like Alzheimer’s disease.
A key concern was side effects. “The chemical we used was toxic to the pancreas and so it was not suitable to be developed into a drug,” Giovanna says. “So we set out to find alternative drugs that that had the same effect on the unfolded protein response but didn’t have toxic side effects.”
Borrowing from other health conditions
Giovanna was awarded a grant through Alzheimer’s Society’s innovative Drug Discovery programme, which focuses on ‘drug repurposing’. In partnership with the Alzheimer’s Drug Discovery Foundation, we fund researchers to test whether drugs that are already being used for other health conditions can also be useful in the treatment of dementia.
“We screened through over 1000 different compounds in the lab to find ones that could block the unfolded protein response and found two promising drug candidates,” explains Giovanna. One, trazodone, is an already-licensed drug used as an antidepressant. The other, called DMB, is a compound found in small quantities in liquorice and is also being tested a potential drug for cancer. It also bears some similarity to curcumin, which has previously been investigated as a potential way to treat or prevent Alzheimer’s.
Both drugs were tested in mice that had prion-related diseases, to see if they had the same effect as the original chemical. Not only did they target the
right pathway in cells, but they protected brain cells from dying and the mice showed improvements in disease-related behaviour. Importantly, these drugs did not damage the pancreas.
Next, the researchers tested the drugs on mice that developed frontotemporal dementia. They were particularly looking at how the drug affected the protein tau, which forms toxic clumps in several forms of dementia, including Alzheimer’s disease. They found that the drugs were also able to prevent the death of brain cells in these mice. The mice also had an improved performance in memory tests.
What happens next?
Before you start overdosing on liquorice, it is worth bearing in mind that there we now need to understand whether these drugs will be effective for people in with Alzheimer’s disease or other forms of dementia. The findings are an important step forward but the research has so far only been done in animals.
The next steps are for these drugs to be tested in animal models of Alzheimer’s disease – something that we are currently funding Giovanna to do – but critically, to begin testing the licenced drug in people with different types of dementia in the earlier stages of disease.
“A clinical trial is now possible, to test whether the protective effects of the drug we see on brain cells in mice with neurodegeneration also applies to people in the early stages of Alzheimer’s disease or other dementias,” says Giovanna. “We could know in two to three years whether this approach can slow down disease progression, which would be a very exciting first step in treating these disorders.”
This article has been re-purposed from the original article on the Alzheimer’s Society blog.
*The MRC has funded the team’s research since 2008.