Universal plaque-busting drug could treat various brain diseases, Andy Coghlan
A virus found in sewage has spawned a unique drug that targets plaques implicated in a host of brain-crippling diseases, including Alzheimer’s disease, Parkinson’s disease and Creutzfeldt-Jakob disease (CJD).
Results from tests of the drug, announced this week, show that it breaks up plaques in mice affected with Alzheimer’s disease or Parkinson’s disease, and improves the memories and cognitive abilities of the animals.
Other promising results in rats and monkeys mean that the drug developers, NeuroPhage Pharmaceuticals, are poised to apply for permission to start testing it in people, with trials starting perhaps as early as next year.
The drug is the first that seems to target and destroy the multiple types of plaque implicated in human brain disease. Plaques are clumps of misfolded proteins that gradually accumulate into sticky, brain-clogging gunk that kills neurons and robs people of their memories and other mental faculties. Different kinds of misfolded proteins are implicated in different brain diseases, and some can be seen within the same condition (see “Proteins gone rogue”, below).
One thing they share, however, is a structural kink known as a canonical amyloid fold, and it is this on which the new drug acts (Journal of Molecular Biology, DOI: 10.1016/j.jmb.2014.04.015).
Animal tests show that the drug reduces levels of amyloid beta plaques and tau protein deposits implicated in Alzheimer’s disease, and the alpha-synuclein protein deposits thought to play a role in Parkinson’s disease.
Tests on lab-made samples show that the drug also targets misfolded transthyretin, clumps of which can clog up the heart and kidney, and prion aggregates, the cause of CJD, another neurodegenerative condition.
Because correctly folded proteins do not have the distinct “kink”, the drug has no effect on them. “This is a next-generation drug,” says Maria Carrillo, chief science officer at the US Alzheimer’s Association. “It could be stopping the root causes of these diseases and preventing them happening,” she says.
But there is still a long way to go. Progress treating brain diseases characterised by plaques, particularly Alzheimer’s disease, has been slow and there have been many false dawns, where initially promising drugs have failed when tested in people. Because the new drug acts in a different way, there is reason to think that it could be the real deal.
For example, most drugs that have been tried against Alzheimer’s so far target the individual proteins that make up the plaques, rather than the plaques themselves. The only drug that does target the plaques – aducanumab – is also the only one to show signs of halting progression of the disease. Because NeuroPhage’s drug targets both types of plaque involved in Alzheimer’s disease, it has the potential to perform even better, says Richard Fisher, chief scientist at NeuroPhage, who presented the latest results from mice at the annual Alzheimer’s Association International Conference in Washington DC.
“This is something very novel,” he says. “There’s never been anything that can target all these plaques simultaneously.”
Biggest challenge: Other researchers want to see more results. The key thing is whether reducing the plaque results in the death of fewer brain cells, says Michel Goedert of the Medical Research Council Laboratory of Molecular Biology in Cambridge, UK. “To give patients a compound that reduces plaque by, say, 30 per cent without affecting brain degeneration is of no use.”
“It’s too early to conclude that the cognitive improvements in mice will have relevance for those living with dementia, but as the condition poses our biggest medical challenge, testing new approaches is vital in the hunt for better treatments,” says Simon Ridley, head of research at the charity Alzheimer’s Research UK.
If the drug is approved for clinical testing, Fisher and his colleagues hope to test it in people with early-stage Alzheimer’s disease who have detectable amyloid-beta and tau plaques in their brains. The hope is that the drug will slow the progression of their disease. The next stage will be trials on people with Parkinson’s disease and possibly other diseases that involve the build-up of plaques outside the brain.