SAN FRANCISCO: A drug that reverses Alzheimer’s by destroying proteins that cause the disease could be on the horizon.
It targets the ‘tangles’ that destroy nerve cells in the brain – leading to the memory loss and confusion that blights the lives of sufferers and their families.
Experiments on mice and monkeys suggest the compound could treat neuro-degenerative diseases characterised by abnormal tau levels – including dementia and Parkinson’s.
Scientists are so excited they are now hoping to carry out trials in people.
Professor Timothy Miller, of Washington University in St Louis, said: “We’ve shown tthis molecule lowers levels of the tau protein, preventing and, in some cases, reversing the neurological damage.
“This compound is the first that has been shown to reverse tau-related damage to the brain that also has the potential to be used as a therapeutic in people.”
In healthy people the protein contributes to the normal functioning of the brain.
But in some it collects into toxic tangles that damage neurons. These are a hallmark of Alzheimer’s and other neuro-degenerative diseases.
The new drug – known as an antisense oligonucleotide reduces tau by targeting the protein’s genetic instructions before it’s made.
In the study, published in the journal Science Translational Medicine, mice were genetically engineered to produce a mutant form of human tau that easily clumps together.
They started showing tangles at around six months of age and some neuronal damage by nine months. It was then the researchers began injecting them every day for a month with the anti-tau oligonucleotide.
Two months later levels of the protein were significantly reduced compared to those that received a placebo.
They were also lower than in untreated nine-month-old mice – suggesting the treatment not only had stopped but reversed the buildup of tau.
By the time this strain of genetically modified mice reaches nine months of age, the hippocampus – a part of the brain important for memory – typically is visibly shrunken and shows dying neurons.
But with the treatment the shrinkage and cell death were halted. There was not, however, any evidence of reversal of neuronal death.
The treated mice lived an average of 36 days longer than untreated mice, and they were better at building nests, which reflects a combination of social behaviour, cognitive performance and motor capabilities.
All of these functions can be impaired in people with Alzheimer’s disease and other tau-related neuro-degenerative diseases.
So the researchers decided to see how the drug worked in an animal more similar to people than a mouse.
They treated crab-eating macaque monkeys with two doses of oligonucleotide or a placebo – one week apart – directly into the cerebrospinal fluid that surrounds the spinal cord and brain, just as would be done with human patients.
After two weeks the drug reduced tau in the brain and cerebrospinal fluid.
Prof Miller said: “The monkey study showed us lower tau in the cerebrospinal fluid correlates with lower tau in the brain.
“This is important if we’re going to evaluate this treatment approach in people, because there’s no non-invasive way of measuring tau levels in the brain.
“This correlation tells us that we can use levels of tau in the cerebrospinal fluid as a proxy for levels of tau in the brain.
“Tau tangles correlate with cognitive decline in several diseases.
“This is a promising new approach to lowering tau, but we have to test whether it is safe in people, and whether it actually lowers tau, as it is designed to do, before we get to the question of whether it has any effect on the disease.
“But everything we’ve seen so far says that this is worth investigating as a potential treatment for people.”
Dr Doug Brown, Director of Research and Development at Alzheimer’s Society, said: “Toxic clumps of the amyloid and tau proteins are the two best known hallmarks of Alzheimer’s disease but, up until recently, amyloid has been the main focus for research.
“This research into a potential treatment that targets tau is still in the early stages in mice and there are a few questions that need to be addressed – we need more in-depth laboratory studies to understand what effect this approach might have before we can move on to testing it in people.
“Our understanding of tau and its role in dementia is now beginning to catch up with amyloid, leading to creative approaches for treatment such as this.
“If we can build on this early potential, this treatment approach could hold benefits for people with rarer conditions associated with the tau protein such as frontotemporal dementia as well as Alzheimer’s disease”
Dr David Reynolds, Chief Scientific Officer at Alzheimer’s Research UK, added: “This robust study presents an interesting and potentially powerful approach to target tau build-up in the brain.
“Recent disappointing results from clinical trials using anti-amyloid therapies highlight the importance of researching other areas of the underlying biology of Alzheimer’s disease in the search for new treatments.”
Amyloid is another rogue protein believed to cause dementia by clumping together in the brain.
Dr Reynolds said: “While several anti-tau drug approaches are already in testing in people animal studies like this can provide promising new leads to develop towards clinical trials.
“Tau protein is an attractive target for the development of new treatments for dementia due to its central role in several neuro-degenerative diseases including Alzheimer’s.
“It’s important to remember all new drugs need to be thoroughly tested in people to make sure they’re safe and effective.
“We’re already seeing encouraging results with this RNA approach in several other rare inherited diseases.
“While we don’t yet know how safe and effective such a therapy would be in Alzheimer’s this data provides a strong case that it could be a valid therapeutic approach.
“It’s vital we continue to invest in research to understand the biology of different forms of dementias to develop the drugs that are so desperately needed by the 850,000 people living with the condition in the UK.”
Oligonucleotide treatments recently have been approved by the Food and Drug Administration in the US for two neuromuscular diseases: Duchenne’s muscular dystrophy and spinal muscular atrophy (SMA).
Washington University holds joint patent applications with Ionis Pharmaceuticals on the use of oligonucleotides for reducing tau levels.
Human trials of oligonucleotides for several other neurological diseases are underway, including Huntington’s disease and amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig’s disease.
Alzheimer’s disease effects about 850,000 people in the UK – with the figure set to rise to a million by 2025. Current drugs can only treat the symptoms – not the cause…