A new genetic therapy for Alzheimer’s is safe and successfully lowered levels of the harmful tau protein known to cause the disease, a new world first trial suggests.
The researchers at University College London Hospitals (UCLH) NHS Foundation Trust and UCL, say the findings “are a significant step forward” in showing it may be possible to target tau to slow, or maybe even reverse, the devastating progressive neurological condition.
The phase 1b trial represents the first time that a ‘gene silencing’ approach has been taken in dementia and Alzheimer’s.
The findings suggest scientists can change the amount of tau by silencing its gene coding with a drug called BIIB080 (MAPTRx), which is an antisense oligonucleotide (short, synthetic, chemically modified chains of nucleotides that have the potential to target any gene product of interest).
This prevents the gene being translated into the protein in a doseable, reversible way. This can then lower the production of that protein and alter the course of disease.
Consultant neurologist Dr Catherine Mummery at the National Hospital for Neurology and Neurosurgery, who led the trial, said: “We will need further research to understand the extent to which the drug can slow progression of physical symptoms of disease and evaluate the drug in older and larger groups of people and in more diverse populations.
“But the results are a significant step forward in demonstrating that we can successfully target tau with a gene silencing drug to slow – or possibly even reverse – Alzheimer’s disease, and other diseases caused by tau accumulation in the future.”
Further trials will be needed in larger groups of patients to determine whether this then leads to clinical benefit, but the phase 1 results published in the journal Nature Medicine are the first indication that this method has a biological effect.
There are currently no treatments targeting tau. The drugs aducanumab and lecanemab – recently approved for use in some situations by the US Food and Drug Administration (FDA) – target a separate disease mechanism in Alzheimer’s, the accumulation of amyloid plaques.
The phase 1 trial looked at the safety of MAPTRx, what it does to the body, and how well it targets the gene.
It involved the UCL Dementia Research Centre, was supported by The National Institute for Health and Care Research (NIHR) UCLH Biomedical Research Centre, and took place at the NIHR UCLH Clinical Research Facility at Queen Square in London.
Forty-six patients with an average age of 66 were enrolled in the trial which took place between 2017 and 2020. The trial looked at three doses of the drug, given by injection into the nervous system via the spinal canal, compared with placebo.
According to the study, the drug was well tolerated, with all patients completing the treatment period and over 90% completing the post-treatment stage. 
Patients in both the treatment and placebo groups experienced either mild or moderate side effects.
The most common was headache after injection of the drug. But no serious adverse events were seen in patients given the drug.
The research team also looked at levels of two forms of the tau protein in the central nervous system (CNS) – a reliable indicator of disease – over the duration of the study.
They found a greater than 50% reduction in levels of total tau and phosphor tau concentration in the CNS after 24 weeks in the two treatment groups which received the highest dose of the drug.
Dr Liz Coulthard, Associate Professor in Dementia Neurology at the University of Bristol, said the study was exciting “because it shows that we can alter the amount of tau – one of the proteins that causes Alzheimer’s disease.
“This reduction is achieved by blocking the messages from DNA that make the abnormal protein within each cell. It is a very high tech method of treating patients with Alzheimer’s.
“We know it might be useful because a similar drug is now used successfully to treat a rare neurological condition of childhood (spinal muscular atrophy).
“As this is a phase 1 study, all it tells us is that the drug is good enough to take to full trials, i.e. the drug blocks the production of harmful protein without causing obvious dangerous side effects.
“Bigger trials are needed to test whether this effect actually helps individual patients. These trials are underway.
“This treatment works on a different protein to lecanemab, the drug recently licensed in the US and under regulatory review here.”
But she added: “One major drawback to this treatment is that it needs to be given by injection into the lumbar spine.”
Prof Tara Spires-Jones, Professor of Neurodegeneration and deputy director of the Centre for Discovery Brain Sciences at the University of Edinburgh, and BNA President, said while there is a long way to go in larger trials to decide whether the drug will help people living with dementia, she described the data as “very promising.”
“This type of treatment targeting tau has the potential to slow or even hopefully stop Alzheimer’s disease progression, so I very much look forward to seeing results from the next stages of testing.”