The results of a world-first clinical trial have shown promise for a new genetic therapy in reducing the amount of harmful proteins that build up in the brain of Alzheimer’s (AZ) patients, offering a tentative hope that the condition could be slowed or even reversed. Using a the therapy on a small number of patients, researchers managed to halve the concentration of tau protein in their brains, which is thought to be implicated in the cognitive decline seen in people with AZ.
Alzheimer’s disease is infamous in the research community as a contender for the most challenging disease to understand. Hampered by animal models that may not accurately represent it and numerous dead-end hypotheses that show promise in theory but fail in practise, research has continuously resulted in disappointment when it comes to creating a viable AZ treatment.
Our best understanding of the underlying cause of AZ relies on two main mechanisms: the build-up of harmful tau tangles; and amyloid protein plaques. Both are proteins that go awry as they form, misfolding and joining together to stop brain cells from communicating with each other, and even causing neuron death.
This research focused on tau. Tau is an insoluble protein that is encoded by the gene microtubule-associated protein tau (MAPT) and forms tangles in the brain of AZ patients, making it a prime target for therapies.
The new approach, with the incredibly catchy name BIIB080 (/IONIS-MAPTRx), targets MAPT with a “gene-silencing” oligonucleotide (a short bit of DNA or RNA) that prevents the gene from creating more tau.
As a Phase 1b trial, the clinical trials were designed to see if the drug is safe for humans and well-tolerated, not to see if it is effective at treating the disease – that comes later. The researchers tested it on 46 patients with an average age of 66, with some given the drug via injection into the spinal cord, while others got a placebo.
All patients in the group completed the course and only minor side-effects were noted, indicating the treatment is safe. Upon completion of the trial, the researchers discovered a tau reduction of over 50 percent in the central nervous system of the group that received the highest dose after 24 weeks, suggesting the drug had a significant biological effect.
The researchers now need to push towards further clinical trials over a longer period of time to evaluate if this effect actually impacts AZ symptoms. It is typically at the next stage that AZ drugs tend to fail, as translating these successes into symptom reduction is a difficult task – but this is one of the first promising results from such a therapy in a long time.
“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,” said Dr Catherine Mummery, lead author of the study, in a statement.
“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.”
The research was published in the journal CNS Neuroscience and Therapeutics.