Clinical trials show promise for first ‘gene silencing’ treatment for Alzheimer’s disease
A new RNA-based therapy for Alzheimer’s disease that’s in clinical trial phase could be the first of its kind to use ‘gene silencing’ for the condition
Alzheimer’s disease is a progressive neurodegenerative disorder that affects brain function and results in substantial disability and although there are treatments available to reduce symptoms, there is currently no cure for it.
The new treatment that is in clinical trial phase at the University College London (UCL) and University College London Hospitals (UCLH) is using a genetic therapy to safely lower levels of the harmful tau protein known to cause the disease.
Tau protein
The gene that encodes the tau protein, MAPT, has over 40 different variants known to increase a person’s risk of developing Alzheimers’ disease and is also associated with Parkinson’s disease.
Tau proteins are found in nerve cells, where they are an important component of the microtubules (microscopic tubes) that form the cells’ ‘skeleton’ and transport essential molecules around the cell. However, in Alzheimers’ disease the tau proteins get tangled up together, obstructing cellular processes.
These tau accumulations inside cells are – along with another type of protein accumulation outside cells, called amyloid plaques – one of the hallmarks of Alzheimers’ disease.
There are currently no treatments available that target the accumulation of tau protein. Lecanemab, a drug that targets amyloid proteins is currently undergoing a fast-track evaluation by the UK Medicines and Healthcare products Regulatory Agency, which decides which medicines can be sold in the UK. This drug is a type of immunotherapy known as a ‘monoclonal antibody’ which binds to the amyloid proteins and signals to the body’s immune system to destroy them.
- Further reading: Understanding Alzheimer’s
Clinical trial
The results published by UCL and UCLH come from a Phase 1 clinical trial which was set up to assess the safety of the drug, known as BIIB080, as well as its effects in the body. Phase 1 trials look at the chemical effects of a drug in the body, but not the effect on symptoms.
The trial included 46 patients, of whom 34 received the drug, and 12 a placebo, delivered into the cerebrospinal fluid. None of the participants had serious side effects, and those who received the highest dose of the drug showed over 50% reduction in tau levels after 24 weeks.
“We will need further research to understand the extent to which the drug can slow progression of physical symptoms of disease,” said UCL Queen Square Institute of Neurology and the National Hospital for Neurology and Neurosurgery consultant neurologist Dr Catherine Mummery, who led the clinical trial.
Gene silencing
BIIB080 is an antisense oligonucleotide RNA-based therapy. It is made up of pieces of RNA that have complementary sequences to the messenger RNAs that act as templates for the MAPT gene to be turned into Tau protein.
Because the sequences match, the single stranded RNA and the antisense RNA ‘zip’ together, like double stranded DNA does. The messenger RNA is inactivated as a result, and subsequently destroyed by the cell.
The outcome is that the MAPT gene is not affected, but the messenger RNAs are destroyed (or a significant proportion of them are), and the amount of protein being made is substantially reduced.
“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,” said Dr Mummery.
There is still a long way to go before this treatment can be used clinically, but the results of the clinical trials so far do offer hope for new treatments in the future.
