Promising ‘Trojan horse’ potential therapies against Alzheimer’s and other diseases developed by Cambridge scientists

Two exciting potential therapies that act like Trojan horses to remove the tau ‘tangles’ that form in Alzheimer’s and other neurodegenerative diseases have been developed by Cambridge scientists.

They are able to destroy the tau aggregates that are linked to disease, while leaving healthy tau proteins in the brain intact - and have been shown to improve symptoms of neurodegeneration in mice.

The scientists, from the MRC Laboratory of Molecular Biology in Cambridge and the UK Dementia Research Institute (UK DRI) at the University of Cambridge, say that while there is some way to go before this approach can be tested in humans, it could in future also be applied to other brain disorders driven by protein aggregation inside cells, such as motor neuron disease, Huntington’s disease and Parkinson’s disease.

Alzheimer’s disease and dementia now affect one in three people in the UK and are the leading cause of death in England and Wales, yet there are currently no cures or effective treatment options.

Two main proteins become misfolded and accumulate into aggregates in the brains of people affected by Alzheimer’s disease: tau and amyloid.

Scientists are exploring new antibody therapies, such as lecanemab, to target amyloid aggregates, which form in the spaces between brain cells.

But tau ‘tangles’ typically form inside nerve cells, where it is hard for antibody therapies to access them, meaning they can remove existing aggregates. These aggregates can also spread from cell to cell, leading to cognitive decline.

There have been other techniques to target tau inside cells, such as anti-sense oligonucleotides (ASOs), which have been shown to reduce tau in promising early-stage clinical trials. But they act on all tau in the brain, including the healthy tau protein, and the long-term side-effects of this are unknown. Healthy tau protein helps provide structural support inside nerve cells in the brain, like a type of scaffolding.

The new treatments build upon 15 years of work from Dr Leo James’ group at LMB on the antiviral protein TRIM21.

In 2010, his lab discovered its unique role in the immune response to viruses.

Our bodies produce antibodies to bind to invading viruses outside of cells. When the antibody-bound virus enters a cell, TRIM21 detects it and tags the virus as ‘garbage’ and effectively hands it to the cell’s ‘garbage chute’ - the proteasome - for destruction.

In 2023, the same team, working across the UK DRI and MRC LMB, demonstrated that TRIM21 could be repurposed to destroy tau protein aggregates associated with Alzheimer’s disease.

They switched out antibodies that bind viruses for antibodies that bind to tau in order to redirect TRIM21 to send tau aggregates to be destroyed by the proteasome.

Part of the protein, called ‘RING’ is only activated when two or more TRIM21 proteins cluster together, meaning it only activates and marks the target for destruction if TRIM21 proteins are bound to adjacent, aggregated tau proteins.

The first therapy created by the team is called ‘RING-nanobody’ and combines a tau-binding nanobody – a miniature version of an antibody – with the TRIM21 RING.

The second, ‘RING-Bait’, joins the TRIM21 RING to a copy of the tau protein itself. The RING-linked tau protein acts as bait so that the aggregates incorporate it - with the TRIM21 RING. Once multiple RING-Baits are added to the aggregate, they become activated, causing the entire aggregate to be destroyed.

When the researchers delivered the DNA encoding the TRIM21 therapies into cells containing aggregated tau, they found it cleared the tau clumps but left normal tau undamaged.

Dr Will McEwan, co-leader of the studies, from the UK DRI at Cambridge, said: “Tau aggregates are tucked away inside brain cells and very difficult to degrade. Critically, these new TRIM21-based therapies can be delivered directly inside cells, where the majority of tau aggregates reside.

“We’ve found a way that not only degrades the tau aggregates, but leaves the healthy tau intact to do its job. The new strategy goes beyond what can be achieved with current ASO therapies that are being trialled, as it could avoid any potential long-term side-effects of eliminating normal tau.”

Neurodegenerative diseases have different types of misfolded tau.

The team tested their therapies on cells containing aggregated tau proteins from brain tissue donated by people who had Alzheimer’s or progressive supranuclear palsy, which have different misfolded tau structures.

The RING-Bait therapy prevent tau aggregation induced by proteins from both.

Dr James, co-leader of the studies, said: “Neurodegenerative diseases can have tau proteins that misfold in many different ways, raising the possibility of needing a different treatment for every disease. A useful aspect of RING-Bait is because it is attached to a tau protein, it’s a universal Trojan horse that should be incorporated into different types of tau aggregates exactly like the cell’s own misfolding tau protein.”

The treatments can only work if they get into the cells within the brain.

The researchers used a harmless virus previously developed to deliver therapies like this, called an adeno-associated virus (AAV), which delivers DNA instructions to make the custom proteins inside brain cells.

They injected elderly mice with tau protein aggregates with a single dose of the gene therapy vector containing either the treatment or a placebo.

And within a few weeks, there was a significant reduction in aggregated tau in the brain cells of the treated animals.

The researchers worked with the LMB Workshops to construct a bespoke MouseWalker platform that allowed video tracking of the depressions from the animals’ paws as they ran.

The AI-powered programme showed that in the mice given the RING-Bait treatment, the progression of their neurodegeneration symptoms slowed and they had significantly better motor function.

Dr Lauren Miller, who worked across both the UK DRI and LMB, said: “It was unknown whether specifically removing tau aggregates inside the cell would be enough to halt the progression of disease.

“It is encouraging that a RING-Bait approach reduces disease severity in our model systems, as this suggests that the selective removal of tau aggregates is a valid therapeutic approach. Further work will be needed to demonstrate this beneficial effect is found across multiple models of human disease.”

Dr Guido Papa, from the LMB, added: “The beauty of RING-Bait lies in its broad adaptability and the potential to tackle other conditions characterised by the accumulation of pathological protein clusters. Other neurodegenerative diseases are caused by aggregates formed by other proteins, such as TDP43 in motor neuron disease and alpha-synuclein in Parkinson’s disease. It is hoped that RING-Bait will allow the development of future therapies that directly target the aggregation process in these diseases.”

One of the challenges with progressing testing to humans is developing an AAV vector that can safely deliver RING-nanobody or RING-bait therapies to cells throughout the human brain.

Dr Jonathan Benn, from the UK DRI at Cambridge, said: “It’s important to stress that although we have shown it works in a mouse model, this is a long way from a therapeutic that could be used in humans. It would need to be determined that it is safe to use TRIM21-based therapies in the human brain and that the treatments are effective in both removing aggregates and improving the course of disease.

“Some AAV vectors are already approved for use in humans – for instance in degenerative eye diseases and genetic diseases like spinal muscular atrophy. However, getting enough AAV into the adult brain remains a significant challenge - the human brain is about 1,000 times bigger than a mouse brain. But this is a rapidly moving field and there are cutting edge gene delivery methods that we hope will allow our therapies to be delivered at scale in the future.”

These studies were primarily funded by Wellcome, MRC, UK DRI, and The Lister Institute of Preventative Medicine.