Targeting Tau

We’ve heard a lot about mRNA vaccines, but what about mRNA treatments for Alzheimer’s disease (AD)? Scientists from The Florey – a brain research institute in Australia – are using mRNA-encoded antibodies to target tau in the brain. An early study has been published in Brain Communications. We speak with Rebecca Nisbet, who leads the Antibody Therapeutics Group at The Florey, to find out how mRNA could overcome some of the challenges facing standard monoclonal antibodies against AD.

How did you first become interested in the science of AD?
 

When I was an undergraduate student at the University of Melbourne, I had a highly engaging biochemistry lecturer who introduced me to the world of proteinopathies (diseases that are caused by misfolded proteins that aggregate). From then on, I knew this was the area of research I wanted to go into. I reached out to this lecturer and he offered me an undergraduate research project in his lab investigating familial Alzheimer’s disease mutations. I accepted – and the rest is history!

And how did you become interested in exploring the potential of mRNA?
 

I started to get really frustrated with continually delivering our antibody therapeutics as proteins, knowing that only a tiny amount was getting into the brain and essentially nothing was getting into neurons.  As Einstein famously said, “Insanity is doing the same thing over and over and expecting different results.”

Over the years, we generated more data to suggest that, to have effective and safe antibody target engagement in AD, the drug may need to enter the brain in stealth mode to stop it from engaging to its target in the vasculature. I was drawn to mRNA because it can be easily encapsulated in nanoparticles and delivered to its required destination. During the COVID-19 pandemic, the Australian government offered grants to support mRNA research – and I thought it would be a great opportunity to try this strategy. I love working with mRNA, it is so versatile and easy to synthesize. We can make and test new constructs now much faster and cheaper than conventional antibodies.

A great deal of attention in AD research has focused on amyloid beta; why did you choose to target tau for this work?
 

Although historically most therapies have been designed to target amyloid, rather than tau, I believe this stems from the fact that extracellular proteins, such as amyloid beta, are easier to target than intraneuronal proteins, such as tau.

But amyloid accumulation does not correlate well with cognitive decline and there are many people living with high levels of amyloid in their brain but are cognitively normal. On the other hand, the accumulation of intraneuronal tau tangles in the brain does correlate well with cognitive decline. Tau also misfolds and accumulates in several other neurodegenerative diseases. Therefore, if you develop an effective tau targeting therapy, it can be used to treat a variety of neurodegenerative diseases. Another attraction to targeting tau is that amyloid beta monoclonal antibody therapy is associated with brain swelling and bleeding known as ARIA (amyloid-related imaging abnormalities) and can be extremely dangerous.

How could your approach overcome limitations with current monoclonal antibody treatments for AD?
 

Conventional monoclonal antibodies for Alzheimer’s disease are relatively expensive and require high doses. For example, the recently approved anti-amyloid monoclonal antibody, lecanemab, has an annual price tag of US$26,500 and consists of fortnightly treatments of 10 mg/kg for 18 months. This is approximately 800 mg a fortnight for an adult of average weight. What’s more, only about 0.1 percent of this antibody is predicted to enter the brain. Most healthcare systems will unlikely be able to sustain this cost for the large number of people affected by the disease.

mRNA therapeutics are a less expensive alternative. Because the mRNA is translated directly in the cell, it also offers the advantage of allowing intracellular proteins, such as tau, to be targeted. Our approach, therefore, uses mRNA-encoded antibodies, rather than conventional protein antibodies, to target the tau protein in Alzheimer’s disease. In our recent study, we synthesized mRNA that encodes a full-sized tau antibody and mRNA that encodes a tau antibody fragment. We demonstrated that following mRNA delivery to cells in culture, the synthetic mRNA was translated into a functional tau-specific antibody. Furthermore, we showed that the translation of the tau specific antibody fragment as an intracellular antibody (intrabody) resulted in the engagement of tau directly within the cells. To our knowledge, this is the first demonstration of a tau antibody directly binding intracellular tau.

Since the pandemic, the mRNA therapeutic pipeline has been established, making it easier than ever before for mRNA therapeutics to enter human clinical trials. We are currently working with the team that developed Australia’s first COVID-19 vaccine to ensure our current work can be seamlessly translated to human trials. We are in the process of developing brain-penetrating lipid nanoparticles (LNPs) to facilitate mRNA delivery to the brain. We also need to conduct the relevant safety studies in mice. 

In recent years, what do you think have been the biggest milestones in terms of AD research?
 

Recent technology and the identification of blood biomarkers in Alzheimer’s disease patients means that we are now on the verge of being able to accurately diagnose someone with Alzheimer’s disease from a simple blood test. Not only will this help with patient care, but it could also improve clinical trial outcomes by facilitating screening of trial participants and ensuring eligibility.

Although the current Alzheimer’s monoclonal antibodies are not a magic bullet, they have opened the doors to new therapies and provided us with a benchmark – something we can improve upon. Now that we have an approved disease-modifying treatment, I look forward to seeing clinical trials starting to combine these monoclonals with other drugs to really improve patient outcomes. Alzheimer’s disease is such a complex disease and I think we need to start thinking about combination therapy, as we commonly see in oncology.