Patrick O'Donoghue, PhD, is exploring a new route to suppress the toxic huntingtin protein.

By Megan Stacey

With a goal to accelerate life-changing treatments and advance patient care outcomes, Western University and the Huntington Society of Canada partnered to create a $3-million endowed research chair in 2023, paving the way for accelerated advances in Huntington’s disease.

Patrick O’Donoghue, PhD, who leads innovative research into how cells build proteins, is the inaugural Huntington Society of Canada Research Chair. The chair, housed at Schulich School of Medicine & Dentistry, is a first of its kind in North America.

O’Donoghue’s work explores how errors in protein production can contribute to or surprisingly rescue genes that cause disease. His lab focuses on developing new therapeutic tools, which could help correct or suppress the consequences of genetic mistakes that cause diseases, including Huntington’s disease.

In this conversation, O’Donoghue shares insights on Huntington’s disease from his lab, the future of therapeutics and the promise of his team’s emerging research.

What does it mean to you to be named the inaugural Huntington Society of Canada Research Chair?

It’s a deep honour. My lab first became interested in Huntington’s disease in 2021, which in the world of research is not that long ago.

When we first started, we were focused on fundamental questions about how proteins behave inside cells, what goes wrong and why. It was extremely gratifying that the search committee felt our work was worth investing in and I feel genuinely humbled, because there were many strong candidates.

What first drew you to this field, and was there a defining moment that shaped your direction?

During my undergraduate degree in biophysics at the University of Illinois, I took a physical chemistry course in quantum mechanics that I found absolutely fascinating. I told my professor, Zan Luthey-Schulten, I wanted to do research in that field. I worked in her lab over the next year and published my first paper in 1999, which really sparked my excitement about research.

During my PhD, I worked on molecular evolution. During that time, we developed an approach that used protein structures to build phylogenetic or family trees. What was exciting about this work is that structure can remain conserved for longer than a protein’s sequence, so it allows you to “see” further back in evolutionary time.

I worked on enzymes called aminoacyl-tRNA synthetases, which attach amino acids to transfer RNAs (tRNAs) — a key step in building proteins. After that, I did my postdoctoral training at Yale in molecular biophysics and biochemistry with Dieter Söll. That’s where I really became immersed in lab work, and it helped shape the foundation for where my research has gone, including its relevance to neurodegenerative disease.

In simple terms, what is Huntington’s disease?

To put it as plainly as possible, Huntington’s disease is caused by a genetic change in the huntingtin gene. A short DNA sequence in that gene is repeated too many times, almost like a word being typed over and over again.

Most people have 10 to 35 repeats in the gene. When the number rises above 35, the gene produces an abnormal form of the huntingtin protein. To some extent, the longer the repeated sequence, the more severe the disease can become, although several other factors contribute to disease onset and severity.

Over time, this altered protein can clump together inside cells. Although the detailed molecular basis of Huntington’s disease is still debated and not completely understood, these protein clumps (called aggregates) are toxic — especially to brain cells — and are strongly linked to the symptoms of Huntington’s disease, such as a decline in mobility, memory loss and emotional dysregulation.

What kind of work is your research team doing?

A major focus of my lab is transfer RNAs, or tRNAs – essential molecules found in all cells and organisms that are involved in turning genetic information into proteins. In a way, they serve as the link between the instructions in our genes and the proteins our cells build from those instructions.

Because of their central role, we’ve used tRNAs over the years to explore many biological questions and, more recently, their potential in medicine. Initially, we became interested in the mutations in human tRNAs that cause errors during protein production.

This matters because many genetic diseases are caused by mutations in protein-coding genes — in principle, tRNA-based approaches could help correct those mistakes while proteins are being made.

Since 2018, our lab published a series of papers showing how naturally occurring human tRNA variants behave when expressed in different human cells. This work helped establish how these molecules can be engineered and applied in meaningful ways.

Ultimately, Huntington’s disease is driven by a toxic protein. If we can reduce or suppress the harmful effects of that protein, it may move us closer to real therapies. We’re seeing increasing momentum in the field, including other RNA-based approaches that have emerged in recent years and have shown promising results in clinical trials.

What are we still trying to understand about Huntington’s disease?

We’re still trying to understand exactly why the huntingtin protein becomes so harmful, and how it causes disease.

Surprisingly, even the normal function of the huntingtin protein is not fully understood. We know it’s involved in important cellular processes, especially in neurons, but its precise role — and what is lost or disrupted when it expands into the disease-causing form — is still being studied. Huntington’s disease is also a challenging field because there remains substantial ongoing debate about the underlying drivers of the disease.

What is very clear, though, is that reducing levels of the toxic huntingtin protein can relieve symptoms, which is what many of the most promising therapeutic strategies aim to do.

Personally, I’m especially excited by the therapeutic side of research. I studied tRNAs for more than 25 years largely out of scientific curiosity, and it’s been incredible to see that basic research evolve into something with real potential to make a difference for people suffering from diverse genetic disease for which treatments are limited or do not yet exist.

What does the Huntington Society of Canada Research Chair allow you to do?

The chair allows me to do something incredibly meaningful: connect students directly with those who have intimate knowledge of Huntington’s disease, including patients, families and fellow researchers.

That connection matters. It helps build a network of collaboration, and it reminds students their work isn’t abstract. The opportunity to interact one-on-one with people living with Huntington’s disease brings a deeper sense of purpose to the research.

This funding is a critical element that helps support my team of seven graduate students and a postdoctoral fellow as well as undergraduate researchers. Without this support, it becomes much harder to grow the lab, and that means leaving talent on the table or risking our research momentum.

This support helps us generate early research results that can lead to additional funding to accelerate progress in Huntington’s disease treatment.

What would you want families impacted by Huntington’s to know about where research is headed?

Families can be cautiously optimistic because of the sheer number of therapies currently in development or clinical trials. There’s an incredible amount of momentum in Huntington’s research right now. For example, a new microRNA-based therapy introduced by the University of Alabama at Birmingham has shown promising early results—reporting that at a high dose, it reduced the rate of disease progression by 75 per cent after three years.

More broadly, many of these approaches are part of a new wave of “nucleic acid medicines” — tools that aim to suppress the effects of toxic proteins. What’s especially promising is that in principle, some of these therapies could be adapted to treat other disorders caused by harmful proteins.

That’s why continued support matters. The more investment there is, the faster we can move research forward, not only for Huntington’s disease, but potentially for other neurodegenerative and genetic conditions as well.

If this Chair has a long-term legacy, what do you hope it will be?

The reason this position exists is simple: to help cure Huntington’s disease, and to use what we learn along the way to help treat or cure other genetic diseases.

That’s an ambitious goal, and I know it will be hard to reach. But moving the field forward by developing new tools, training the next generation of researchers and building momentum in Canadian Huntington’s disease research would represent a meaningful and lasting legacy.

Learn more about how Western is turning curiosity into solutions.