This conversation with D2R Training Program Officer, Anthony Van Kessel, has been edited for length and clarity.

Hi Caitlin, thanks for joining me for this interview! You are doing your PhD at ºÚÁÏÍø±¬³Ô¹Ï supervised by Professor Benoit Gentil and are a D2R Doctoral Scholar. How did you learn about D2R and what made you want to apply for the award?

I had heard about D2R through last year’s Symposium, so I wanted to apply in the first year of the awards. It's an opportunity where I can grow my career as well as my community and network. I was really involved in undergrad with different communities and societies, and I'm really excited for an opportunity where I can do that at a grad school level. The two main things that were most exciting were the Trainee Committee, which I've been involved with, and then also the opportunity for potential internships, which is really unique and exciting in the RNA therapeutics field.

Is there anything from the D2R Training events that you've most enjoyed?

The events are very welcoming and supportive of everyone. They feel collaborative. It’s great that we are working on establishing a community, but I also feel this was present from the first Orientation event last October.

How did you first become interested in working in a research lab?

I first became interested during my undergrad in the Honours Neuroscience program at McMaster University. It was a small cohort of about 20 people, so we had the opportunity to join a research lab in our second year through a research practicum. And I found an opportunity with Dr. Angela Scott – she ran the Molecular Biology and Pathology lab at McMaster University. I was able to gain three years of experience where I was working on Fragile X Syndrome, a neurodevelopmental disorder. I had experience first with data analysis during COVID, and then in my 4th year, I was able to get into the lab where I learned mouse brain dissections, primary cell culture techniques, and live cell imaging.

Was this experience valuable because it made you more excited to do research or do you feel the skills you learned directly translate to your research now?

I'm very, very thankful for that opportunity because it first helped me establish that I do really enjoy working in a wet lab. It was so cool to be a part of a lab when I was that young and I hadn't really built my career. But then as I started learning the techniques, it actually is directly translatable - I do similar cell culture techniques during my PhD research, but now I have a foundation.

Shifting gears, let’s talk about your project.

Yes. I work on Autosomal Recessive Ataxia of the Charlevoix-Saguenay (ARSACS), which is a very rare progressive neurodegenerative disorder that was first discovered in that region, thought to arise from a founder mutation from early French settlers. It has now been described worldwide, but the incidence rate isn’t known. Symptoms arise in childhood, on average at age 4-6, and we typically see a triad of common symptoms which include ataxia (or poor motor control), spasticity (or increased muscle tone), and then peripheral neuropathy (or damage to your peripheral nerves). ARSACS is a monogenic disorder caused by recessive mutations in the SACS gene, which encodes for this very large protein called sacsin. Sacsin's functions remain unclear, but it seems to be involved with a wide variety of processes, and the current working hypothesis is that sacsin functions as a chaperone protein and controls many aspects of protein folding and function that seem to be compromised in ARSACS.

And what is your work specifically focused on?

There are two aspects of what I'm interested in looking at. The first one is biomarker discovery. In many rare diseases, there are very few biomarkers that we're working with, especially in this field when SACS was only discovered in 2000. I'm focused on biomarker discovery that can be translated into the second part of my PhD, which is working toward developing nucleotide-based therapies for ARSACS. Before I started in the lab, we had a gene therapy that we've been working on and tested in vitro as well as in vivo mouse models. And the data are really promising, but the longer-term data suggest that the effect wears off over time and the animal may benefit from an additional dose. So we are working with and supported by D2R in transitioning this gene therapy into an RNA therapy, which will enable repeat and precise dosing that can be tailored to individual patient needs.

So, your goal is to treat with the correct version of the sacsin protein?

Yes, effectively. Sacsin is a multi-domain protein with several repeat regions, so based on previous work in our lab that discovered what the domains do, the gene therapy is a construct of the essential domains.

You mentioned that the incidence rate of this disease isn’t really known worldwide. Why do you think it’s important for initiatives like D2R to support research on rare diseases?

That's a great question. Even though so many individuals suffer from a type of rare disease, there are not many funding opportunities to discover the biomarkers of these diseases. Funding can increase the personnel and time spent discovering those biomarkers. And for initiatives like D2R, I feel it is really a low risk, high reward effort because there is so many aspects of the disease that are currently unexplored.

Building on this, how far do you see this project moving during your degree?

For my degree, it will be a lot of preclinical models with our mice. If that is promising, then we optimise dosage and delivery in in vivo models. And then my supervisor will step in and ensure it is translatable for clinical trials. So, my role will be the preclinical work, but I love the opportunities within D2R to learn about what those next steps will be.

Thanks so much for doing this. Before we wrap up, I wanted to ask if there is anything that you want the D2R community to know about you? Maybe outside of the lab?

Well, outside of the lab I make a constant effort to listen to as many albums as I can and read as many books as I can. And also, I’ve really been into just walking everywhere. Montreal is such a great walking city so I spend most of my free days wandering around and trying to discover as much of the city as I can!

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