Martine Tétreault and Éric Samarut, researchers at the CHUM Research Centre (CRCHUM), have received funding for their research project, which will be financed by Génome Québec, Ataxia Canada and Muscular Dystrophy Canada. Their project is one of three winners of the Innovative Therapies for Hereditary Ataxias competition.

The two CRCHUM researchers will more specifically focus on CANVAS syndrome (Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome), one of the most common forms of late-onset cerebellar ataxia. The term “cerebellar” refers to everything pertaining to the cerebellum, the part of the brain which controls movement and coordination.

The prevalence of this large family of diseases is estimated to impact 1 to 3 people in 100,000 people.

The most recent data in the European registry of rare diseases, Orphanet, shows that more than 25,000 people in Europe are diagnosed with an illness that is part of the ataxia family. 

To date, there is no available treatment.

Éric Samarut, assistant professor at the Université de Montréal, believes that the number of CANVAS syndrome diagnoses is underestimated, primarily because its genetic cause was only identified in 2019. 

The funding of our project by Ataxia Canada brings people together: we are working hand in hand with the patient community to advance available knowledge and to identify new treatment options.

Cell machinery failures

The genetic cause of the disease, repeat expansion in the RFC1 gene, doesn’t explain how it triggers cerebellar anomalies.

These repeat expansions occur when the cellular machinery responsible for copying DNA makes the mistake of adding extra nucleotides in a gene.

Tétreault and Samarut, who specialize in the functional genomics of rare neurological and metabolic diseases, are investigating two hypotheses to explain the harm caused by these expansions: 

1. They disrupt the normal function of genes neighbouring RFC1; 
2. They produce toxic molecules that affect the cerebellum.

They will be conducting their research on cells of people living with CANVAS syndrome with the help of cutting-edge technologies (sequencing, induced pluripotent stem cells).

“Repeat expansions in the RFC1 gene are extremely difficult to study due to their large size and the complexity of their sequences. Our laboratories have unique tools to meet the challenge and better our understanding of this disease,” says Martine Tétreault, who is also an assistant professor at the Université de Montréal.

Potential outcomes for the ataxic community

To test their two hypotheses, the scientific team will design zebrafish models mimicking one or other of the scenarios at the origin of the harmfulness of repetitions in RFC1.

This animal model, whose brain structures are fairly similar to those of human beings, makes it possible to rapidly study the development and functions of the central nervous system.

Thanks to this model, the knowledge acquired will help them to understand what is happening in people suffering from the disease, with the hope of identifying possible remedies.

“Our primary objective is to use the knowledge gained through this project to develop new treatments. This project has the potential to have a big impact not only for the patients involved in this study, but for the larger ataxic community,” says Tétreault.