Project goal: Explore the link between the RFC1 gene and CANVAS to help uncover therapeutic avenues.
The genetic cause of CANVAS (Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome) was only recently discovered: a repeated expansion1 in the RFC1 gene. However, we still don’t know how this expansion causes cerebellar anomalies. This lack of knowledge and tools is preventing any drug development projects, leaving patients with this late-onset form of ataxia without therapy.
There are two main hypotheses as to how these expansions can be harmful: (1) they disrupt the normal function of the neighboring RFC1 gene, and/or (2) they produce toxic molecules affecting the cerebellum. We will study the cells of CANVAS patients using cutting-edge technologies (sequencing, induced pluripotent stem cells) to detect the slightest clue supporting either hypothesis.
We will also create zebrafish models to test both hypotheses. The zebrafish is a good choice for several reasons. Firstly, the brain structures of this fish are quite similar to those of humans. The knowledge gained from this model will help us to understand what is happening in patients. Secondly, their rapid life cycle and the ability to hold large numbers of them means we can test a wide range of potential drugs and treatments.
In summary, by elucidating the mechanism by which this repeated expansion of the RFC1 gene affects the integrity of the cerebellum, we hope to be able to propose tangible solutions for developing therapies. This is a step towards identifying a potential treatment for CANVAS patients, one of the most common forms of late-onset cerebellar ataxia.
1Repeated expansions occur when the cellular machinery to copy DNA makes mistakes and adds additional nucleotides in a gene.