The Neuro continues to expand its clinical research into rare genetic conditions with a groundbreaking study of the first potential RNA therapy for individuals with Spinocerebellar Ataxia Type 2 (SCA2).
This experimental therapy aims to block the faulty ataxin-2 gene in the brain and spinal cord, potentially halting or even reversing the damage caused by the disease. Until now, there have been no effective treatments for SCA2, a fatal disorder that is disproportionately common in Quebec.
What is Spinocerebellar Ataxia Type 2
Spinocerebellar ataxia (SCA) is a group of rare, inherited neurological disorders that progressively impair movement. Over time, they cause loss of balance, coordination, and muscle control, affecting gait, speech, swallowing, bladder function, and memory.
According to the Ataxia Foundation of Canada, SCA2 typically begins around age 40, with an average survival of 10 to 20 years after symptom onset.
The genetic cause of SCA2
SCA2 is caused by a mutation in the ataxin-2 gene. Specifically, an abnormal repetition of the three-letter genetic code "CAG" results in an extended stretch of the amino acid glutamine in the ataxin-2 protein. When this repeat exceeds a certain threshold, the protein becomes toxic, misfolding and clumping inside nerve cells, ultimately leading to their death.
鈥淲hen there are too many CAG repeats, the cell produces a mutant form of ataxin-2 that accumulates in the brain regions responsible for movement coordination and, in some cases, memory,鈥� explained Dr. Massimo Pandolfo, a leading ataxia researcher and Medical Director of the Clinical Research Unit (CRU) at The Neuro.
A New RNA-based approach
The clinical trial at The Neuro will test a small interfering RNA (siRNA) molecule designed to precisely reduce the production of ataxin-2. This approach leverages the cell鈥檚 natural mechanisms to lower ataxin-2 levels, targeting the disease at its molecular source.
A 2017 study published in Nature demonstrated that silencing the ataxin-2 gene prevented disease onset in animal models. While this therapy will reduce both mutant and normal ataxin-2 levels, preclinical studies suggest this poses no significant risk.
Notably, this RNA-based treatment differs from antisense oligonucleotide therapies previously tested in related diseases, which have been associated with toxicity issues.
鈥淚f effective, this therapy could prevent or even reverse the toxic effects of mutant ataxin-2, potentially improving gait and other symptoms in people with SCA2,鈥� added Pandolfo.
A critical focus for Quebec
Quebec has an unusually high prevalence of rare neurological diseases due to the 鈥渇ounder effect,鈥� where genetic conditions become more concentrated in certain populations.
鈥淚n families affected by SCA2, children have a 50% chance of inheriting the mutated gene. As the disease progresses, they experience increasing difficulty with walking, speech, and hand coordination, making everyday activities challenging. Cognitive decline can also occur,鈥� explained Pandolfo.
Each generation may develop symptoms at an earlier age, and when multiple family members are affected, accessing adequate care and support becomes even more complex.
The Neuro鈥檚 role in a global study
The Neuro is one of only three sites in Canada participating in this international Phase 1 clinical trial. The study will assess the therapy鈥檚 safety, determine the optimal dose, and monitor potential side effects. Participants will be randomly assigned to receive either the investigational treatment or a placebo.
At the end of the trial, all participants will have the option to access the treatment early.
For current trials at The Neuro鈥檚 CRU, visit cru.mcgill.ca/mvtdis, or contact (514) 398-5500; info-neuro.cru [at] mcgill.ca.
