A targeted approach to treating SCA3
Since 2023, Ataxia UK has funded two research projects led by Dr Stefan Hauser at the German Center for Neurodegenerative diseases (DZNE), Tübingen, Germany. These projects were focused on identifying ways to treat Spinocerebellar ataxia type 3 (SCA3), by specifically targeting the SCA3-causing gene. Results from these research projects have recently been published in the journal Science Translational Medicine.
Why was this research needed?
SCA3, also called Machado–Joseph disease (MJD), is caused by a change in a gene that makes a protein called ataxin-3. The condition is inherited in what is known as a dominant manner. This means that people with SCA3 usually inherit one gene copy from one parent that produces harmful ataxin-3, and another from the other parent which produces a healthy ataxin-3 protein. The healthy ataxin-3 protein has important roles in cells.
What did the researchers do?
The team developed experimental treatments called antisense oligonucleotides (ASOs). These are short, specially designed molecules that attach to messenger RNA: the instructions cells use to make proteins. Attaching an ASO can trigger the breakdown of these instructions, reducing protein production. The researchers used small differences in the genetic code to help distinguish instructions for harmful ataxin-3 from those for the normal protein. The aim was to reduce production of the harmful ataxin-3 protein, whilst leaving the healthy version of the protein to function in the cell. They tested their approach on human neurons grown from patient stem cells in the laboratory.
What did they find?
The most effective ASO reduced harmful ataxin-3 protein by up to 90%, while largely preserving the normal protein. This suggests it may be possible to target the disease-causing protein, whilst leaving the normal version of the protein to carry out its role in the cell.
What does this mean for people with SCA3?
This is an encouraging early step towards a more targeted treatment. However, the findings come from laboratory-grown cells, not a trial treating people. A reduction in harmful ataxin-3 protein does not yet show that the treatment improves symptoms or slows SCA3. Further research is needed to establish whether this approach can be delivered safely and effectively to the brain, and provide lasting benefits.
