Experimental treatment selectively reduces harmful protein in lab models of rare inherited brain disorder

Researchers from the DZNE and the Hertie Institute for Clinical Brain Research, in collaboration with experts from Bonn, London, and Portugal, have developed and tested a novel treatment for the rare inherited brain disorder spinocerebellar ataxia type 3 (SCA3) in human neurons grown in a laboratory setting. Their findings, published in Science Translational Medicine, suggest that the approach could lead to a therapy that eases the disease's symptoms and slows its progression.

SCA3, also referred to as Machado-Joseph disease, is a severe genetic condition that can result in issues with walking, speech, eye movements, and other symptoms. The treatment focuses on custom-designed drugs called antisense oligonucleotides (ASOs), which aim to lower the levels of a harmful protein known as ataxin-3. This protein is produced due to a change in the gene responsible for making it, which typically occurs in only one copy of the gene in individuals with SCA3.

By developing ASOs that specifically target and reduce the production of the harmful ataxin-3 while preserving the normal protein, the research team hopes to avoid the collateral damage caused by previous ASO-based therapies. The most effective of the tested substances reduced the harmful protein by approximately 90%, while the normal protein was largely preserved.

The team identified subtle genetic differences between the disease-causing and healthy copies of the gene, allowing the ASOs to selectively target the harmful protein. The researchers plan to further refine this therapeutic concept in more complex laboratory studies, optimize the most promising ASOs, and investigate their efficacy and safety in further studies before testing the treatment in humans through clinical trials.