Researchers from DZNE and the Hertie Institute for Clinical Brain Research (HIH) at the University of Tübingen, together with experts from Bonn, London, and Portugal, have developed and successfully tested in human neurons cultured in the lab a new approach for treating the rare neurodegenerative disease Spinocerebellar Ataxia Type 3 (SCA3) . Their findings, published in the journal Science Translational Medicine , could pave the way for a therapy that alleviates the disease's symptoms and slows its progression. SCA3, also known as "Machado-Joseph disease", is a severe inherited brain disorder that can cause difficulties with walking, speech, eye movements, and other symptoms.
The research team's concept is based on custom-designed drugs known as antisense oligonucleotides (ASOs). These are intended to specifically reduce the levels of a disease-causing protein. "The disorder is triggered by a harmful form of a protein called Ataxin-3. This form arises from a disease-causing change in the corresponding gene: A particular stretch of DNA is repeated too many times," explains Dr. Stefan Hauser , a research group leader at DZNE and HIH. "Humans generally have two copies of this gene, and in SCA3, usually only one carries the disease-causing change. The other copy continues to produce normal Ataxin-3, which performs important functions in the cell. Our goal is therefore to develop a treatment that reduces the amount of harmful Ataxin-3 while largely preserving the normal protein. This is the key difference from previous ASO-based therapeutic approaches: While they attack the toxic protein, its healthy form is often caught as collateral damage. This should be avoided."
Targeted Breakdown of mRNA
Therefore, the research team synthesized ASOs that specifically reduce the production of the harmful protein. To this end, these drugs intervene at a critical point in the production chain: They bind to so-called mRNA molecules, which carry the blueprint for manufacturing proteins from the genome to the cell's protein factories. "The key point is that our ASOs attach primarily to the mRNA relevant for the disease and trigger its degradation. As a result, less of the harmful protein is produced. The most effective of the substances we tested reduced the amount of toxic Ataxin-3 by approximately 90 percent, while the normal protein was largely preserved. Our approach is therefore highly specific," Hauser says.
Precise Target Recognition
Despite their different effects, the disease-causing gene copy and its healthy counterpart are very similar. The same applies to their molecular transcripts in the form of mRNA. So, how did Hauser's team find a way to distinguish the two variants? By analyzing the genome of 79 individuals with SCA3, the researchers identified subtle differences: so-called SNPs—an acronym for "Single Nucleotide Polymorphisms". "Our ASOs are designed to specifically identify these differences," the scientist explains. "Therefore, they preferentially promote the degradation of mRNA from the disease-causing gene copy, while largely preserving mRNA from the other copy. This allows the production of the normal protein to continue."
The research team intends to further refine this new therapeutic concept in more complex laboratory studies. "The next step is to optimize the most promising ASOs and investigate their efficacy and safety in further studies. The long-term goal is to test this treatment in humans through clinical trials. However, getting there will likely take some time," Hauser says.
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About Deutsches Zentrum für Neurodegenerative Erkrankungen, DZNE (German Center for Neurodegenerative Diseases):
DZNE is among the world's leading research centers dedicated to neurodegenerative diseases, including Alzheimer's, Parkinson's, and ALS. These conditions are linked to dementia, movement disorders, and other severe health impairments. They place an enormous burden on patients and their families, as well as on society and the health care system. DZNE plays a key role in developing novel strategies for prevention, diagnosis, care, and treatment – and in bringing them into practice. With ten sites across Germany, it collaborates closely with universities, university hospitals, and other research institutions both in Germany and internationally. DZNE is publicly funded and is a member of the Helmholtz Association and the German Centers for Health Research. www.dzne.de/en
