Press release

Published: 09 September 2024

Scientists from Berlin and Düsseldorf are researching rare diseases using mini-brains

Huntington's disease is an inherited neurodegenerative disorder. About 5 to 10 out of 100,000 people are affected by it. The disease leads to uncoordinated movements, psychological changes, dementia, and eventually death due to the loss of nerve cells. Current therapies only alleviate the symptoms but can neither halt nor slow down the progression of the disease. Researchers from the Heinrich Heine University Düsseldorf (HHU) and the Max Delbrück Center (MDC) in Berlin have now gained new insights into how the disease progresses by using human mini-brains and found a potential target for future therapies. The nationwide association Doctors Against Animal Experiments is calling for a consistent switch to animal-free methods - for all diseases.

The cause of Huntington's disease is a mutation in the so-called huntingtin gene (HTT), where an abnormal multiplication of a small DNA segment occurs. As a result, the huntingtin protein, which is translated from the DNA, changes its three-dimensional structure and can clump together. This leads to protein deposits in the patients' nerve cells. "However, it was not previously known how the mutation leads to neurodegeneration and the death of nerve cells. The targeted development of therapies is not possible without this knowledge," explains Dr. Johanna Walter, scientific advisor at Doctors Against Animal Experiments.

Researchers from the MDC and HHU used human stem cells to decipher the mechanisms underlying the disease (1). Using the CRISPR-Cas gene-editing tool, they introduced the DNA changes typical of Huntington's disease into the HTT gene. They then allowed the altered cells to grow into so-called mini-brains or brain organoids, which are three-dimensional cell constructs. They discovered that the development of organoids with mutated HTT differs significantly from those carrying a healthy HTT variant. The mutated HTT impairs brain development at an early stage, contradicting the previous belief that Huntington's disease only affects mature neurons (2).

The researchers also discovered that in the organoids with mutated HTT, the protein CHCHD2 is produced in lower amounts. This protein is linked to the function of mitochondria - the powerhouses of our cells. As a result, the mutation leads to poor energy supply and reduced metabolism in the nerve cells. This was also confirmed in experiments with cells derived from Huntington's disease patients. When the researchers increased the production of CHCHD2, mitochondrial function returned to normal. Thus, the gene represents a promising target for the development of new drugs (2).

Professor Alessandro Prigione from HHU, who was significantly involved in the Huntington study, has previously conducted research on another neurodegenerative disease using organoids. In this case, cells from patients with the rare Leigh syndrome were used (3). The work not only provided insights into the mechanisms underlying the disease but also made it possible to identify drugs for treating Leigh syndrome. This directly benefited a first patient, who had already been paralyzed due to the disease and had been in a coma for weeks. After treatment with a drug identified with the organoids, the 15-year-old patient quickly recovered. He was able to breathe independently again, move, and - while sitting in a wheelchair - return to school. Other patients have also been helped with this therapy (4).

"These works were rightly awarded the Eva Luise Köhler Research Prize for Rare Diseases (5)," reports Walter. The studies also demonstrate the potential of organoids based on human cells to finally improve our understanding of human diseases and develop therapies. The fact that this potential has so far been used primarily for rare diseases like Huntington's disease or Leigh syndrome is due to the lack of model systems for these conditions. "Modern, animal-free methods can exemplary be used as models for rare diseases and show what they are capable of. Hopefully, the success of this research will accelerate the shift away from animal experiments and toward human-relevant model systems. This would not only benefit animals but, above all, countless patients who have so far waited in vain for effective treatments," Walter continues.