Leigh syndrome
https://www.nature.com/articles/s41467-026-71391-2
Children with Leigh syndrome, a progressive genetic neurological disorder, often experience developmental regression, movement problems, brain damage, and early loss of life as their cells cannot produce energy properly. To study the disease, the authors of this study used stem cells from patients to grow brain organoids. These organoids reproduced key features of the disorder, including poor development of neurons and abnormal brain growth. The team then combined this model with advanced deep learning tools that analysed gene activity and predicted existing drugs that might reverse the disease process. At the same time, they carried out a large drug screen in genetically modified yeast cells that mimic aspects of Leigh syndrome. Both approaches independently identified a group of compounds called azoles as promising candidates. Two drugs in particular, talarozole and sertaconazole, improved the growth and development of neurons in patient-derived cells and brain organoids. The drugs also reduced harmful lactate build-up, a common sign of mitochondrial dysfunction, and improved organoid growth. Further analysis suggested that these compounds work by influencing vitamin A–related signalling pathways and lipid metabolism in cells. The study demonstrates how artificial intelligence, combined with human brain organoids, can accelerate the search for treatments for rare neurological diseases. Although more research and clinical testing are still needed, the findings provide encouraging leads for future therapies for Leigh syndrome.