Leigh syndrome: possible therapy chosen from 5,600 candidates tested on patients' stem cells

An international study, published in the journal Cell, opens up new therapeutic perspectives for Leigh syndrome, a serious paediatric mitochondrial disease that has so far lacked effective treatments. The work represents a breakthrough in the field of rare diseases and translational medicine and was coordinated by Alessandro Prigione of the University of Düsseldorf, assisted in Italia by Dario Brunetti, researcher at the Department of Clinical and Community Sciences of the University of Milan and the Carlo Besta Neurological Institute, and Emanuela Bottani, researcher and professor of Pharmacology at the University of Verona. The research was developed as part of the European consortium CureMILS, funded by the European Joint Programme on Rare Diseases with €2.4 million and involving numerous centres of excellence in Europe and the United States.

Leigh's syndrome is a progressive genetic disease that affects the central nervous system and impairs energy production in cells, causing, from the earliest years of life, delayed psychomotor development, metabolic crises, muscle weakness, respiratory difficulties and, in the most severe cases, rapid clinical deterioration with death of patients in the first years of life. To date, there has been no therapy capable of modifying the course of the disease.

The study adopted an innovative translational pharmacology approach, i.e. integrating basic research, advanced experimental models and early clinical applications.

Starting with induced pluripotent stem cells (iPSCs) derived from patients' skin cells, the researchers recreated nerve cells affected by the disease in the laboratory, thus being able to study the biological mechanisms directly. A high throughput screening of more than 5,600 repositionable drugs was carried out on these neural progenitors, identifying phosphodiesterase type 5 inhibitors, in particular sildenafil, already approved for clinical use, as promising candidates. The latter improved the energy metabolism and function of cells affected by the disease, the results were subsequently confirmed in animal models and, based on these data, the treatment was then administered to a small group of patients for individual use, showing good tolerability and preliminary signs of clinical benefit.

The drug showed the ability to correct defects in mitochondrial function and restore nervous system developmental programmes in patient cells and brain organoid models. Subsequently, efficacy and safety were validated in a stepwise pathway that included a mouse model and a pig model of the disease (generated by the biotech company Avantea), and finally compassionate treatment in patients with Leigh syndrome. In animal models, sildenafil improved the disease phenotype and extremely prolonged survival, while improved motor function and increased resistance to metabolic seizures were observed in treated patients.