Sildenafil – an active ingredient also marketed under the name of Viagra – improves symptoms in patients with Leigh syndrome. This has now been reported in the Cell* journal by researchers at Charité – Universitätsmedizin Berlin, together with teams from Heinrich Heine University Düsseldorf (HHU), University Hospital Düsseldorf (UKD), and the Fraunhofer Institute for Translational Medicine and Pharmacology ITMP in Hamburg. Leigh syndrome is a rare, previously untreatable metabolic disorder occurring in childhood and causing severe neurological and muscular symptoms. In a pilot study involving six patients, sildenafil showed a positive effect on the course of the disease.
Leigh syndrome is a congenital disorder of the brain and muscles caused by a defective energy metabolism, often manifesting in infancy or early childhood. The disorder progresses slowly and is accompanied by severe symptoms such as epileptic seizures, muscular weakness and paralysis, while mental development may also be impaired. Patients with Leigh syndrome have a significantly lower life expectancy, and there is currently no approved drug therapy.
A genuine surprise: Potency drug proves effective
Now, however, a research team has identified a candidate drug that showed promising effects in a pilot study – and which may seem surprising at first glance: sildenafil, a so-called PDE-5 inhibitor. The drug is best known as a treatment for erectile dysfunction in adults. However, thanks to its vasodilatory effect, it also finds use in the treatment of pulmonary hypertension in infants. The study entailed administering sildenafil continuously to six Leigh syndrome patients between the ages of 9 months and 38 years. Within the time span of only a few months, their muscular strength in particular improved, and in some cases the neurological symptoms also disappeared. Moreover, they recovered more quickly from metabolic crises, i.e., overloads of the energy metabolism, which can suddenly worsen the course of this disorder.
"For example, in the case of a child undergoing sildenafil treatment, the walking distance increased tenfold, from 500 to 5,000 meters," as Prof. Markus Schuelke explains. "In another child, the therapy completely suppressed metabolic crises that occurred almost monthly, while another patient no longer suffered from epileptic seizures." Markus Schuelke is a physician and scientist at Charité's Department of Pediatric Neurology and one of the lead authors of the recently published study. He went on to emphasize: "Such effects significantly improve the quality of life of Leigh syndrome patients. While we will have to confirm these initial observations in a more comprehensive study, we are very pleased to have found a promising drug candidate for the treatment of this serious hereditary disease."
Why the search for therapies for rare diseases is difficult
Such success cannot be taken for granted, as Leigh syndrome is rare, affecting only one in 36,000 children. "The low case numbers make it difficult to research the disease and present some obstacles in our urgent search for effective therapies," explains Markus Schuelke. With such a small number of patients, large-scale studies are hardly possible, meaning that specialists from several centers must collaborate internationally. What is more, it is not possible to simply remove brain or nerve tissue from patients in order to investigate the causes of the disease.
In order to identify sildenafil as a potentially effective drug, the researchers had to resort to some methodological tricks. In an initial step, they took skin cells from the patients and used them to produce so-called induced pluripotent stem cells in the laboratory – cells that are capable of developing into very different cell types. From the stem cells, they cultured nerve cells whose metabolism exhibited the same defective functionality as that of the patients. In the next step, the researchers selected over 5,500 active substances that were already approved for the treatment of other diseases or for which extensive safety and efficacy data were available, and tested their effect on the cultured nerve cells.
Positive effect on cells, in animal models, and in patients
"This is the largest drug screening for the treatment of Leigh syndrome to date," emphasizes Dr. Ole Pless, lead author of the study from ITMP. "It showed that sildenafil, among other drugs, improved the electrical functionality of the nerve cells." Additional laboratory tests supported the results obtained at the cellular level: In three-dimensional miniature replicas of the brain, known as organoids, sildenafil enhanced the growth of nerve cells, for example. The drug also improved the energy metabolism and increased life expectancy in animal models.
"Based on these results, we decided to administer the drug as part of an individual therapeutic trial in six patients with Leigh syndrome," as Prof. Alessandro Prigione, lead author from the Department of General Pediatrics, Neonatology, and Pediatric Cardiology at the UKD stated. "Another decisive factor was the fact that detailed safety data was available for the long-term use of sildenafil in children, as the active ingredient is already approved for other pediatric disorders." The first patient with Leigh syndrome was treated at Charité. Following positive results, additional patients were treated in Düsseldorf, Munich, and Bologna. All of the patients tolerated the drug well overall.
Comprehensive clinical study planned
Based on the results now published, the European Medicines Agency (EMA) has granted sildenafil the status of an orphan drug (ODD), meaning a drug for rare diseases. Such drugs can undergo a simplified approval process, which is intended to support the development of therapies for rare diseases. In order to validate the new findings and – given that the previous observations are confirmed – prepare for the approval of sildenafil for Leigh syndrome, the research team is planning a Europe-wide placebo-controlled clinical trial as the next step. The trial will be conducted as part of the SIMPATHIC EU project.
*Zink A et al. Pluripotent stem cell-based drug discovery uncovers sildenafil as a treatment for mitochondrial disease. Cell 2026 Mar 11. doi: 10.1016/j.cell.2026.02.008
About the Leigh syndrome
The Leigh syndrome is one of the so-called mitochondriopathies, i.e., diseases of the energy metabolism. Mitochondria are the powerhouses of the cell and supply it with energy. In Leigh syndrome, mutations in the genetic material result in mitochondrial dysfunction, resulting in cerebral tissue damage. Depending on which region of the brain is affected, different symptoms occur, which already manifest in infancy or early childhood. These include muscle weakness, difficulty swallowing, respiratory disorders, epileptic seizures, and delayed mental development. The hereditary disease is currently incurable, and most affected children die within a few years of diagnosis. With one case occurring per 36,000 live births, Leigh syndrome classifies as a "rare disease." According to the European classification, these are diseases that affect fewer than five in 10,000 people.
About the study
The study was conducted under the auspices of Charité (Prof. Markus Schuelke), HHU and UKD (Prof. Alessandro Prigione), ITMP (Dr. Ole Pless), Université du Luxembourg (Prof. Antonio del Sol), and Università di Verona (Dr. Emanuela Bottani). Research groups from Germany, Austria, Finland, the Netherlands, Poland, Italy, Greece, and the USA were also involved. The work was mainly funded by the German Research Foundation (DFG), the German Federal Ministry of Education and Research, the Excellence Strategy of the German federal & state governments (NeuroCure Cluster of Excellence), and the European Commission.
