New potential therapy approach for Leigh Syndrome Blueprint for new treatments for rare diseases

An international research team, including researchers of the Radboud university medical center (Radboudumc), identified a promising drug for the treatment of Leigh Syndrome. In this study, evidence is provided that the drug sildenafil has a beneficial effect on the disease course. 

Leigh Syndrome is an inherited progressive disease. It is a so-called mitochondrial disease in which energy metabolism is affected. The syndrome, which usually manifests in childhood, causes brain damage, which can lead to severe symptoms such as neurodevelopmental delay, epileptic seizures, muscular weakness, and respiratory failure. Leigh Syndrome is classified as a ‘rare disease’. According to the European definition, a rare disease affects less than five in 10,000 people. The life expectancy of children with Leigh Syndrome is limited and most die within a few years of diagnosis. No approved medication is currently available. 

The international research consortium CureMILS, funded by the European Joint Programme on Rare Diseases (EJP-RD), set out to develop alternative model systems to progress Leigh Syndrome research. The researchers used skin cells from patients as a basis for deriving induced pluripotent stem (iPS) cells, which have the ability to differentiate into various somatic cells – for example nerve cells – in the laboratory. Also, so-called brain organoids can be derived from iPS cells, which represent 3D models of the brain. On the basis of the nerve cells generated from patient stem cells, the researchers conducted an extensive drug screening process. They compiled a library of more than 5,500 drugs or drug-like molecules, which have in-part been approved for other conditions and for which extensive safety and efficacy data are already available. These drugs were then tested on the nerve cells in the laboratory. In the course of the screening process, sildenafil was identified as a potential therapeutic candidate. 

In the cell model, the researchers were able to prove that the drug had a positive effect on metabolism and improved the function of the cells affected by the disease. Sildenafil is currently approved for the treatment of erectile dysfunction in adults. It is also approved for the treatment of pulmonary hypertension in infants. Sildenafil thus offers a good safety profile and promising results in terms of effectiveness in the cell model.

During the course of the study, it was also possible to confirm these results in brain organoids and in relevant animal models, which encouraged the researchers to try sildenafil as individual basis treatment in six patients. Sildenafil had a positive effect on the disease course in all patients treated.

On behalf of Radboudumc, researchers Jesper Bergman, Merel Adjobo-Hermans and Werner Koopman were involved in CureMILS. Koopman: ‘The fact that positive effects of sildenafil were observed across different research methods is encouraging. Although the initial group is small and further research remains necessary, the results may offer perspective for Leigh syndrome patients. We therefore hope to conduct a larger clinical study soon. Moreover, this research can serve as a blueprint for the search for new treatments for other rare energy metabolism disorders.’ This strategy is now being applied within the currently running international SIMPATHIC research program.

Important message for patients and healthcare providers

The CureMILS researchers strongly emphasize that sildenafil must not be administered to patients with Leigh syndrome without strict medical supervision. Although the initial results appear promising, a larger study with more participants is essential to determine how the medication truly works in this patient group.

Radboudumc is the VWS‑recognized expertise center for this condition and treats approximately 800 patients each year with various types of energy metabolism disorders. Healthcare providers are therefore urgently requested to always consult the researchers of the SIMPATHIC team (simpathic.mbs@radboudumc.nl) before prescribing or considering treatment.

About this publication

This article appeared in Cell: Pluripotent stem cell­based drug discovery uncovers sildenafil as a treatment for mitochondrial disease. (2026) Annika Zink, Dao­Fu Dai, Jesper Bergmans […], Merel J.W. Adjobo­Hermans […], Werner J.H. Koopman […], Ole Pless, Markus Schuelke, Alessandro Prigione. DOI: 10.1016/j.cell.2026.02.008. 

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