Microscopic image of a 3D brain model, as used in the study
(red: neural progenitor cells; blue: neurons).
Image Credit: © HHU / Stephanie Le, AG Prigione
Scientific Frontline: "At a Glance" Summary: Sildenafil as a Therapy for Leigh Syndrome
- Main Discovery: Researchers identified the repurposed drug Sildenafil as a highly promising and effective treatment capable of improving the disease course of Leigh Syndrome, a severe and previously untreatable mitochondrial disorder affecting brain energy metabolism.
- Methodology: The international research consortium derived induced pluripotent stem cells from patient skin cells to cultivate 3D brain organoids and nerve networks, subsequently utilizing these models to screen a comprehensive library of over 5,500 approved drugs and molecules.
- Key Data: Affecting roughly one in 36,000 live births, Leigh Syndrome had no approved treatments until this study screened 5,500 compounds and successfully administered the leading candidate, Sildenafil, to six human patients, all of whom demonstrated rapid recovery from critical episodes and increased muscular strength.
- Significance: Because Sildenafil already possesses a well-documented long-term safety profile for treating pulmonary hypertension in infants, this discovery bypasses standard early-phase toxicity hurdles, offering an immediate and safe therapeutic intervention for a fatal childhood neurodevelopmental disease.
- Future Application: The European Medicines Agency has officially granted Sildenafil an Orphan Drug Designation, enabling the SIMPATHIC research consortium to initiate a multinational, placebo-controlled clinical trial aimed at securing formal regulatory approval for widespread clinical use.
- Branch of Science: Pediatric Neurology, Cellular Biology, and Molecular Pharmacology.
- Additional Detail: The study represents the largest drug screening process ever conducted specifically for Leigh Syndrome, successfully overcoming the traditional lack of accurate cellular and animal models that historically hindered rare disease research.
An interdisciplinary research team at Heinrich Heine University Düsseldorf (HHU) and University Hospital Düsseldorf (UKD) has, in collaboration with researchers from the Charité – Universitätsmedizin Berlin and the Fraunhofer Institute ITMP in Hamburg, identified a promising drug for the treatment of Leigh Syndrome. In the study, which has now been published in Cell, the researchers were able to prove that the drug Sildenafil had a beneficial effect on the course of the disease. The study was headed by Professor Dr Alessandro Prigione (Department of General Pediatrics, Neonatology and Pediatric Cardiology, UKD) and Professor Dr Markus Schuelke (Department of Pediatric Neurology, Charité).
Leigh Syndrome is an inherited, progressive disease that affects the brain. It is a so-called mitochondrial disease, i.e. it affects the energy metabolism. The syndrome, which usually manifests in childhood, causes damage in the brain, which can lead to severe symptoms such as neurodevelopmental delay, epileptic seizures, muscular weakness, and respiratory failure. No approved medication is currently available. The life expectancy of children with the disease is limited, and most die within a few years of diagnosis.
With one case in 36,000 live births, 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 low number of cases makes research for treatments more difficult, resulting in a lack of approved therapies for many rare diseases. Another challenge is that these low patient numbers make larger-scale studies difficult. Studying Leigh Syndrome is further complicated by the lack of cellular or animal models, which can faithfully recapitulate the disease course of affected individuals.
The international research consortium set out to develop alternative model systems that can advance Leigh Syndrome research. In addition to HHU and the UKD, Charité and the Fraunhofer Institute for Translational Medicine and Pharmacology ITMP are also involved, together with several other research groups in Germany, Austria, Finland, the Netherlands, Poland, Italy, Greece and the USA. Headed by Professor Prigione, 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. So-called brain organoids can also be derived from iPS cells, which represent 3D models of the brain. Patient-derived iPS cells served as an important foundation for the research findings, which have now been published.
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. During 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. “With more than 5,500 compounds tested, this was the largest screening process to tackle Leigh Syndrome ever conducted. We are very proud that we have succeeded in realizing this process and been able to identify a potential therapeutic agent”, says Dr Ole Pless (ITMP). 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 the brain organoid and in different animal models, which encouraged the researchers to try Sildenafil as an individual basis treatment in six patients. The first Leigh Syndrome patient was treated with Sildenafil at Charité. Following positive results, further patients in Düsseldorf, Munich and Bologna were also treated. Sildenafil had a positive effect on the disease course in all patients treated. The medication was well-tolerated. “Extensive safety data on the long-term use of Sildenafil in children are already available, so we can assume that this could be a safe drug candidate for Leigh Syndrome,” reports Professor Prigione. “In the patients treated to date, we were able to observe that they recovered quickly from critical medical situations, their neurological function improved, and their muscular strength increased,” adds Professor Schuelke (Charité).
As a result of these findings, the European Medicines Agency (EMA) has granted Sildenafil an Orphan Drug Designation (ODD). The ongoing Horizon research consortium SIMPATHIC, in which Professor Prigione and Professor Schuelke are also involved, is currently planning a multinational placebo-controlled clinical trial to determine whether Sildenafil is effective and safe in this patient population, and thus whether the EMA can approve it for the treatment of Leigh Syndrome.
Funding: The publication is the result of a multinational collaboration within the framework of the CureMILS consortium funded by the European Joint Program on Rare Diseases (EJP RD) and coordinated by Professor Prigione.
Published in journal: Cell
Title: Pluripotent stem-cell-based screening uncovers sildenafil as a mitochondrial disease therapy
Authors: A. Zink, D-F. Dai, A. Wittich, M-T. Henke, G. Pedrotti, S. Heiduschka, G. Santamaria, T. M. Pentimalli, C. Brueser, S. Notopoulou, A. R. Umar, A. Zhaivoron, L. Petersilie, C. Jerred, J. Bergmans, L. A. Neu, F. Schumacher, J. Keller-Findeisen, A. Rybak-Wolf, D. Stach, J. Reinshagen, U. Haferkamp, K. Krieg, A. Zaliani, L. Euro, A. Di Donfranceso, C. Santanatoglia, E. Cappellozza, M. Suarez Cubero, M. Pavez-Giani, O. Bakumenko, D. Meierhofer, A. Foley, S. Morales-Gonzalez, I. Tolle, D. Herebian, D. Bonesso, G. Cecchetto, S. Nagumo Wong, M. Moresco, A. Maresca, I. Decimo, F. De Sanctis, A. Adamo, M. J. W. Adjobo-Hermans, R. Duchi, M. Barandalla, M. Scaglia, A. Perota, C. Galli, B. Kleuser, L, Cyganek, C. Mühlhausen, L. Schlotawa, V. Tiranti, E. Mayatepek, I. Szabo, C. La Morgia, T. Klopstock, V. Carelli, F. Distelmaier, A. Rossi, N. Rajewsky, G. Ullah, S. Jakobs, C. R. Rose, S. Petrakis, F. Edenhofer, W. J. H. Koopman, P. Lisowski, A. Suomalainen, D. Brunetti, A. del Sol, E. Bottani, O. Pless, M. Schuelke, and A. Prigione.
Source/Credit: Heinrich Heine University Düsseldorf | Anne Wansing
Reference Number: cbio031126_01