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| Item Type: | Article |
|---|---|
| Title: | Pluripotent stem-cell-based screening uncovers sildenafil as a mitochondrial disease therapy |
| Creators Name: | Zink, Annika, Dai, Dao-Fu, Wittich, Annika, Henke, Marie-Thérèse, Pedrotti, Giulia, Heiduschka, Sonja, Santamaria, Guillem, Pentimalli, Tancredi Massimo, Brueser, Christian, Notopoulou, Sofia, Umar, Abdul Rahim, Zhaivoron, Aleksandra, Petersilie, Laura, Jerred, Caleb, Bergmans, Jesper, Neu, Louis Anton, Schumacher, Fabian, Keller-Findeisen, Jan, Rybak-Wolf, Agnieszka, Stach, Daniel, Reinshagen, Jeanette, Haferkamp, Undine, Krieg, Kim, Zaliani, Andrea, Euro, Liliya, Di Donfrancesco, Alessia, Santanatoglia, Chiara, Cappellozza, Enrica, Suarez Cubero, Marta, Pavez-Giani, Mario, Bakumenko, Oleh, Meierhofer, David, Foley, Alan, Morales-Gonzalez, Susanne, Tolle, Isabella, Herebian, Diran, Bonesso, Daniele, Cecchetto, Giulia, Wong, Sakurako Nagumo, Moresco, Monica, Maresca, Alessandra, Decimo, Ilaria, De Sanctis, Francesco, Adamo, Annalisa, Adjobo-Hermans, Merel J.W., Duchi, Roberto, Barandalla, Maria, Scaglia, Marco, Perota, Andrea, Galli, Cesare, Kleuser, Burkhard, Cyganek, Lukas, Mühlhausen, Chris, Schlotawa, Lars, Tiranti, Valeria, Mayatepek, Ertan, Szabo, Ildiko, La Morgia, Chiara, Klopstock, Thomas, Carelli, Valerio, Distelmaier, Felix, Rossi, Andrea, Rajewsky, Nikolaus, Ullah, Ghanim, Jakobs, Stefan, Rose, Christine R., Petrakis, Spyros, Edenhofer, Frank, Koopman, Werner J.H., Lisowski, Pawel, Suomalainen, Anu, Brunetti, Dario, Del Sol, Antonio, Bottani, Emanuela, Pless, Ole, Schuelke, Markus and Prigione, Alessandro |
| Abstract: | Mitochondrial disease encompasses inherited disorders affecting mitochondrial function. A severe and untreatable form of mitochondrial disease is Leigh syndrome (LS), causing psychomotor regression and metabolic crises. To accelerate drug discovery for LS, we screen a library of 5,632 repurposable compounds in neural cells from LS-patient-derived induced pluripotent stem cells (iPSCs). We identify phosphodiesterase type 5 (PDE5) inhibitors as leads and prioritize sildenafil for its clinical safety. Sildenafil corrects mitochondrial membrane potential defects, restores neurodevelopmental pathways, and normalizes calcium responses in LS brain organoids. In small and large mammalian models of LS, sildenafil extends lifespan and ameliorates disease phenotypes. Off-label treatment on an individual basis with sildenafil in six LS patients improves their motor function and resistance to metabolic crises. Collectively, the findings highlight the potential of iPSCdriven drug discovery and position sildenafil as a promising drug candidate for mitochondrial disease. |
| Keywords: | Induced Pluripotent Stem Cells, Leigh Disease, Mitochondria, Mitochondrial Diseases, Mitochondrial Membrane Potential, Organoids, Phosphodiesterase 5 Inhibitors, Sildenafil Citrate, Animals, Mice |
| Source: | Cell |
| ISSN: | 0092-8674 |
| Publisher: | Elsevier / Cell Press |
| Volume: | 189 |
| Number: | 6 |
| Page Range: | 1656-1679.e42 |
| Date: | 19 March 2026 |
| Additional Information: | Accession "GSE293573" is currently private and is scheduled to be released on Jun 01, 2026. |
| Official Publication: | https://doi.org/10.1016/j.cell.2026.02.008 |
| PubMed: | View item in PubMed |
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