Pluripotent stem-cell-based screening uncovers sildenafil as a mitochondrial disease therapy.

Leigh syndrome; PDE5 inhibitors; PRKG1; brain organoids; drug repurposing; drug screening; high-content analysis; iPSCs; mitochondrial diseases; sildenafil; Biochemistry, Genetics and Molecular Biology (all)

Abstract :

[en] 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 iPSC-driven drug discovery and position sildenafil as a promising drug candidate for mitochondrial disease.

Disciplines :

Life sciences: Multidisciplinary, general & others

Author, co-author :

Zink, Annika ; Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-Düsseldorf, 40225 Düsseldorf, Germany

Dai, Dao-Fu; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA. Electronic address: ddai4@jh.edu

Wittich, Annika; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort, 22525 Hamburg, Germany

Henke, Marie-Thérèse; Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Neuropediatrics, 10117 Berlin, Germany, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, NeuroCure Clinical Research Center, 10117 Berlin, Germany

Pedrotti, Giulia; Department of Diagnostics and Public Health, University of Verona, 37134 Verona, Italy

Heiduschka, Sonja; Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-Düsseldorf, 40225 Düsseldorf, Germany, Faculty of Mathematics and Natural Sciences, Heinrich Heine University, 40225 Düsseldorf, Germany

SANTAMARIA AGUILAR, Guillem ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Computational Biology

Pentimalli, Tancredi Massimo; Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 10115 Berlin, Germany, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany

Brueser, Christian; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Translational Neuroinflammation and Automated Microscopy, 37037 Göttingen, Germany

Notopoulou, Sofia; Institute of Applied Biosciences (INAB), Centre For Research and Technology Hellas (CERTH), 57001 Thessaloniki, Greece

More authors (67 more)

^✱ These authors have contributed equally to this work.

External co-authors :

yes

Language :

English

Title :

Pluripotent stem-cell-based screening uncovers sildenafil as a mitochondrial disease therapy.

Publication date :

11 March 2026

Journal title :

Cell

ISSN :

0092-8674

eISSN :

1097-4172

Publisher :

Elsevier B.V.

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

https://api.elsevier.com/content/article/PII:S009286742600173X?httpAccept=text/xml

Funders :

Federal Ministry of Education and Research Bonn Office
AFM-Telethon
European Commission
United Mitochondrial Disease Foundation
German Research Foundation

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