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Koopman16,17,42 ∙ Pawel Lisowski9,43,44 ∙ Anu Suomalainen14,45,46 ∙ Dario Brunetti19,47,52 Send email to [email protected] ∙ Antonio del Sol8,48,49,52 Send email to [email protected] ∙ Emanuela Bottani6,52 Send email to [email protected] ∙ Ole Pless3,52 Send email to [email protected] ∙ Markus Schuelke4,5,50,52 Send email to [email protected] ∙ Alessandro Prigione1,52,53 Send email to [email protected] … Show more Show less 1Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-Düsseldorf, 40225 Düsseldorf, Germany 2Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA 3Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort, 22525 Hamburg, Germany 4Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Neuropediatrics, 10117 Berlin, Germany 5Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, NeuroCure Clinical Research Center, 10117 Berlin, Germany 6Department of Diagnostics and Public Health, University of Verona, 37134 Verona, Italy 7Faculty of Mathematics and Natural Sciences, Heinrich Heine University, 40225 Düsseldorf, Germany 8Computational Biology Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 4366 Esch-sur-Alzette, Luxembourg 9Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 10115 Berlin, Germany 11Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Translational Neuroinflammation and Automated Microscopy, 37037 Göttingen, Germany 12Institute of Applied Biosciences (INAB), Centre For Research and Technology Hellas (CERTH), 57001 Thessaloniki, Greece 13Department of Physics, University of South Florida, Tampa, FL 33620, USA 14Stem Cells and Metabolism Program, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland 15Institute of Neurobiology, Heinrich Heine University, 40225 Düsseldorf, Germany 16Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands 17Department of Pediatrics, Amalia Children’s Hospital, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands 18Institute of Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany 19Fondazione IRCCS Istituto Neurologico Carlo Besta, 20126 Milan, Italy 20Department of Molecular Biology & CMBI, Genomics, Stem Cell & Regenerative Medicine Group, University of Innsbruck, 6020 Innsbruck, Austria 21Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, 37075 Göttingen, Germany 22Experimental Cardiology Institute, Medical Clinic I/Cardiology and Angiology, Justus Liebig University of Giessen, 35392 Giessen, Germany 23Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany 24Department of Biology, University of Padova, 35121 Padova, Italy 25IRCCS Istituto delle Scienze Neurologiche di Bologna, Programma di Neurogenetica, 40139 Bologna, Italy 26Department of Medicine, Section of Immunology, University of Verona Hospital Trust, 37134 Verona, Italy 27Department of Medical BioSciences, Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands 29Department of Pediatrics and Adolescent Medicine, University Medical Center, Georg-August-University, 37075 Göttingen, Germany 30German Center for Child and Adolescent Health (DZKJ), Section CNS Development and Neurological Disease, partner site Göttingen, Robert-Koch-Str.

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31Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, 40127 Bologna, Italy 32Friedrich-Baur-Institute, Department of Neurology, LMU University Hospital, Ludwig-Maximilians-Universität München, 80336 Munich, Germany 33Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany 34German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany 35Genome Engineering and Model Development lab (GEMD), IUF-Leibniz Research Institute for Environmental Medicine, 40223 Düsseldorf, Germany 36NeuroCure Cluster of Excellence, 10117 Berlin, Germany 37German Center for Cardiovascular Research (DZHK), partner site Lower Saxony and Berlin, 10785 Berlin, Germany 38National Center for Tumor Diseases (NCT), German Cancer Consortium (DKTK), 13125 Berlin, Germany 39German Center for Neurodegenerative Diseases (DZNE), 10117 Berlin, Germany 40Department of NanoBiophotonics, Max Planck Institute for Multidisciplinary Sciences, 37077 Göttingen, Germany 41Department of Neurology, University Medical Center Göttingen, 37075 Göttingen, Germany 42Human and Animal Physiology, Wageningen University, 6708 WD Wageningen, the Netherlands 43Neuropsychiatry and Laboratory of Molecular Psychiatry, Department of Psychiatry and Neurosciences, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany 44Department of Molecular Biology, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, 05-552 Jastrzebiec n/Warsaw, Poland 45HiLife, University of Helsinki, 0004 Helsinki, Finland 46HUS Diagnostics, Helsinki University Hospital, 00290 Helsinki, Finland 47Department of Clinical Sciences and Community Health, Dipartimento di Eccellenza 2023-2027, University of Milan, 20122 Milan, Italy 48IKERBASQUE, Basque Foundation for Science, 48009 Bilbao, Spain 49CIC bioGUNE-BRTA (Basque Research and Technology Alliance), Bizkaia Technology Park, 48160 Derio, Spain 50German Center for Child and Adolescent Health (DZKJ), Section CNS Development and Neurological Disease, partner site Berlin, 13353 Berlin, Germany Received April 14, 2025; Revised August 19, 2025; Accepted February 6, 2026; Published online March 11, 2026 DOI: 10.1016/j.cell.2026.02.008 External LinkAlso available on ScienceDirect External Link Repurposable drug screen in Leigh syndrome neural cells identifies PDE5 inhibitors PDE5 inhibitor sildenafil rescues the neurodevelopmental disease signature in vitro PDE5 inhibitor sildenafil extends the lifespan of Leigh syndrome animal models in vivo Sildenafil treatment on an individual basis clinically improves symptoms in six LS patients 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.

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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).

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Koopman16,17,42 ∙ Pawel Lisowski9,43,44 ∙ Anu Suomalainen14,45,46 ∙ Dario Brunetti19,47,52 Send email to [email protected] ∙ Antonio del Sol8,48,49,52 Send email to [email protected] ∙ Emanuela Bottani6,52 Send email to [email protected] ∙ Ole Pless3,52 Send email to [email protected] ∙ Markus Schuelke4,5,50,52 Send email to [email protected] ∙ Alessandro Prigione1,52,53 Send email to [email protected] … Show more Show less 1Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich-Heine-Düsseldorf, 40225 Düsseldorf, Germany 2Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA 3Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort, 22525 Hamburg, Germany 4Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Neuropediatrics, 10117 Berlin, Germany 5Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, NeuroCure Clinical Research Center, 10117 Berlin, Germany 6Department of Diagnostics and Public Health, University of Verona, 37134 Verona, Italy 7Faculty of Mathematics and Natural Sciences, Heinrich Heine University, 40225 Düsseldorf, Germany 8Computational Biology Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 4366 Esch-sur-Alzette, Luxembourg 9Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 10115 Berlin, Germany 11Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Translational Neuroinflammation and Automated Microscopy, 37037 Göttingen, Germany 12Institute of Applied Biosciences (INAB), Centre For Research and Technology Hellas (CERTH), 57001 Thessaloniki, Greece 13Department of Physics, University of South Florida, Tampa, FL 33620, USA 14Stem Cells and Metabolism Program, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland 15Institute of Neurobiology, Heinrich Heine University, 40225 Düsseldorf, Germany 16Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands 17Department of Pediatrics, Amalia Children’s Hospital, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands 18Institute of Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany 19Fondazione IRCCS Istituto Neurologico Carlo Besta, 20126 Milan, Italy 20Department of Molecular Biology & CMBI, Genomics, Stem Cell & Regenerative Medicine Group, University of Innsbruck, 6020 Innsbruck, Austria 21Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, 37075 Göttingen, Germany 22Experimental Cardiology Institute, Medical Clinic I/Cardiology and Angiology, Justus Liebig University of Giessen, 35392 Giessen, Germany 23Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany 24Department of Biology, University of Padova, 35121 Padova, Italy 25IRCCS Istituto delle Scienze Neurologiche di Bologna, Programma di Neurogenetica, 40139 Bologna, Italy 26Department of Medicine, Section of Immunology, University of Verona Hospital Trust, 37134 Verona, Italy 27Department of Medical BioSciences, Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands 29Department of Pediatrics and Adolescent Medicine, University Medical Center, Georg-August-University, 37075 Göttingen, Germany 30German Center for Child and Adolescent Health (DZKJ), Section CNS Development and Neurological Disease, partner site Göttingen, Robert-Koch-Str. 31Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, 40127 Bologna, Italy 32Friedrich-Baur-Institute, Department of Neurology, LMU University Hospital, Ludwig-Maximilians-Universität München, 80336 Munich, Germany 33Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany 34German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany 35Genome Engineering and Model Development lab (GEMD), IUF-Leibniz Research Institute for Environmental Medicine, 40223 Düsseldorf, Germany 36NeuroCure Cluster of Excellence, 10117 Berlin, Germany 37German Center for Cardiovascular Research (DZHK), partner site Lower Saxony and Berlin, 10785 Berlin, Germany 38National Center for Tumor Diseases (NCT), German Cancer Consortium (DKTK), 13125 Berlin, Germany 39German Center for Neurodegenerative Diseases (DZNE), 10117 Berlin, Germany 40Department of NanoBiophotonics, Max Planck Institute for Multidisciplinary Sciences, 37077 Göttingen, Germany 41Department of Neurology, University Medical Center Göttingen, 37075 Göttingen, Germany 42Human and Animal Physiology, Wageningen University, 6708 WD Wageningen, the Netherlands 43Neuropsychiatry and Laboratory of Molecular Psychiatry, Department of Psychiatry and Neurosciences, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany 44Department of Molecular Biology, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, 05-552 Jastrzebiec n/Warsaw, Poland 45HiLife, University of Helsinki, 0004 Helsinki, Finland 46HUS Diagnostics, Helsinki University Hospital, 00290 Helsinki, Finland 47Department of Clinical Sciences and Community Health, Dipartimento di Eccellenza 2023-2027, University of Milan, 20122 Milan, Italy 48IKERBASQUE, Basque Foundation for Science, 48009 Bilbao, Spain 49CIC bioGUNE-BRTA (Basque Research and Technology Alliance), Bizkaia Technology Park, 48160 Derio, Spain 50German Center for Child and Adolescent Health (DZKJ), Section CNS Development and Neurological Disease, partner site Berlin, 13353 Berlin, Germany Received April 14, 2025; Revised August 19, 2025; Accepted February 6, 2026; Published online March 11, 2026 DOI: 10.1016/j.cell.2026.02.008 External LinkAlso available on ScienceDirect External Link Repurposable drug screen in Leigh syndrome neural cells identifies PDE5 inhibitors PDE5 inhibitor sildenafil rescues the neurodevelopmental disease signature in vitro PDE5 inhibitor sildenafil extends the lifespan of Leigh syndrome animal models in vivo Sildenafil treatment on an individual basis clinically improves symptoms in six LS patients 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.

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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 buy sildenafil citrate online canada 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. Mitochondrial disease encompasses rare genetic conditions caused by dysfunction in the cell’s energy-producing organelles.1 A severe form of mitochondrial disease is Leigh syndrome (LS, OMIM #256000), which is characterized by neurodevelopmental regression and muscle weakness, with early death following metabolic crises.2,3 LS can result from pathogenic variants in more than 100 genes in nuclear DNA or mitochondrial DNA (mtDNA) involved in oxidative phosphorylation (OXPHOS),4 including complex V (CV) gene MT-ATP6 (mitochondrially encoded ATP synthase subunit 6),5 complex IV (CIV) assembly factor gene SURF1 (SURFEIT1),6 and complex I gene NDUFS4 (nicotinamide adenine dinucleotide [NAD] + hydrogen [NADH] dehydrogenase [ubiquinone] iron-sulfur protein 4).7 Currently, there are no treatments for LS.8 One obstacle to therapy discovery is the paucity of model systems.9 The difficulties in mtDNA editing have hindered the establishment of models for mtDNA defects.10 A pig model of LS due to SURF1 knockout (KO) showed neurodevelopmental defects and early lethality,11 but Surf1 KO mice failed to replicate LS phenotypes.12,13 The most widely used model of LS is the homozygous Ndufs4 KO mouse, characterized by progressive encephalopathy, growth retardation, and premature death.14,15 This model has been used to propose therapeutic interventions, including antioxidants,16,17,18 rapamycin,19 interferon-gamma-targeting therapies,20 cannabidiol,21 or hypoxia.22,23 Only a few of these strategies have been tested in LS individuals, and no successful results have been obtained. 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 buy sildenafil citrate online canada 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.

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Collectively, the findings highlight the potential of iPSC-driven drug discovery and position sildenafil as a promising drug candidate for mitochondrial disease.

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Mitochondrial disease encompasses rare genetic conditions caused by dysfunction in the cell’s energy-producing organelles.1 A severe form of mitochondrial disease is Leigh syndrome (LS, OMIM #256000), which is characterized by neurodevelopmental regression and muscle weakness, with early death following metabolic crises.2,3 LS can result from pathogenic variants in more than 100 genes in nuclear DNA or mitochondrial DNA (mtDNA) involved in oxidative phosphorylation (OXPHOS),4 including complex V (CV) gene MT-ATP6 (mitochondrially encoded ATP synthase subunit 6),5 complex IV (CIV) assembly factor gene SURF1 (SURFEIT1),6 and complex I gene NDUFS4 (nicotinamide adenine dinucleotide [NAD] + hydrogen [NADH] dehydrogenase [ubiquinone] iron-sulfur protein 4).7 Currently, there are no treatments for LS.8 One obstacle to therapy discovery is the paucity of model systems.9 The difficulties in mtDNA editing have hindered the establishment of models for mtDNA defects.10 A pig model of LS due to SURF1 knockout (KO) showed neurodevelopmental defects and early lethality,11 but Surf1 KO mice failed to replicate LS phenotypes.12,13 The most widely used model of LS is the homozygous Ndufs4 KO mouse, characterized by progressive encephalopathy, growth retardation, and premature death.14,15 This model has been used to propose therapeutic interventions, including antioxidants,16,17,18 rapamycin,19 interferon-gamma-targeting therapies,20 cannabidiol,21 or hypoxia.22,23 Only a few of these strategies have been tested in LS individuals, and no successful results have been obtained. New approach methodologies (NAMs) with LS patient-derived induced pluripotent stem cells (iPSCs)24 have been instrumental in uncovering pathological mechanisms. These include neuronal outgrowth defects,25 altered calcium homeostasis,26,27 and glutamate toxicity in neuronal cultures,28 as well as impaired cortical development and neuromorphogenesis in brain organoids.25,29,30 Despite these advances, large-scale drug screens in iPSC models of mitochondrial disease have yet to be performed.

• Sildenafil 100g is rarely prescribed and considered an experimental or off-label dose.
• Like all medications, it should only be used as directed by a healthcare professional.
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• Use with caution in patients with liver or kidney impairment.
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We previously demonstrated that iPSC-derived neural precursor cells (NPCs) are an effective drug discovery platform for mtDNA diseases.27 LS NPCs carrying a MT-ATP6 variant exhibited abnormal mitochondrial membrane potential (MMP), a feature that can be exploited for high-throughput screens.31 Here, we leveraged this MMP phenotype to screen a library of 5,632 repurposable drug candidates in LS NPCs.

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We identified phosphodiesterase type 5 (PDE5) inhibitors as lead compounds and prioritized sildenafil for its safety profile.32 Sildenafil rescued the neurodevelopmental disease signature, promoted neuronal outgrowth, and normalized calcium homeostasis in human LS models.

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New approach methodologies (NAMs) with LS patient-derived induced pluripotent stem cells (iPSCs)24 have been instrumental in uncovering pathological mechanisms. These include neuronal outgrowth defects,25 altered calcium homeostasis,26,27 and glutamate toxicity in neuronal cultures,28 as well as impaired cortical development and neuromorphogenesis in brain organoids.25,29,30 Despite these advances, large-scale drug screens in iPSC models of mitochondrial disease have yet to be performed. We previously demonstrated that iPSC-derived neural precursor cells (NPCs) are an effective drug discovery platform for mtDNA diseases.27 LS NPCs carrying a MT-ATP6 variant exhibited abnormal mitochondrial membrane potential (MMP), a feature that can be exploited for high-throughput screens.31 Here, we leveraged this MMP phenotype to screen a library of 5,632 repurposable drug candidates in LS NPCs. We identified phosphodiesterase type 5 (PDE5) inhibitors as lead compounds and prioritized sildenafil for its safety profile.32 Sildenafil rescued the neurodevelopmental disease signature, promoted neuronal outgrowth, and normalized calcium homeostasis in human LS models.

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