Chandelier
Senior Member (Voting Rights)
Pluripotent stem-cell-based screening uncovers sildenafil as a mitochondrial disease therapy
• 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
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.
Web | DOI | Cell
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; Prigione, Alessandro
Highlights
• 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
Summary
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.
Graphical abstract
Web | DOI | Cell
