Publications

Authors:

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

Title:

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

Year:

2026

Type of item:

Articolo in Rivista

Tipologia ANVUR:

Articolo su rivista

Language:

Inglese

Format:

Elettronico

Referee:

No

Name of journal:

CELL

ISSN of journal:

0092-8674

N° Volume:

189

Number or Folder:

6

Page numbers:

1656-1679

Keyword:

Leigh syndrome; PDE5 inhibitors; PRKG1; brain organoids; drug repurposing; drug screening; high-content analysis; iPSCs; mitochondrial diseases; sildenafil

Short description of contents:

: 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.

Note:

Epub 2026 Mar 11

Product ID:

150360

Handle IRIS:

11562/1186271

Last Modified:

May 17, 2026

Bibliographic citation:

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, Pluripotent stem-cell-based screening uncovers sildenafil as a mitochondrial disease therapy «CELL» , vol. 189 , n. 6 , 2026 , pp. 1656-1679

Consulta la scheda completa presente nel repository istituzionale della Ricerca di Ateneo