为了加速LS药物的发现，研究团队在LS患者来源的诱导多能干细胞（iPSCs）的神经细胞中筛选了5632种可重复利用的化合物。该研究组确定磷酸二酯酶5型（PDE5）抑制剂作为先导，并优先考虑西地那非的临床安全性。西地那非纠正线粒体膜潜在缺陷，恢复神经发育途径，并使LS脑类器官的钙反应正常化。在小型和大型LS哺乳动物模型中，西地那非延长了寿命并改善了疾病表型。在6例LS患者的个体基础上使用西地那非进行标签外治疗，改善了他们的运动功能和对代谢危机的抵抗力。总的来说，这些发现突出了iPSC驱动的药物发现的潜力，并将西地那非定位为线粒体疾病的有希望的候选药物。
研究人员表示，线粒体疾病包括影响线粒体功能的遗传性疾病。一种严重且无法治疗的线粒体疾病是Leigh综合征（LS），导致精神运动衰退和代谢危机。
附：英文原文
Title: Pluripotent stem-cell-based screening uncovers sildenafil as a mitochondrial disease therapy
Author: Annika Zink, Dao-Fu Dai, Annika Wittich, Marie-Thérèse Henke, Giulia Pedrotti, Sonja Heiduschka, Guillem Santamaria, Tancredi Massimo Pentimalli, Christian Brueser, Sofia Notopoulou, Abdul Rahim Umar, Aleksandra Zhaivoron, Laura Petersilie, Caleb Jerred, Jesper Bergmans, Louis Anton Neu, Fabian Schumacher, Jan Keller-Findeisen, Agnieszka Rybak-Wolf, Daniel Stach, Jeanette Reinshagen, Undine Haferkamp, Kim Krieg, Andrea Zaliani, Liliya Euro, Alessia Di Donfrancesco, Chiara Santanatoglia, Enrica Cappellozza, Marta Suarez Cubero, Mario Pavez-Giani, Oleh Bakumenko, David Meierhofer, Alan Foley, Susanne Morales-Gonzalez, Isabella Tolle, Diran Herebian, Daniele Bonesso, Giulia Cecchetto, Sakurako Nagumo Wong, Monica Moresco, Alessandra Maresca, Ilaria Decimo, Francesco De Sanctis, Annalisa Adamo, Merel J.W. Adjobo-Hermans, Roberto Duchi, Maria Barandalla, Marco Scaglia, Andrea Perota, Cesare Galli, Burkhard Kleuser, Lukas Cyganek, Chris Mühlhausen, Lars Schlotawa, Valeria Tiranti, Ertan Mayatepek, Ildiko Szabo, Chiara La Morgia, Thomas Klopstock, Valerio Carelli, Felix Distelmaier, Andrea Rossi, Nikolaus Rajewsky, Ghanim Ullah, Stefan Jakobs
Issue&Volume: 2026-03-11
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 iPSC-driven drug discovery and position sildenafil as a promising drug candidate for mitochondrial disease.
DOI: 10.1016/j.cell.2026.02.008
Source: https://www.cell.com/cell/abstract/S0092-8674(26)00173-X