Pluripotent stem cell-based drug discovery uncovers sildenafil as a treatment for mitochondrial disease
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 screened a library of 5,632 repurposable compounds in induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPCs) from LS patients. We identified phosphodiesterase 5 inhibitors (PDE5i) as leads, and prioritized sildenafil due to its safety profile. Sildenafil restored pathways regulating nervous system development, enhanced neurite outgrowth in LS neurons, and mitigated abnormal calcium responses in LS brain organoids under metabolic stress. In a mouse model of LS, sildenafil extended the lifespan and ameliorated metabolic and encephalopathy phenotypes. Chronic off-label compassionate treatment with sildenafil in six LS patients showed improvements in motor function and resistance to metabolic crises. These findings highlight the potential of iPSC-driven drug discovery and position sildenafil as a promising candidate for mitochondrial diseases.
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