Reprogramming-driven drug discovery uncovers sildenafil as a candidate drug for mitochondrial disease

Mitochondrial diseases are a group of rare inherited disorders that affect mitochondrial function. A severe untreatable form of mitochondrial disease is Leigh syndrome (LS), which is characterized by psychomotor regression and acute metabolic crises during which patients quickly deteriorate. To accelerate drug discovery for mitochondrial diseases, we focused on drug repurposing and used induced pluripotent stem cell (iPSC)-derived neuronal precursor cells (NPCs) from LS patients to screen a library of 5,632 repurposable compounds. We identified phosphodiesterase 5 inhibitors (PDE5i) as leads capable of normalizing mitochondrial polarization in NPCs of LS patients. Among the PDE5i, we prioritized Sildenafil due to its established safety profile in children and adults. Sildenafil restored key pathways regulating nervous system development, enhanced neurite outgrowth in LS neurons, and mitigated abnormal calcium responses in LS brain organoids under metabolic stress. Chronic off-label compassionate treatment of six LS patients with Sildenafil showed good tolerability and clear clinical improvements. Our findings highlight the potential of iPSC-driven drug discovery for rare diseases and position Sildenafil as a promising drug candidate for patients with mitochondrial diseases.