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

Mitochondrial disease is a group of rare inherited conditions affecting mitochondrial function. A severe untreatable form of mitochondrial disease is Leigh syndrome (LS) characterized by psychomotor regression and acute metabolic crises. To accelerate drug discovery for mitochondrial disease, we focused on drug repurposing and made use of 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 LS NPCs. Among PDE5i, we prioritized Sildenafil due to its established safety profile in children. 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. In a mouse model of LS, Sildenafil led to lifespan extension and amelioration of metabolic and encephalopathy phenotypes. Lastly, chronic off-label treatment with Sildenafil in six LS patients demonstrated good tolerability and clinical improvements. Our findings highlight the potential of iPSC-driven drug discovery for rare diseases and position Sildenafil as a promising candidate drug for patients with mitochondrial disease.