FOCUS on Mitochondrial Disease. Leigh syndrome (LS) is a mitochondrial disease characterized by neurodevelopmental regression and muscle weakness with early death following metabolic crises. In a paper just out in Cell, a large multinational group of researchers used LS patient-derived induced pluripotent stem cell-derived neural precursor cells to screen a library of “repurposable” compounds seeking to modulate abnormal mitochondrial membrane potential. They identified sildenafil (and other PDE5 inhibitors) and went on to show that it rescued the neurodevelopmental disease signature, promoted neuronal outgrowth, and normalized calcium homeostasis in human LS models. They then carried out a limited clinical study with six LS patients and showed that sildenafil improved muscle strength and resistance to metabolic crisis. Thus, sildenafil may be a repurposing candidate for mitochondrial disorders.
