Two tales of therapeutic innovations for Leigh syndrome spectrum

Leigh syndrome spectrum is the most common form of childhood-onset mitochondrial encephalopathy and is characterized by progressive neurodegeneration. Treatment options for this condition remain limited to date. Nonetheless, two lines of research endeavor in the past decade have shown encouraging results worthy of further investigations. First, therapeutic hypoxia appears to improve neurological outcomes, which is somewhat counterintuitive but supported by preclinical evidence. Furthermore, nicotinic acid or nicotinamide riboside could be an adjunctive therapy that enhances the neuroprotective effect of hypoxia. Second, preclinical studies and preliminary clinical experience suggest that sildenafil is potentially disease-modifying for Leigh syndrome. Sildenafil has already been used to treat pulmonary hypertension, and its repurposing for Leigh syndrome has been endorsed by European Medicines Agency. This perspective aims to raise awareness about these progresses, as well as to call for more clinical studies to ensure safe and effective implementation of these treatment approaches in clinical practice.