DeveLopment of a pharmacologIcal neonatal treatment and an in uterO fetal gene therapy for leigh syNdrome – LION

Surf1 mutations represent the main cause of Leigh syndrome (LS), a rare neurometabolic genetic disease with onset in the first months of life that causes severe neuromuscular disabilities and patient death in the first three years of life. Surf1 is involved in the correct functioning of mitochondria, the energy plants of the cell. We have recently developed sophisticated preclinical models both in vitro (NPCs and brain organoids from patient cells) and in vivo (SURF1^KO pigs) which have allowed us to understand that SURF1 mutations cause a metabolic block of the cell which hinders the correct differentiation of neurons during neurodevelopment. We will use this large animal model to develop: i) a Neonatal Pharmacological Therapy, aimed at restoring cellular metabolism during postnatal neurodevelopment and prevent neurodegeneration. If effective, this treatment could be quickly translated to patients. ii) an In Utero Fetal Gene Therapy, aimed at restoring the expression of the Surf1 gene in the prenatal phase. If effective, this strategy could be applied for the prevention of many genetic diseases