LHON is a common mitochondrial DNA disorder causing optic atrophy and blindness due to defective respiratory complex I. Idebenone, the only EMA-approved therapy for LHON, is a ubiquinone analogue with features as mitochondrial electron carrier and antioxidant. Idebenone therapy leads to visual improvement in about 50% of LHON patients. For its therapeutic action Idebenone needs to be reduced by the cytoplasmic flavoprotein NQO1, allowing mitochondrial respiration downstream of defective complex I and rescuing oxidative damage.

We recently demonstrated that NQO1 expression depends on two polymorphic variants that drastically reduce NQO1 protein levels and strictly correlate with therapeutic efficacy of idebenone in cellular models and treated patients. Several drugs and natural molecules act as NQO1 inducers, while NQO1 is stabilized by FAD or its precursor riboflavin.

We aim at testing therapeutic efficacy of FAD and its precursor, alone and in combination with NQO1 inducers, on LHON cell models carrying the two NQO1 polymorphic variants hampering idebenone efficacy. By increasing NQO1 expression and protein stability we expect to improve idebenone efficacy on rescuing the mitochondrial energetic defect. We will then test the NQO1 “enhancer therapy” in vivo, in a selected group of chronic LHON patients carrying the NQO1 polymorphic variants. If the NQO1 levels are effectively enhanced, we will further undertake a combination therapy adding idebenone to the NQO1 “enhancer therapy” in an open exploratory trial with the same chronic LHON patients.