LHON is the most common primary 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 shows variable visual improvement in about 50% of LHON patients. Idebenone needs for its therapeutic action 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 both in LHON cellular models and in clinical response of treated patients.
NQO1 is a highly inducible enzyme and several molecules like drugs and natural molecules act as NQO1 inducers. In addition, 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 different LHON cell models (patient-derived fibroblasts, cybrids and iPSCs/NPCs/RGCs) 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. These results will be instrumental to identify the most effective combination of compounds that may tailor idebenone therapy to NQO1-related pharmacogenomics of LHON patients, according to the principle of personalized medicine. 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.