Speed the Efficacy of Idebenone on LHON Targeting NQO1

Leber hereditary optic neuropathy (LHON) is a rare disease of the optic nerve that manifests itself solely with a painless and usually rapidly progressing loss of vision in both eyes. The result is a severe damage to the optic nerve and, in most cases, a permanent loss of visual acuity to the level of functional blindness. LHON typically affects young, healthy men, but it can occur at any age and in any gender. The cause of the disease is a genetic predisposition in the genetic information of the mitochondria, which leads to a disruption in cellular energy production and in some cases to the onset of the disease. Idebenone is currently the only approved treatment for LHON and supports the recovery of damaged cells in the optic nerve by improving the impaired energy production of the mitochondria and binding of cell-damaging free oxygen radicals that occur in higher quantities in LHON. Treatment with idebenone leads to a clinically relevant recovery of vision in around 50% of patients. In order for idebenone to have a therapeutic effect, it must be activated in the cells by the enzyme NQO1. If too little NQO1 is present in the cells, the activation of idebenone is impaired. As has already been shown, in this case the efficacy of idebenone is reduced both in cell models and in the clinical response of treated individuals. Two common genetic variants in the NQO1 gene play an important role here. The amount of NQO1 in the cells can be increased by various drugs, and NQO1 is also stabilized by the co-enzyme FAD and its precursor riboflavin (vitamin B2). In our multi- national research project, we are investigating the therapeutic efficacy of FAD and riboflavin alone and in combination with NQO1 inducers, initially in the cell model of LHON patients carrying variants in the NQO1 gene. In combination with idebenone, we expect to improve the efficacy of idebenone in correcting the impaired mitochondrial energy production. We will then conduct a clinical trial using NQO1-enhancing therapy in chronic LHON patients who also carry these variants. If NQO1 levels can be effectively increased, the same patients will eventually receive a combination therapy of idebenone in addition to the NQO1-enhancing therapy. The results from our studies will help determine the most effective combination of agents to enable personalized treatment of LHON patients with idebenone tailored to individual limitations of NQO1 function.