Gene therapy in LHON

SummaryGene therapy is a promise for the treatment of Leber hereditary optic neuropathy (LHON). The techniques required for introducing genes into mitochondria have not yet been developed and allotopic expression is one means of circumventing this barrier. To ensure efficient mitochondrial uptake of the nuclear expressed mtDNA gene, the protein should have a mitochondrial targeting signal (MTS). We have optimized allotopic expression by targeting the mRNAs to the mitochondrial surface with a specific 3′UnTranslated Region (UTR) which can cooperate with the MTS for ensuring the localization of ND4 mRNA to the mitochondrial surface. After having collected data proving that an AAV2/2 vector carrying this therapeutic ND4 gene meets the criteria of robust, long-duration gene expression, and safety in LHON rat model and non human primate retinas, we are leading a phase I/II, open-label, prospective clinical trial with dose escalation, which intends to evaluate safety of this gene therapy administered in one single intravitreal (IVT) injection in humans with chronic ND4 LHON. Actually 9 patients were included and no SAE or treatment-related systemic AE occurred. At last, we look forward to be successful in the generation of a treatment for patients suffering from ND4 LHON.