Comparison of different gene-therapy methods to treat Leber hereditary optic neuropathy in a mouse model

Comparison of different gene-therapy methods to treat Leber hereditary optic neuropathy in a mouse model

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IntroductionTherapies for Leber hereditary optic neuropathy (LHON), in common with all disorders caused by mutated mitochondrial DNA, are inadequate.We have developed two gene therapy strategies L-METHIONINE for the disease: mitochondrial-targeted and allotopic expressed and compared them in a mouse model of LHON.MethodsA LHON mouse model was generated by intravitreal injection of a mitochondrialtargeted Adeno-associated virus (AAV) carrying mutant human NADH dehydrogenase 4 gene (hND4/m.

11778G>A) to induce retinal ganglion cell (RGC) degeneration and axon loss, the hallmark of the human disease.We then attempted to rescue those mice using a second intravitreal injection of either mitochondrial-targeted or allotopic expressed wildtype human ND4.The rescue of RGCs and their axons were assessed using serial pattern electroretinogram (PERG) and transmission electron microscopy.

ResultsCompared to non-rescued LHON controls where PERG amplitude was much reduced, both strategies significantly preserved PERG amplitude over 15 months.However, the rescue effect was more marked with mitochondrial-targeted therapy than with allotopic therapy (p = 0.0128).

Post-mortem analysis showed that mitochondrial-targeted Artwork human ND4 better preserved small axons that are preferentially lost in human LHON.ConclusionsThese results in a pre-clinical mouse model of LHON suggest that mitochondrially-targeted AAV gene therapy, compared to allotopic AAV gene therapy, is more efficient in rescuing the LHON phenotype.