M. Corral-Debrinski, Institut de la Vision, Université Pierre et Marie Curie-Paris, Paris, France

Mitochondrial diseases due to mutations in mitochondrial DNA can not be ignored anymore in most medical areas. With prevalence certainly higher than one in 6000, they probably represent the most common form of metabolic disorders. Despite progress made in identification of their molecular mechanisms, little has been done regarding therapy. We have recently optimized the allotopic expression for the mitochondrial genes ATP6, ND1 and ND4 and obtained a complete and long-lasting rescue of mitochondrial dysfunction in human fibroblasts in which these genes were mutated. However, biosafety and benefit to mitochondrial function must be validated in animal models prior to clinical applications.

To create an animal model of Leber Hereditary Optic Neuropathy (LHON), the human ND4 gene harboring the G11778A mutation, responsible of 60% of LHON cases, was introduced to rat eyes by in vivo electroporation. The treatment induced retinal ganglion cells (RGC) degeneration, with up to 39% less RGCs relative to control eyes. This deleterious effect was also confirmed in primary cell culture, since both RGC survival and neurite outgrowth were compromised. Importantly, RGC loss was clearly associated with visual performance decline. Performing a subsequent electroporation with wild-type ND4 led to prevention of RGC loss and alleviation of visual function impairment. Hence, these data provide the proof-of-principle of optimized allotopic expression effectiveness as a treatment for LHON and open the way to clinical studies on other devastating mitochondrial disorders.