Loss of Vision Corrected in an Animal Model of Mitochondrial Dysfunction

A recent article described the development of an animal model for testing and validating gene therapies aimed at correcting mistakes in mitochondrial DNA.

Since the prevalence of diseases caused by mutations to mitochondrial DNA is probably about one in 6,000, they represent the most common form of metabolic disorder. Yet, despite progress in identification of their molecular mechanisms, little has been done with regard to therapy.

In a new study, investigators from the Pierre and Marie Curie University (Paris, France) sought to create an animal model of Leber hereditary optic neuropathy (LHON), loss of vision caused by the most common mitochondrial disorder. To this end, they introduced the human ND4 gene harboring the G11778A mutation, responsible of 60% of LHON cases, to rat eyes by in vivo electroporation. The treatment induced the degeneration of retinal ganglion cells (RGCs), which were 40% less abundant in treated eyes than in control eyes. RGC loss was clearly associated with a decline in visual performance.

The subject rats were then exposed to a second round of electroporation with wild-type ND4, and results published in the September 4, 2008, online issue of the American Journal of Human Genetics (AJHG) revealed that this treatment corrected both RGC loss and the impairment of visual function.

"Despite progress made in identification of their molecular mechanisms, little has been done regarding therapy,” explained senior author Dr. Marisol Corral-Debrinski, professor of vision science at the Pierre and Marie Curie University. "We obtained a complete and long-term restoration of mitochondrial function in human fibroblasts in which the mitochondrial genes ATP6, ND1, and ND4 were mutated. These data represent the ‘proof of principle' that optimized allotropic expression is effective in vivo and can be envisaged as a therapeutic approach for mitochondrial DNA-related diseases. The next step towards our goal of clinical trials for preventing blindness in patients suffering from LHON disease will be to assess the long-term safety of our approach in large animals.”

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