Gene therapy prevents blindness in an animal model of mitochondrial dysfunction

Scientists have created an animal model suitable for testing and validating gene therapies for treatment of a common mitochondrial dysfunction that causes loss of vision. The research, published by Cell Press in the September issue of the American Journal of Human Genetics, describes an innovation that represents a significant advance toward development of the first treatment for one of the many devastating disorders caused by mitochondrial disruption.

The most common forms of metabolic disorders are due to mutations in mitochondrial DNA (mtDNA). Mitochondria are the cell's energy producers, and mitochondrial diseases involve tissues with high energy needs, such as retina, brain, heart, muscle, liver, and endocrine systems. Although 300 mtDNA alterations have been identified as the genetic cause of mitochondrial diseases, there are not, as of yet, any effective treatments available. "Despite progress made in identification of their molecular mechanisms, little has been done regarding therapy," says senior author Dr. Marisol Corral-Debrinski from the Pierre and Marie Curie University in Paris.

Dr. Corral-Debrinski and colleagues recently perfected a strategy for expression of mitochondrial genes transferred to the nucleus; such expression is called allotropic expression. "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," explains Dr. Corral-Debrinski. ND1 and ND4 are mutated in nearly all cases of Leber hereditary optic neuropathy (LHON). LHON is the most common mitochondrial disorder and is characterized by a loss of vision.

The researchers sought to create and animal model of LHON to further test their technique and work toward clinical application of their strategy. They introduced the human ND4 gene with the mutation present in the majority of LHON patients into rat eyes. The treatment caused retinal ganglion cells (RGCs) to degenerate significantly when compared to those from control eyes and was associated with decreased visual performance. Importantly, reintroducing normal ND4 led to prevention of RGC loss and visual impairment, effectively rescuing the animals from impending blindness.

"These data represent the 'proof of principle' that optimized allotropic expression is effective in vivo and can be envisaged as a therapeutic approach for mtDNA-related diseases," concludes Dr. Corral-Debrinski. "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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The researchers include Sami Ellouze, Sébastien Augustin, Aicha Bouaita, Crystel Bonnet, Manuel Simonutti, Valérie Forster, Serge Picaud, Jose-Alain Sahel and Marisol Corral-Debrinski, of the Institut de la Vision, Université Pierre et Marie Curie-Paris, Paris, France.