Leber Hereditary Optic Neuropathy: Gene Therapy Trial

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DESCRIPTION (provided by applicant): Our understanding of human diseases caused by mutated mitochondrial DNA has recently evolved dramatically. This is a group of untreatable disorders affecting the eye, nervous system and heart, some that have been clinically characterized over a century ago, but they are now known to be a spectrum of molecularly defined diseases. We have chosen to start with one of the most severe, the G11778A mutation in mitochondrial DNA responsible for Leber Hereditary Optic Neuropathy (LHON) a disease group renowned for causing blindness in later childhood and early adulthood. It shows little or no propensity for recovery. In previous work we have made major strides towards determining the pathogenesis and testing a treatment for LHON. First, we discovered that ND4 mutant cells have a severe reduction in ATP synthesis, even though mild reductions in complex I activity appear insufficient to induce disease. Since no technology existed to introduce DNA directly into mitochondria, we overcame this deficiency in oxidative phosphorylation by constructing a "nuclear version" of the mitochondrial gene then targeted the cytoplasmically synthesized protein to the mitochondria by using a targeting sequence appended to the reading frame (allotopic expression). When delivered to cultured cells containing a mutant ND4, respiratory function was restored. Next, we created a bona fide animal model for LHON. Using site directed mutagenesis of the nuclear version of ND4 we replaced the codon for arginine to that for histidine at amino acid 340. Injection of this construct into the mouse visual system disrupted mitochondrial cytoarchitecture, elevated reactive oxygen species, induced swelling of the optic nerve head and induced apoptosis, with a progressive demise of ganglion cells in the retina and their axons comprising the optic nerve. In contrast, ocular expression of the wild-type human ND4 subunit appeared safe, suggesting that it may be useful for treatment of patients with LHON. Here by using the scientific and clinical knowledge acquired to date we will begin the journey towards genetic therapy for human optic neuropathy and mitochondrial disease. Our goal in this application is to test the relevance of allotopic rescue of our LHON animal model; the safety of AAV mediated delivery of the ND4 gene and the effectiveness of this therapy in preventing and restoring visual loss in our patients with LHON.