MT-ND4 and mitochondrial disease: Gene replacement therapy based around the AAV2 vector has shown modest, but promising, success in mice for a variety of nuclear-encoded mitochondrial disease genes.44–46 However, the only primary mitochondrial disease currently involved in active clinical trials of gene replacement therapy is Leber’s hereditary optic neuropathy (LHON), caused by mutations in the mitochondrially-encoded MT-ND4 gene.