Abstract

Mitochondrial DNA (mtDNA) disorders include a vast range of pathological conditions, despite each sharing a mutual inability to produce ATP efficiently as a result of defective oxidative phosphorylation. There is no clear consensus regarding an effective therapeutic approach, and consequently the current treatment strategies are largely supportive rather than curative. This is almost certainly the result of there being virtually no defined genotype–phenotype relationships among the mtDNA disorders; hence an identical mutation may be responsible for multiple phenotypes, or the same phenotype may be produced by different mutations. In light of this, the development of gene therapy to treat mtDNA disorders offers a promising approach, as it potentially circumvents the complication of the aforementioned genotype–phenotype inconsistency and ultimately the current inability to treat individual disorders with sufficient efficacy. Such an approach will ultimately require the combination of efficient mitochondrial targeting, and an effective therapeutic molecule. Although promising proof-of-principle developments in this field have been demonstrated, the realization of a successful therapeutic mitochondrial gene therapy strategy has not come to fruition. This review critiques the key approaches under development by discussing the theory underlying each strategy, and detailing the current progress made. We also emphasize the potential hurdles that must be acknowledged and overcome if the potential of a therapeutic gene therapy to treat mitochondrial DNA disorders is to be realized.