Advances Towards Therapeutic Approaches for mtDNA Disease

Mitochondria maintain and express their own genome, referred to as mtDNA, which is required for proper mitochondrial function. While mutations in mtDNA can cause a heterogeneous array of disease phenotypes, there is currently no cure for this collection of diseases. Here, we will cover characteristics of the mitochondrial genome important for understanding the pathology associated with mtDNA mutations, and review recent approaches that are being developed to treat and prevent mtDNA disease. First, we will discuss mitochondrial replacement therapy (MRT), where mitochondria from a healthy donor replace maternal mitochondria harbouring mutant mtDNA. In addition to ethical concerns surrounding this procedure, MRT is only applicable in cases where the mother is known or suspected to carry mtDNA mutations. Thus, there remains a need for other strategies to treat patients with mtDNA disease. To this end, we will also discuss several alternative means to reduce the amount of mutant mtDNA present in cells. Such methods, referred to as heteroplasmy shifting, have proven successful in animal models. In particular, we will focus on the approach of targeting engineered endonucleases to specifically cleave mutant mtDNA. Together, these approaches offer hope to prevent the transmission of mtDNA disease and potentially reduce the impact of mtDNA mutations.