# A decisive technical leap forward for personalized medicine to treat mitochondrial diseases

## TL;DR

A new method using gene editing reduces harmful mtDNA mutations in muscles, offering hope for treating mitochondrial diseases.

## Contribution

A novel tandem mtZFN strategy delivered via AAV to reduce disease-linked mtDNA heteroplasmy in muscle tissues.

## Key findings

- The tandem mtZFN approach significantly reduced mtDNA mutation load in a mouse model.
- This method alleviated molecular phenotypes associated with mtDNA mutations in cardiac and skeletal muscles.
- The strategy shows promise as a therapeutic intervention for mitochondrial diseases.

## Abstract

Mitochondrial diseases, arising from mutations in mitochondrial DNA (mtDNA), are a diverse group of disorders that lead to severe conditions. Expression of mtDNA is a prerequisite for ATP production by oxidative phosphorylation. Individual cells contain many hundred copies of mtDNA and mutated mtDNA coexist with wild type genomes, a phenomenon termed heteroplasmy, rendering the diagnosis and treatment of mtDNA-caused diseases challenging. In this issue of EMBO Molecular Medicine, Nash et al report an effective method to decrease heteroplasmy levels of disease-linked mtDNA in cardiac and skeletal muscles of a mouse model. For this, the team developed a novel strategy relying on a tandem mitochondrial-targeted zinc finger nuclease (tandem mtZFN) delivered via adeno-associated virus (AAV) particle to tissues. This approach significantly reduced the mtDNA mutation load, thereby shifting heteroplasmy levels and alleviating molecular phenotypes associated with the mutation. This breakthrough provides a promising new avenue for therapeutic interventions to treat mitochondrial diseases.

M. Ott and A. Ghifari discuss a method to decrease heteroplasmy levels of disease-linked mtDNA in cardiac and skeletal muscles as a potential strategy for personalized medicine to treat mitochondrial diseases as reported by M. Minczuk and colleagues, in this issue of EMBO Mol Med.