Base editing corrects mitochondrial DNA mutation in human cells

A precision genome-editing approach has successfully corrected harmful mutations in mitochondrial DNA (mtDNA), offering new hope for treating currently incurable mitochondrial diseases.

Scientists from University Medical Centre Utrecht in the Netherlands, used a DNA base editor called DdCBE to repair pathogenic mutations in patient-derived cells and liver organoids. The team demonstrated they could both introduce disease-causing mtDNA mutations and correct them, restoring normal cellular energy production.

'Our research demonstrates the effectiveness of mitochondrial base editing in primary adult human cells, leading to the recovery of mitochondrial function – two critical aspects for further development of mitochondrial gene therapy,' the research team wrote in their paper published in PLOS Biology.

Mitochondrial diseases affect approximately one in 5000 people and include some severe genetic disorders. Conditions like MELAS syndrome, which causes stroke-like episodes, and Leber hereditary optic neuropathy, which leads to vision loss, currently have no curative treatments.

Mitochondrial DNA has proven challenging to edit because CRISPR/Cas9-based genome editing cannot target mitochondria – the guide RNA molecules cannot cross the mitochondrial membrane. The DdCBE approach comprises two protein components, each containing half of a bacterial toxin and guided by TALE (transcription activator-like effector) proteins, which bind to specific DNA sequences next to the target mutation (see BioNews 1143 and 1055). They form an active enzyme that converts cytosine (C) to thymine (T) when brought together, enabling precise C-to-T editing without cutting the DNA.

The researchers tested their approach using liver organoids and skin cells from a patient with Gitelman-like syndrome. They successfully corrected mutations and restored healthy mitochondrial function, including membrane potential. The study also showed that packaging the mRNA mitochondrial base editors as modified RNA within lipid nanoparticles was more efficient and less toxic than traditional DNA-based approaches.

However, important limitations remain. Previous studies identified significant off-target effects, with the mitochondrial base editor DdCBE causing hundreds of unintended changes in nuclear DNA. In addition, DdCBE has also resulted in 'bystander editing', where unintended nearby sequences are modified. While this latest study showed fewer off-target effects in the specific cells tested, a comprehensive safety evaluation will be crucial before clinical applications.

'This work is certainly relevant, as it opens the door to treating extremely serious congenital mitochondrial diseases, which until now have been incurable,' commented Professor Lluís Montoliu – research professor at the National Biotechnology Centre, Spain, and the Spanish National Research Council – who was not involved in the study.

This approach is not yet ready to be used in clinical trials but may provide the foundation for developing therapies for diseases that have long been considered untreatable, potentially transforming the outlook for thousands of patients worldwide affected by mitochondrial diseases.

Mitochondrial donation pioneers Professor Mary Herbert and Professor Sir Doug Turnbull will discuss their work at the free-to-attend online event Mitochondrial Donation: Does It Work? What Next?, taking place on Wednesday 8 October 2025.

This will be a joint UK/Australian event. Find out more and register here.