Scientists use base editing to repair mitochondrial DNA mutations

Scientists use base editing to repair mitochondrial DNA mutations

In a move toward treating mitochondrial diseases, researchers in the Netherlands have successfully edited harmful mutations in mitochondrial DNA using a genetic tool known as a base editor. The results, published June 24 in the open access journalPLOS biologyOffer new hope to people with rare genetic conditions.

Mitochondria, often referred to as the powerhouses of the cell, have their own small line of DNA. Mutations in this mitochondrial DNA can cause a variety of diseases, cancers and age-related diseases to be inherited from the mother's side. While the development of CRISPR technology has given scientists new ways to correct mutations in nuclear DNA, this system cannot effectively cross the mitochondrial membrane and reach mitochondrial DNA.

In the new study, researchers used a tool called Base Editor-specific, a DDCBE (double-stranded DNA DEAMinase toxin A-derived cytosine base editor). This tool allows scientists to change a single letter in the DNA code without cutting it, and it works on mitochondrial DNA.

The team showed that they could effectively create and correct mitochondrial DNA mutations in several disease-linked cell types in the laboratory. First, they engineered liver cells to carry a mitochondrial mutation that impairs energy production. They then showed that they could repair a different mutation in skin cells from a patient with Gitelman-like syndrome of mitochondrial dysfunction, restoring key signs of healthy mitochondrial function.

To move the therapy toward clinical use, the researchers also tested the effectiveness of delivering the mitochondrial base editors in mRNA form rather than DNA and in lipid nanoparticles for delivery. They showed that these approaches are more efficient and less toxic to cells than older methods such as DNA plasmids. Importantly, the changes were highly specific, with minimal off-target changes detected in nuclear DNA and multiple detections in mitochondrial DNA.

“The potential of mitochondrial base editing in disease modeling and potential therapeutic interventions makes it a promising avenue for future research and development in mitochondrial medicine“The authors say.

The authors add, “Mitochondrial patients have been unable to benefit from the CRISPR revolution for so long, but recently the technology has become available that allows us to finally repair mitochondrial mutations. In our study, we used this technology on human liver organoids to generate a mitochondrial disease model. We used a clinical-grade technique to repair a mutation in the mitochondrial DNA of patient-derived cells.“

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