Mitochondria, the structures inside our cells that use food to produce energy, have been gene-edited for the first time. A new kind of “base editor” was used, opening the door to treating disorders related to faulty mitochondria.
These organelles have their own genomes and mutations in this DNA can lead to everything from muscle weakness to intellectual disability. Some inherited mitochondrial mutations result in death in early childhood, while an accumulation of mitochondrial mutations may be one of the causes of age-related diseases.
Two problems have thwarted previous attempts to gene-edit mitochondria. The first is that most gene editors work by cutting DNA, but mitochondrial genomes break down if cut.
In 2016, David Liu at the Broad Institute of MIT in Massachusetts developed base editors that change one DNA letter – or base pair – to another without cutting DNA. “You are directly rearranging the atoms in one base pair to become another, without cutting the double helix,” says Liu.
But these base editors consist of proteins adapted from the CRISPR gene-editing method, which need an RNA molecule to guide them to their target. That brings up the second problem: no one has managed to get RNA into mitochondria.
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Now Liu’s team has collaborated with two other groups to create an entirely new kind of base editor that doesn’t rely on CRISPR. The researchers, including Beverly Mok at Harvard and Marcos de Moraes at the University of Washington, in Seattle, fused proteins that can make the necessary chemical changes to mitochondrial DNA with proteins that bind to specific sequences. They added a kind of delivery address to get them into mitochondria.
In tests in human cells growing in a dish, this base editor made the desired change in up to 50 per cent of mitochondrial genomes. “If true, that’s quite impressive,” says Nick Lane at University College London.
Different variants of the mitochondrial base editor have to be created for each target – the teams have made six so far. With CRISPR base editing, by contrast, only the guide RNA needs changing, which is much easier. “For sure, it’s not as convenient,” says Liu.
The hope is that this new kind of base editor can treat disorders linked to mitochondria by correcting mutations inside people. “Introducing this into people will be enormously more difficult,” says Lane. “There are typically hundreds or thousands of copies of mitochondrial DNA in every cell.”
In theory, the base editor could also correct mutations in eggs to prevent children inheriting mitochondrial disorders, providing an alternative to using donor mitochondria – so-called three-parent babies.
At first, though, the main use of the technique will be to study the effects of mitochondrial mutations, which has been very hard to do until now. “It may be an extremely helpful research tool even if any clinical use is a way off,” says Lane.
Journal reference: Nature, DOI: 10.1038/s41586-020-2477-4
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