3D rendered Illustration, visualisation of a anatomically correct Mitochondrion, a organelle of most eukaryotic and other cells - to illustrate mitochondrial DNA changes in cancer
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Defective mitochondria could be repaired using gene-editing, according to work from scientists at the University of Cambridge. They have modified the mitochondrial genome in live mice, paving the way for new treatments for incurable mitochondrial disorders. Their work is published today in Nature Communications.

Pedro Silva-Pinheiro, a postdoctoral researcher and first author of the study, said, “This is the first time that anyone has been able to change DNA base pairs in mitochondria in a live animal. It shows that, in principle, we can go in and correct spelling mistakes in defective mitochondrial DNA, producing healthy mitochondria that allow the cells to function properly.”

Michal Minczuk, senior author, and colleagues used a tool called a mitochondrial base editor. The treatment is delivered into the bloodstream of the mouse using a modified virus, which is then taken up by the mouse’s cells. The tool seeks a unique sequence of base pairs. It then changes the DNA base—in this case, changing a C to a T. This corrects certain mutations that cause the mitochondria to malfunction.

Mitochondrial DNA makes up only 0.1% of the overall human genome and is passed down exclusively from mother to child. But faults in mitochondrial DNA can affect how these organelles operate, leading to serious and often fatal conditions that affect around 1 in 5,000 people. The diseases are incurable and largely untreatable.

There are typically around 1,000 copies of mitochondrial DNA in each cell, and the percentage of these that are damaged, or mutated, will determine whether or not a person will suffer from disease. Usually, more than 60% of the mitochondria in a cell need to be faulty for the disease to emerge, and the more defective mitochondria a person has, the more severe their disease will be. Reducing the percent of defective DNA could potentially treat disease.

A cell that contains a mixture of healthy and faulty mitochondrial DNA is described as ‘heteroplasmic’. If a cell contains no healthy mitochondrial DNA, it is ‘homoplasmic’.

In 2018, a team from the MRC Mitochondrial Biology Unit at the University of Cambridge applied an experimental gene therapy treatment in mice and were able to target and eliminate damaged mitochondrial DNA in heteroplasmic cells, allowing mitochondria with healthy DNA to take their place.

“Our earlier approach was very promising and was the first time that anyone had been able to alter mitochondrial DNA in a live animal,” explained Minczuk. “But it would only work in cells with enough healthy mitochondrial DNA to copy themselves and replace the faulty ones that had been removed. It would not work in cells whose entire mitochondria had faulty DNA.”

There are currently no suitable mouse models of mitochondrial DNA diseases, so the researchers used healthy mice to test the mitochondrial base editors. However, it shows that it is possible to edit mitochondrial DNA genes in a live animal.

Minczuk said, “There’s clearly a long way to go before our work could lead to a treatment for mitochondrial diseases. But it shows that there is the potential for a future treatment that removes the complexity of mitochondrial replacement therapy and would allow for defective mitochondria to be repaired in children and adults.”

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