Mice study shows potential for gene-editing to tackle mitochondrial disease

Mice study shows potential for gene-editing to tackle mitochondrial disease
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New research showed how modifying the mitochondrial genome in live mice could lead to new treatments for mitochondrial disease.

Our cells contain mitochondria, which provide the energy for our cells to function. Each of these mitochondria is coded for by a tiny amount of mitochondrial DNA. Mitochondrial DNA makes up only 0.1% of the overall human genome and is passed down exclusively from mother to child. Faults in our mitochondrial DNA affects how the mitochondria operate, leading to mitochondrial disease and affecting around one in 5,000 people.

Scientists from the University of Cambridge have published their findings in Nature Communications.

Mitochondrial disease

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 a person will suffer from mitochondrial disease or not. Usually, more than 60% of the mitochondria in a cell needs to be faulty for disease to emerge – the more defective the cells are, the more severe the mitochondria disease will be. However, if the percentage of defective DNA could be reduced, the mitochondria disease could potentially be treated.

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

Targeting damaged mitochondria DNA

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 successfully target and eliminate damaged mitochondria 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 Dr Michal 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.”

The scientists used a biological tool known as a mitochondrial base editor to edit the mitochondrial DNA of live mice. The treatment was delivered into the bloodstream of the mouse using a modified virus, which is taken up by its cells. The tool searches for a unique sequence of base pairs – combinations of A, C, G, and T molecules that make up DNA. Following this, it changes the DNA base – in this case, changing a C to a T. In principle, this would enable the tool to correct certain mitochondria malfunctions.

There are no suitable mouse models with mitochondrial disease, 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.

Pedro Silva-Pinheiro, a postdoctoral researcher in Dr Minczuk’s lab 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.”

An approach pioneered in the UK known as mitochondrial replacement therapy – sometimes referred to as ‘three-person IVF’ – allows a mother’s defective mitochondria to be replaced with those from a healthy donor. However, this technique is complex, and even standard IVF is successful in fewer than one in three cycles.

Dr Minczuk added: “There’s clearly a long way to go before our work could lead to a treatment for mitochondrial disease. 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.”

The research was funded by the Medical Research Council UK, the Champ Foundation and the Lily Foundation.

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