̽��ֱ�� of Cambridge - Michal Minczuk

Study in mice shows potential for gene-editing to tackle mitochondrial disorders

cjb250 — Tue, 08 Feb 2022 10:00:16 +0000

Our cells contain mitochondria, which provide the energy for our cells to function. Each of these mitochondria contains 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 can affect how well the mitochondria operate, leading to mitochondrial diseases, serious and often fatal conditions that affect around 1 in 5,000 people. ̽��ֱ��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 a person will suffer from mitochondrial disease or not. 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. If the percentage of defective DNA could be reduced, the disease could potentially be treated.

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 ̽��ֱ�� of Cambridge applied an experimental gene therapy treatment in mice and were able to successfully target and eliminate the damaged mitochondrial DNA in heteroplasmic cells, allowing mitochondria with healthy DNA to take their place.

“Our earlier approach is 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.”

In their latest advance, published today in Nature Communications, Dr Minczuk and colleagues used a biological tool known as a mitochondrial base editor to edit the mitochondrial DNA of live mice. ̽��ֱ��treatment is delivered into the bloodstream of the mouse using a modified virus, which is then taken up by its cells. ̽��ֱ��tool looks for a unique sequence of base pairs – combinations of the A, C, G and T molecules that make up DNA. It then changes the DNA base – in this case, changing a C to a T. This would, in principle, enable the tool to correct certain ‘spelling mistakes’ that cause the mitochondria to malfunction.

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.

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 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.”

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

Reference
Silva-Pinheiro, S et al. In vivo mitochondrial base editing via adenoassociated viral delivery to mouse post-mitotic tissue. Nature Comms; 8 Feb 2022; DOI: 10.1038/s41467-022-28358-w

Defective mitochondria – the ‘batteries’ that power the cells of our bodies – could in future be repaired using gene-editing techniques. Scientists at the ̽��ֱ�� of Cambridge have shown that it is possible to modify the mitochondrial genome in live mice, paving the way for new treatments for incurable mitochondrial disorders.

[This] 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

Pedro Silva-Pinheiro

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Mitochondria - 3D illustration

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Mitochondrial diseases could be treated with gene therapy, study suggests

sc604 — Mon, 24 Sep 2018 15:00:00 +0000

̽��ֱ��researchers, led by the ̽��ֱ�� of Cambridge, applied an experimental gene therapy treatment in mice and were able to successfully target and eliminate the damaged DNA in mitochondria which causes the devastating conditions.

Their results, published in the journal Nature Medicine, could provide a practical route to treating patients with these diseases and may provide a future alternative to mitochondrial replacement therapy, or ‘three-parent IVF’. This is the first time programmable genome engineering tools have been used inside a living animal, resulting in such significant modification of mitochondrial DNA.

Mitochondria are the powerhouses inside our cells, producing energy and carrying their own DNA. They are inherited from a person’s mother via the egg, but if they are damaged, it can result in a serious mitochondrial disease. For example, MELAS Syndrome is a severe multi-system disorder causing progressive loss of mental and movement abilities, which usually becomes apparent in early childhood.

There are typically about 1000 copies of mitochondrial DNA per 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 mitochondrial DNA molecules in a cell need to be mutated for the disease to emerge, and the more mutated mitochondrial DNA a person has, the more severe their disease will be. Conversely, if the percentage of mutated DNA can be reduced, the disease could potentially be treated.

Mitochondrial diseases are currently incurable, although a new IVF technique of mitochondrial transfer gives families affected by mitochondrial disease the chance of having healthy children – removing affected mitochondria from an egg or embryo and replacing them with healthy ones from a donor.

“Mitochondrial replacement therapy is a promising approach to prevent transmission of mitochondrial diseases, however, as the vast majority of mitochondrial diseases have no family history, this approach might not actually reduce the proportion of mitochondrial disease in the population,” said Dr Payam Gammage, a postdoctoral researcher in the MRC Mitochondrial Biology Unit, and the paper’s first author.

“One idea for treating these devastating diseases is to reduce the amount of mutated mitochondrial DNA by selectively destroying the mutated DNA, and allowing healthy DNA to take its place,” said Dr Michal Minczuk, also from the Medical Research Council (MRC) Mitochondrial Biology Unit, and the study’s senior author.

To test an experimental gene therapy treatment, which has so far only been tested in human cells grown in petri dishes in a lab, the researchers used a mouse model of mitochondrial disease that has the same mutation as some human patients.

̽��ֱ��gene therapy treatment, known as the mitochondrially targeted zinc finger-nuclease, or mtZFN, recognises and then eliminates the mutant mitochondrial DNA, based on the DNA sequence differences between healthy and mutant mitochondrial DNA. As cells generally maintain a stable number of mitochondrial DNA copies, the mutated copies that are eliminated are replaced with healthy copies, leading to a decrease in the mitochondrial mutation burden that results in improved mitochondrial function.

̽��ֱ��treatment was delivered into the bloodstream of the mouse using a modified virus, which is then mostly taken up by heart cells. ̽��ֱ��researchers found that the treatment specifically eliminates the mutated mitochondrial DNA, and resulted in measures of heart metabolism improving.

Following on from these results, the researchers hope to take this gene therapy approach through clinical trials, in the hope of producing an effective treatment for mitochondrial diseases.

This work was supported by the Medical Research Council and was performed in collaboration with Sangamo Therapeutics and the Max Planck Institute for Biology of Ageing in Cologne.

Reference:
Payam A. Gammage et al. ‘Genome editing in mitochondria corrects a pathogenic mtDNA mutation in vivo.’ Nature Medicine (2018). DOI: 10.1038/s41591-018-0165-9.

Researchers have developed a genome-editing tool for the potential treatment of mitochondrial diseases: serious and often fatal conditions which affect 1 in 5,000 people.

One idea for treating these devastating diseases is to reduce the amount of mutated mitochondrial DNA by selectively destroying the mutated DNA, and allowing healthy DNA to take its place.

Michal Minczuk

NICHD/U

Mitochondria

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