26 August 2024

A new method of mitochondrial gene editing will make it possible to treat inherited diseases

Researchers from the University of Cambridge have demonstrated the work of a pioneering technology for editing the mitochondrial genome in live mice. It paves the way for new treatments for previously untreatable inherited mitochondrial diseases. Most eukaryotic cells, including human cells, contain very important organelles - mitochondria. They are called the energy stations of the cell because they are involved in the oxidation of organic compounds, which releases energy. Some of this energy they store in the form of ATP, which is then used by the whole cell, and some of it is dissipated as heat.

Each mitochondrion has its own circular DNA, inherited exclusively from the mother. In total, several hundred or even thousands of copies of mitochondrial DNA (mtDNA) are present in human cells at any one time, with 5-10 copies in each mitochondrion. Mutations in mtDNA often lead to inherited diseases that can manifest at any age and affect virtually any organ.

Typically, for mutations in mtDNA to manifest clinically, more than 60% of the mitochondria in the cells of a tissue or organ must be defective, and the more defective mitochondria a person has, the more severe their disease will be. Common clinical manifestations of mitochondrial diseases include problems with muscle development and function (eyes, heart, skeleton), ocular atrophy and visual impairment, seizures, dementia, migraine, diabetes, and liver failure.

Mitochondrial diseases were previously thought to be incurable, but it was clear what the goal was: to reduce the percentage of defective mtDNA in cells. Back in 2018, a team of scientists from the University of Cambridge's Department of Mitochondrial Biology used an experimental gene therapy-based treatment on mice and were able to successfully eliminate damaged mtDNA in target cells, allowing mitochondria with healthy DNA to take their place.

"Our previous approach was promising, and this is the first time anyone has succeeded in altering mitochondrial DNA in a living animal," explained Michal Minczuk, PhD, of the Mitochondrial Biology Department. - But the technology will only work in cells with enough healthy mitochondrial DNA that could copy itself and replace defective DNA. It won't work in cells in which all the mitochondria have defective DNA."

In the new study, published in Nature Communications, Minchuk and colleagues first used a new biological tool known as the double-stranded DNA deaminase-based cytosine base editor (DdCBE) to edit mtDNA in the heart of living mice.

DNA encoding DdCBE is delivered to target cells via the bloodstream using adeno-associated virus vectors. Once DdCBE is synthesized in the cell, an enzyme searches for a unique sequence of base pairs (C-G, T-A) in the mtDNA and catalyzes the replacement of the C-G pair with a T-A pair (unlike the previous method, where nucleotides were excised from the mtDNA). This seemingly simple action will eventually make it possible to get rid of mutations that cause malfunctions in mitochondria and, consequently, to treat associated inherited diseases.

Pedro Silva-Pinheiro, a researcher in Dr. Minchuk's lab and first author of the study, added: "This is the first time anyone has managed to change DNA base pairs in mitochondria in a living animal. It shows that we can correct errors in defective mitochondrial DNA, producing healthy mitochondria and allowing cells to function properly."

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