Mitochondrial gene therapy
A new method of editing mitochondrial genes will allow treating hereditary diseases
Daniil Sukhinov, Naked Science
Most eukaryotic cells, including human cells, contain very important organelles — mitochondria. They are called energy stations of the cell, because they are engaged in the oxidation of organic compounds, which releases energy. They store part of this energy in the form of ATP, which is then used by the whole cell, and part is dissipated in the form of heat.
Each mitochondria has its own ring DNA, inherited exclusively from the mother. In total, several hundred and even thousands of copies of mitochondrial DNA (mtDNA) are simultaneously present in human cells, 5-10 copies in each mitochondria. Mutations in mtDNA often lead to hereditary diseases that can manifest at any age and affect almost any organ.
Usually, in order for mutations in mtDNA to manifest clinically, more than 60% of mitochondria in tissue or organ cells must be defective, and the more defective mitochondria a person has, the more severe his disease will be. Frequent clinical manifestations of mitochondrial diseases are problems with the development and work of muscles (eyes, heart, skeleton), atrophy of the optic nerve and visual impairment, seizures, dementia, migraine, diabetes, liver failure.
Previously, mitochondrial diseases were considered incurable, but it was clear what it was necessary to strive for: reduce the percentage of defective mtDNA in cells. Back in 2018, a team of scientists from the Department of Mitochondrial Biology at Cambridge University applied an experimental treatment based on gene therapy in mice and was 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 that anyone has managed to change the mitochondrial DNA in a living animal," explained Michal Minczuk, doctor of the Department of Mitochondrial Biology. — But the technology will only work in cells with a sufficient amount of healthy mitochondrial DNA that could copy itself and replace the defective one. This will not work in cells where all mitochondria have defective DNA."
In a new study published in the journal Nature Communications (Silva-Pinheiro et al., In vivo mitochondrial base editing via adeno-associated viral delivery to mouse post-mitotic tissue), Minchuk and his colleagues used for the first time a new biological tool known as a cytosine base editor based on double-stranded DNA deaminase (DdCBE), to edit mtDNA in the heart of live mice.
The DNA encoding DdCBE is delivered to the target cells via the bloodstream using vectors of the adeno-associated virus. After DdCBE synthesis in the cell, the enzyme searches for a unique sequence of base pairs (C-G, T-A) in mtDNA and catalyzes the replacement of a pair of C-G by a pair of T-A (unlike the previous method, where nucleotides were cut from mtDNA). Such a seemingly simple action in the future will allow to get rid of mutations that cause malfunctions in the mitochondria, and, accordingly, treat related hereditary diseases.
Pedro Silva-Pinheiro, a researcher in Dr. Minchuk's laboratory and the first author of the article, added: "This is the first time that anyone has managed to change the base pairs of DNA in the mitochondria of a living animal. This shows that we can correct errors in defective mitochondrial DNA by getting healthy mitochondria and allowing cells to function properly."
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