New TALED gene-editing technology can target mitochondrial DNA

Gene-editing tools like CRISPR have the ability to allow us to alter separate parts of our DNA To treat a range of diseases directly at the root. But there is one genetic frontier that scientists have yet to break: the mitochondria. Mitochondria, which are passed from mother to child, have 37 genes in which mutations can lead to about 300 different metabolic diseases, such as Leigh’s syndrome (which affects the brain’s role in motor movements) or Pearson’s syndrome (which causes anemia and other blood problems). Unfortunately, we have had limited success using traditional gene-editing methods to study or correct these disastrous errors.

But scientists are getting close to lifting the mysterious veil of mitochondria. at A new study was published on April 25 in the magazine prison cellSouth Korean researchers have devised a new gene-editing tool that can precisely replace an adenine nucleotide with another guanine nucleotide within the mitochondrial genome.

“This is an innovative study that has the potential to significantly expand the range of mitochondrial mutations — and thus diseases — that can be accessed by therapeutic approaches based on genome editing,” Joseph Mogos, a microbiologist and investigator of the Howard Hughes Medical Institute at the University of Washington, who was not involved in, said. In the study, the Daily Beast in an email.

Mitochondria, found in all trillions of cells in the human body, are widely known as the powerhouse of the cell – responsible for converting food and oxygen into usable energy. Scientists believe they were once independent, single-celled organisms swallowed up by larger cells billions of years ago, which explains why they have their own (minute) genomes passed down.

“There are some very bad genetic diseases that arise due to defects in mitochondrial DNA,” Jin Soo Kim, a biologist at the Center for Genome Engineering and lead investigator on the study, said. He said in a press release. “For example, Leber’s hereditary optic neuropathy, which causes sudden blindness in both eyes, is caused by a simple, single-point mutation in mitochondrial DNA.”

And while CRISPR has been a boon to genetics research in the past decade, it has been difficult to apply to mitochondrial DNA, David Liu, a biologist and Howard Hughes Medical Institute investigator at Harvard University, who was not involved in the study, told The Daily Beast in an email.

In 2020, Liu and Mougous manage to break through this barrier Create a gene editing tool Cytosine can be replaced by thymine (which, together with adenine and guanine, forms the quaternary of the building blocks of DNA). This new platform finally opened the mitochondria for gene-editing work, but it could only handle one type of mutation — when thymine spontaneously converts to cytosine — not when guanine converts to adenine.

Building on previous research by Liu and Mougous, the South Korean group has built a new version of a mitochondrial gene editor called TALED, with a broader range of goals (including reversing mutations of guanine and adenine). It uses a protein called a transcription activator-like effector (or TALE) to target specific mitochondrial DNA sequences, and applies an enzyme that releases adenine to the desired guanine, as well as inversions of cytosine to thymine as well.

“Because adenine base modification can, in principle, correct many of the mutations in mitochondrial DNA that cause genetic diseases, [Kim and his] The group’s work is a major advance toward the precise correction of disease-causing mitochondrial mutations,” said Liu.

Kim and his team are still working to improve the efficiency and specificity of their tool so that it could eventually be used to treat mitochondrial diseases, which can strike at any age but are particularly fatal and life-threatening if undiagnosed in infants and children. young children. In the United States, 1 in 5,000 people suffers from mitochondrial disease and about 1,000 to 4,000 babies are born with one baby each year. According to the Cleveland Clinic.

“Large investments in nuclear genome editing have spanned over the past several years to allow researchers interested in mitochondrial genome editing to make progress at an astonishing rate,” Mojos said. Rest assured, we are riding the fast scientific wave.