New TALED gene editing technology can target mitochondrial DNA

Gene editing tools like CRISPR have the potential to allow us to alter discrete fragments of DNA to directly treat a wide range of diseases. But there is one genetic frontier that scientists have yet to cross: mitochondria. Inherited from mother to child, mitochondria possess 37 genes of which mutations can give rise to about 300 different metabolic diseases, such as Leigh syndrome (which affects the brain’s role in body movements). ) or Pearson syndrome (which causes anemia and other blood problems). And unfortunately, we’ve had limited success using conventional gene-editing methods to study or correct these disastrous mistakes.

But scientists are getting closer to unraveling the mystery of mitochondria. In a new study published April 25 in the journal CabinetSouth Korean researchers have invented a new gene editing tool that can precisely swap the adenine nucleotide for another guanine nucleotide in the mitochondrial genome.

“This is an innovative study that has the potential to dramatically expand the range of mitochondrial mutations — and thus diseases — accessible to genome-editing-based treatments,” said Joseph Mougous, Microbiologist and Howard Hughes Medical Institute investigator at the University of Washington, who was not involved in the study, told The Daily Beast in an email.

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

“There are a number of extremely frustrating genetic diseases that arise from defects in mitochondrial DNA,” said Jin-Soo Kim, a biologist at the Center for Genome Engineering and lead researcher. body. “For example, Leber’s hereditary optic neuropathy, which causes sudden blindness in both eyes, is caused by a simple point mutation in mitochondrial DNA.”

And while CRISPR has benefited genetics research over the past decade, it’s a difficult technology to apply to mitochondrial DNA, said David Liu, a Howard Institute of Medicine biologist and investigator. Hughes at Harvard, who was not involved in the study, told The Daily Beast in an email.

In 2020, Liu and Mougous sought to overcome that barrier by creating a gene-editing tool that can swap cytosine for thymine (which, together with adenine and guanine, makes up the DNA structural quartet). This new platform ultimately opens up mitochondria to gene editing, but it can only deal with one type of mutation — when thymine spontaneously turns into cytosine — not when guanine mutates to adenine.

Building on previous work by Liu and Mougous, the Korean team built a new version of the mitochondrial gene editing kit called TALED, with a broader range of targets (including reversing the guanine-mutated mutation- adenine). It uses a protein called a transcription activator-like effect (or TALE) to target specific mitochondrial DNA sequences and applies an enzyme that induces the desired adenine-to-guanine modification. desired, in addition cytosine-to-thymine can be reversed.

“Since adenine base editing could in principle repair many of the mutations in mitochondrial DNA that cause genetic diseases, [Kim and his] Liu said.

Kim and his team are still working to improve the effectiveness and specificity of their tool so that it could eventually be used to treat mitochondrial diseases, which can occur at any age. but especially fatal and life-threatening if they are not diagnosed in infants and young children. In the US, one in 5,000 people has mitochondrial disease, and between 1,000 and 4,000 children are born each year, according to the Cleveland Clinic.

“The massive investments in nuclear genome editing over the past few years are flooding in to enable researchers interested in mitochondrial genome editing to make progress at an astonishing rate,” says Mougous. surprised,” said Mougous. Rest assured, we are riding on a fast wave of science.