Science Sub-journal: For the first time in the world! Use of base editor in the body to restore partial hearing in recessive genetic deaf mice

, June 9, 2020 /PRNewswire/ --Bio ValleyBIOON/--- When Wei Hsi Yeh was a young undergraduate, one of her male friends went from normal hearing to total deafness in a monthHe was 29No one knows why he lost his hearing, and the doctor still doesn't knowYeh, who received her Ph.Din chemistry from Harvard University last month, was frustrated and frightened by her friend's loss of hearingHer graduate career has been devoted to solving the greatgeneticbehind hearing lossin the United States, one in eight people aged 12 or over has hearing loss in both earsAlthough technologies such as hearing aids and cochlear implants can amplify sound, they do not correct the problemHowever, given that genetic abnormalities cause half of all cases of hearing loss, gene editing may be able to do just thatTwo years ago, Yeh and Professor David RLiu, a member of the Broad Institute, first repaired an dominant mutation in a mouse model and prevented hearing lossHowever, Liu said, "Most genetic diseases are not caused by dominant mutations, but by recessive mutations, including mostgenetic hearing loss." "
now, in a new study, Liu, Yeh, and researchers from Harvard University, the Broad Institute, and the Howard Hughes Institute of Medicine have another "first": they restored part of the hearing of mice who were completely deaf due to the tMC1 recessive mutation, the first successful example of using genome editing to repair recessive disease-causing mutations The findings were published on June 3, 2020 in the journal Science Translational Medicine with the title "In Vivo base editing restores sensory trans and stilly yss auditory function in a mouse model of the research ysnes." images from Science Translational Medicine, 2020, doi: 10.1126/scitranslmed.aay9101 dominant pathogenic mutations, which means mutations that destroy only one copy of the body's two genetic copies and make it easier to attack in some ways Knock out bad copies of genes, and good copies of genes can be saved "But for recessive disease, you can't do that," says Liu By definition, recessive alleles mean you have two bad copies of genes Therefore, you can't just destroy bad copies You have to fix one or two bad copies "
in order to hear the sound, animals rely on hair cells in the inner ear, which bend under the pressure of sound waves and send electrical impulses to the brain The hidden mutation of TMC1 that Liu and Yeh hopes to correct cause these hair cells to deteriorate rapidly, causing the mice to become deeply deaf at 4 weeks old Jeffrey Holt, co-author of the paper and a professor of otolaryngology and neurology at Harvard Medical School, used gene therapy to successfully treat TMC1-related deafness, specifically by delivering healthy versions of the gene to unhealthy cell populations to counteract the disease-causing mutations But Volha Shubina-Aleinik, a postdoctoral researcher at Holt's lab, says the duration of gene therapy may be limited "That's why we need more advanced technologies like gene editing that can last a lifetime "
Yeh spent years designing an alkali editor that could find and eliminate pathogenic mutations and replace them with the correct DNA code But even if she shows good results in vitro, there is a problem: the base editor is too large to fit into traditional delivery vectors --- adeno-associated viruses (AAVs) To solve this problem, her team split the base editor in half, each half delivering it to the body using its own virus vector Once in the body, the two viruses vectors need to co-infect the same cell, where the two halves of the base editor are reconnected and headed for their target Although entering cells is complex, this base editor has proven to be effective, resulting in minimal unnecessary deletion or insertion "We have little evidence of off-target editing," Liu said We noticed that the mice who received base editing maintained good results in hair cell morphology and signal transduction, which meant that hair cells looked more normal and behaved more normally as key cells that converted sound waves into nerve signals after the treatment, Yeh had an informal test: she clapped her hands, and the mice, which had previously lost all of their hearing, jumped up and turned to look Formal tests have shown that the base editor works, at least partially Yeh said the treated mice partially regained their hearing and were able to respond to large sounds and even moderate sounds of course, more research is needed before such treatments can be used in humans Hair cells that have not been edited by the base continue to die, causing deafness to reappear after the base editor regains the function of the edited hair cells , however, the new study also confirms that this AAV delivery method is effective Currently, Liu is already using AAV to address other genetic diseases, including early aging, sickle cells
anemia
and degenerative motor diseases "Actually, we're now working on a number of genetic diseases, including some that have caused a lot of pain, and it's inspiring patients and their families to do anything to find a cure," Liu said There is no cure for early age Even the best treatments can only extend a child's life expectancy from about 14 years old to 14.5 years "
for Yeh, her friend's hearing loss still doesn't know the cause, let alone cure it, and genetic deafness remains her main research goal "There's a lot to explore," she said "(Bio Valley Bioon.com) References: 1.Wei-Hsi Yeh et al.
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