Jeffrey Holt, professor of otolaryngology and neurology at the Harvard Medical School and an author of the paper, successfully treated TMC1-related deafness with gene therapy by situating cells with healthy versions of the gene among the unhealthy to counteract the disease-causing mutation. But Volha Olga Shubina-Aleinik, a postdoctoral fellow in the Holt lab, said gene therapy may have a limited duration. That is why we need more advanced techniques, such as gene editing, which may last a lifetime.
Yeh spent years designing a base editor that could find and erase the disease-causing mutation and replace it with the correct DNA code. But even after she demonstrated good results in vitro, there was a problem: Base editors are too large to fit in the traditional delivery vehicle, adeno-associated virus, or AAV. To solve this problem, the team split the base editor in half, sending each piece in with its own viral vehicle. Once inside, both viruses needed to infect the same cells so the two base editor halves could rejoin and head off to find their target. Despite the labyrinthine entry, the editor proved to be efficient, causing only a minimum of undesired deletions or insertions.
We saw very little evidence of off-target editing, Liu said. And we noticed that the edited animals had much-preserved hair-cell morphology and signal transduction, meaning the hair cells, the critical cells that convert sound waves to neuronal signals, appeared more normal and behaved more normally.
After the treatment, Yeh performed an informal test: She clapped her hands. Mice that had previously lost all hearing ability jumped and turned to look. Formal tests revealed the base editor worked, at least in part: Treated mice had partially restored hearing and could respond to loud and even some medium sounds, Yeh said.
Of course, more work needs to be done before the treatment can be used in humans. Unedited cells continued to die, causing deafness to return even after the base editor restored function to others.
But the study also proved that the clandestine AAV delivery method works. Already, Liu is using AAV to tackle other genetic diseases, including progeria (premature aging), sickle cell anemia, and degenerative motor diseases. Were actually going after quite a few genetic diseases now, including some prominent ones that have caused a lot of suffering and energized pretty passionate communities of patients and patient families to do anything to find a treatment, Liu said. For progeria, theres no cure. The best treatments extend a childs average lifespan from about 14 to 14.5 years.
For Yeh, whose friend is still living with hearing loss, genetic deafness remains her primary target. Theres still a lot to explore, she said. Theres so much unknown.
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Gene editing may be a path to restore partial hearing - Harvard Gazette
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