A Potential Cure for Genetic Deafness

​Researchers from the Howard Hughes Medical Institute have successfully prevented genetic hearing loss in mice through the genome editing technology CRISPR-Cas9 in a recent study. (Nature 2017. doi: 10.1038/nature25164. [Epub ahead of print].) They injected a single treatment of a genome editing cocktail, which acted as molecular scissors and disrupted the mutation in the gene Tmc1, into the inner ears of infant mice with that mutation. The hair cells in treated ears resembled those in healthy animals after eight weeks, and treated ears could hear sounds about 15 dB lower than untreated ears. 

                                                       

Scientists can gauge mouse hearing by measuring how much noise (dB SPL) it takes to trigger an auditory brainstem response (ABR). Sounds starting at roughly 30 decibels can spark brain activity in normal mice (green/bottom line). Mice with the Tmc1 mutation lose their ability to hear and eventually become deaf. But injecting their inner ears with a genome editing agent made them more sensitive to sound (blue/middle line) than ears without an injection (red/top line). Credit: X. Gao, et al./Nature 2017 (http://bit.ly/2CZXbdR). ​

A single spelling error in Tmc1causes the loss of the inner ear's hair cells over time, and just one copy of a mutated Tmc1 gene causes progressive hearing loss leading to profound deafness in both humans and mice. Scientists at Howard Hughes snipped both strands of the DNA double helix with Cas9 to disable the gene. The challenge of the study lied in directing Cas9 to only the bad copy of Tmc1 and not the good one because the two copies differ by just one DNA letter. Researchers in this study packaged Cas9 and the guiding RNA into a greasy bundle that slips inside cells but doesn't stick around, allowing Cas9 to hit the bad gene copy and fade away before it could harm the good one. 

       

In the genome editing technology known as CRISPR-Cas9, RNA (blue) guides the protein Cas9 (large bumpy structure) to a target site in DNA (red). Cas9 unwinds the DNA double helix and acts as molecular scissors, snipping both strands of DNA. This animation is a preview of an interactive web feature that HHMI BioInteractive will debut in March of 2018. Credit: Howard Hughes Medical Institute (http://bit.ly/2CZXbdR).

​David Liu, PhD, a professor of chemistry and chemical biology at Harvard University and an investigator in the study, said the work is among the first to apply a genome editing approach to deafness in animals, and the positive change they observed in the mice could make a major difference in the quality of life for patients with hearing loss. "We hope that the work will one day inform the development of a cure for certain forms of genetic deafness in people," he said. 

Published: 1/14/2018 2:13:00 PM

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