People and mice with a certain dominant mutation in Tmc1--a gene required for normal function of the hair cells that sense sound waves in the inner ear--experience progressive hearing loss. In a study published today (December 20) in Nature, researchers have reduced this hearing loss in mice using a CRISPR-Cas9 genome-editing strategy to inactivate the mutated copy of the gene.
"It's a pretty significant piece of work," says Peter Barr-Gillespie, a sensory biologist at Oregon Health and Science University who was not involved in the study. "It shows that CRISPR-mediated gene editing can lead to real amelioration of hearing loss in vivo."
The so-called Beethoven mouse model has the same point mutation in the mouse version of Tmc1 that in the human gene leads to progressive hearing loss, typically during childhood. Around three weeks, mice begin to lose some of their hearing, and by eight weeks they are profoundly deaf due to the death of hair cells.
Harvard chemical biologist David Liu and colleagues designed a guide RNA that specifically targets the disease-causing copy of the gene, which is autosomal-dominant, to allow the healthy allele to function. But rather than using a virus-based system to deliver the Cas9 and guide RNA sequences, they encapsulated and delivered Cas9-guide RNA ribonucleotide protein (RNP) complexes within lipids. This strategy improved the editing selectivity for the mutant allele, so that it was targeted 20 times more often than the wild-type allele in cultures of mouse fibroblasts.