Young adult mice with a genetic form of progressive deafness can hear again after being treated with an experimental CRISPR gene therapy that its creators hope to eventually use in humans.
In an article published July 10 in Science Translational Medicine, a team of scientists led by researchers from Massachusetts Eye and Ear claimed they used a CRISPR-Cas9 system to alter deafness-causing mutations in the gene microRNA-96 (MIR96) in both young mice and deaf adults. While the treatment worked better the earlier the mice were treated and wasn’t effective after severe hearing loss had set in for long periods, it worked in six-week-old mice, an age that corresponds to roughly 18 years in humans.
“Our research suggested minimal potential risk and supports the feasibility of future clinical applications in humans,” Zheng-Yi Chen, D.Phil., who led the study, said in a press release. “With further study, our intervention using genome editing could potentially halt or reverse hearing loss progression in affected individuals, including adults.”
The gene MIR96 is involved in the development of what are known as hair cells, a type of cell found in an inner ear structure called the cochlea. It suppresses cell signals that would otherwise keep hearing from developing. Both humans and mice with a single copy of a mutation in the MIR96 gene experience delayed-onset hearing loss called autosomal dominant deafness-50 (DFNA50). But because it’s not present from birth, there’s a “window of opportunity to test [a gene therapy] for hearing rescue in the mouse models with the goal of human applications,” the researchers wrote in their paper.
To do that, the researchers injected just one ear each in groups of three-week-old, six-week-old and 16-week-old mice with single MIR96 mutations with an adeno-associated viral vector containing CRISPR-Cas9 machinery. The animals’ hearing was tested in regular intervals to see if the therapy worked.
Prior to receiving the therapy, the 3-week-old mice had hearing loss at high frequencies. Their hearing in the treated ear was better at 13 weeks than the untreated ear and was also better than that of mice that received the therapy at 6 weeks of age. However, the older mice also had hearing restored in their treated ears, which were better able to detect sounds at 20 weeks than the untreated ears. The mice treated at 16 weeks old didn’t improve.
“These data indicate that genome editing therapy is no longer an effective treatment at later stages of severe hearing loss,” the researchers wrote in the paper. “Combined with the data from 3-, 6-, and 16-week injections, the results highlight the importance of early intervention for more effective outcomes before substantial hearing loss is initiated.”
A comparison of hair cells in another set of mouse models’ ears explained the results. The hair cells of untreated ears died as the mice aged, corresponding to hearing loss. But those of treated ears were well-preserved, indicating that altering the gene mutation was effective in preventing the animals from losing their hair cells and therefore their hearing.
“These findings demonstrate that [gene editing] rescues hair cells in the [mice with the gene mutation] by promoting their survival and maintaining the structure of the [hair cells],” the scientists’ paper read.
The researchers also assessed whether the treatment was safe, with special attention to the possibility of the AAV vector integrating into DNA breaks created by CRISPR-Cas9—a risk of AAV-delivered gene therapy with consequences that aren’t yet clear. They found that this wasn’t an issue at doses that were still low enough to edit the gene effectively and didn’t see any other off-target effects or signs of toxicity.
The researchers will do more preclinical studies on different types of animal models as part of an investigational new drug application for the therapy. It’s not their first rodeo in the space: Chen also developed a gene therapy for another form of deafness that’s been successful so far in a clinical trial in China involving children.