Hearing loss is the most common form of sensory loss in humans, and almost half of cases have an underlying genetic cause. Reporting in Nature, a team of researchers have developed a CRISPR-Cas9 genome-editing therapy to prevent hearing loss in a mouse model of human genetic progressive deafness.

The therapy delivers a CRISPR-Cas9 gene-editing protein complex directly into the sound-sensing cells of the inner ear (known as "hair cells") to disrupt a mutation that would otherwise cause the cells to die. The work represents the first time that a genome-editing protein has been ferried directly into the relevant cells to halt progression of genetic hearing loss. Delivering the Cas9 protein itself locally, instead of DNA elements that the cell can use to build Cas9, improved the DNA specificity and potential safety of the treatment.

"We set out to develop a genome-editing strategy to try to address this genetic hearing loss by disrupting the underlying genetic variant," said co-senior author. "A lot of additional work is needed before this strategy might inform the development of a therapy for humans, but at this stage, we're delighted and excited that the treatment preserved some hearing in the animal model."

Hair cells are the specialized inner-ear cells that turn the mechanical vibrations of sound waves into electrical signals that the brain can interpret. One root cause of genetic hearing loss is a single-letter mutation in a gene called TMC1 that causes hair cells to produce a malformed, toxic protein, one which builds up and kills the cell. Humans (and mice) with this mutation suffer progressive hearing loss during youth, and eventually become profoundly deaf.

Because the mutated TMC1 gene only differs from its normal counterpart by a single letter of DNA, Cas9 must target the mutated gene with laser precision. Otherwise, the Cas9 protein would easily cut and disable the functional copy of the gene instead.

The researchers tested the method in a mouse model of progressive hearing loss with a mutated Tmc1 gene. Left untreated, the mice experience hearing loss by four weeks of age and profound deafness at eight. The team injected the gene-editing mix into the cochlea of newborn mice genetically destined for profound hearing loss.

The treated mice maintained a substantial amount of their hearing compared to the untreated mice. At four weeks, the untreated mice had a measurable response in their brainstem to sound starting at roughly 80 decibels, the volume of a garbage disposal or a loud radio. But the treated mice responded to sound starting around 65 decibels -- approximately the same volume as a typical spoken conversation.

Physiological measurements showed that the hair cells survived at a higher rate in the treated cochlea; genetic sequencing showed that among the edited cells, the mutated copy of Tmc1 had successfully been disrupted 94 percent of the time, and the wild-type allele had only been hit 6 percent of the time. At eight weeks, treated mice also retained their instinctive physical "startle" response to sudden loud sound, while the untreated mice did not respond.

The team plans to develop the therapy in larger animal models of genetic progressive hearing loss. "These results inform the potential development of a treatment for a subtype of genetic hearing loss, but making sure the method is safe and effective is critically important before we propose moving closer to human trials," said the co-senior author. "We also recognize the importance and remain mindful of cultural considerations within the Deaf community as this work moves forward."

https://www.masseyeandear.org/news/press-releases/2017/12/crispr-therapy-hearing

https://www.nature.com/articles/nature25164