Researchers Develop CRISPR-Cas9 Model to Simultaneously Target Two Mutations in Dominant Deafness and Partially Restore Hearing

Deafness affects 6% of the world’s population, and over 120 genes have been linked to hereditary hearing loss. However, there are no biological treatments for any form of genetic deafness. A research team led by investigators at Massachusetts Eye and Ear, a member of the Mass General Brigham healthcare system, set out to use CRISPR-Cas9 genome editing to target mouse models of dominant genetic hearing loss. They successfully rescued hearing in these models by targeting a single mutation and two mutations simultaneously.

Dominant hearing loss is difficult to treat as the mutations have to be abolished in order to rescue hearing. The research team used two dominant mouse models: the first with a single mutation in the Atp2b2 gene, and the other with two mutations, one in the Atp2b2 and one in the Tmc1 gene. The team used a gene therapy delivery technique known as liposome-mediated RNP (ribonucleoproteins) delivery of CRISPR-Cas9/gRNA to either abolish the single Atp2b2 mutation or double Atp2b2 and the Tmc1 mutations, simultaneously, ultimately restoring the function of Atp2b2 and Tmc1 in the hair cells, which led to hearing recovery.

The team evaluated hearing recovery eight and 16 weeks after injection, reporting robust hearing recovery by single mutation intervention and partial hearing recovery by double-mutation intervention.  Hearing recovery became less effective after 16 weeks. The research team plans to focus future efforts on gene editing to sustain hearing recovery.

“We effectively used CRISPR-Cas9 to abolish mutations responsible for dominant hearing loss. The ability to target two mutations at the same time is very encouraging as many people are found to have more than one mutation, making it difficult to intervene” said co-corresponding author Zheng-Yi Chen, DPhil, of Massachusetts Eye and Ear. “Our findings widen the path for future development of gene therapies for different types of hearing loss in humans.”

Studies like this one show the promise of gene therapy for treating conditions such as hearing loss. Mass General Brigham’s Gene and Cell Therapy Institute is helping to translate scientific discoveries made by researchers into first-in-human clinical trials and, ultimately, life-changing treatments for patients. The Institute’s multidisciplinary approach sets it apart from others in the space, helping researchers to rapidly advance new therapies and push the technological and clinical boundaries of this new frontier.

Read more in Nature Communications.