For the first time, a team led by researchers from Mass Eye and Ear has successfully restored hearing in an adult mouse model with inherited deafness caused by microRNA mutations using a novel in vivo genome editing approach. The researchers emphasize that mouse and human microRNAs share identical sequences, raising hopes that their study will pave the way for translational research and potential applications for humans with deafness caused by similar mutations.

The study, spearheaded by Zheng-Yi Chen, DPhil, an associate scientist in the Eaton-Peabody Laboratories at Mass Eye and Ear (part of the Mass General Brigham healthcare system), was published on July 10 in Science Translational Medicine.

“Our findings provide a promising pathway for developing treatments by editing many forms of genetic hearing loss,” said Chen, who is the Ines and Fredrick Yeatts Chair in Otolaryngology at Mass Eye and Ear and an associate professor in Otolaryngology–Head and Neck Surgery at Harvard Medical School.

Approximately one in 500 newborns suffer from genetic hearing loss, and there are currently no approved therapeutics to treat this condition.

In the new study, researchers targeted a specific mutation in the microRNA-96 (MiR-96) gene that causes progressive hearing loss in mice and regulates gene expression in hair cells (sensory cells responsible for hearing) in mammals. In humans, this mutation causes a form of dominant inherited progressive hearing loss known as DFNA50. The researchers created a mouse model carrying the mutation to mirror the progressive hearing loss observed in humans with DFNA50; by four weeks of age, these models exhibited complete hearing loss at high frequencies.

The team utilized a CRISPR/Cas9 genome editing approach to target and disrupt this mutation, delivering the editing machinery to the inner ear via an injection of an adeno-associated virus (AAV). They compared injections at two developmental stages—early development and adult—and demonstrated long-term preservation of auditory function in both cases, with earlier intervention proving most optimal.

The study also assessed the safety of the AAV-mediated genome editing approach, finding a favorable safety profile with minimal off-target effects and no detectable long-term integration of the AAV vector in the genome. This suggested minimal potential risk and supports the feasibility of future clinical applications in humans.

Chen and his team have designed a construct to target all known microRNA mutations for use in humans. In collaboration with Mass General Brigham’s Gene and Cell Therapy Institute, they plan to conduct IND-enabling studies in additional preclinical models, with the aim of advancing this treatment approach to a first-in-human clinical trial. This study highlights the potential of gene therapy for treating conditions such as hearing loss, with Mass General Brigham’s Gene and Cell Therapy Institute playing a crucial role in translating scientific discoveries into clinical trials and, ultimately, life-changing treatments for patients.

This groundbreaking research by Chen and his colleagues represents a significant advancement in gene therapy for hearing disorders, offering hope for future clinical trials aimed at restoring auditory function in people with genetic forms of hearing impairment. Chen and his team have also conducted clinical trials for a different gene therapy approach targeting another form of deafness, DFNB9, caused by mutations in the OTOF gene. That clinical trial in China has shown positive results in children treated in one or both ears. Chen hopes that the technology developed in the OTOF trial, such as minimally invasive AAV delivery into the human inner ear, will accelerate the development of editing therapy into clinical practice.

“With more than 150 forms of genetic deafness, our research offers hope for patients who previously had no options beyond a cochlear implant,” said Chen. “These findings suggest a need for more rigorous studies building on proof-of-concept papers like these to achieve our goal of developing various treatment approaches to target each of these mutations.”