Genome editing restores hearing in mice with progressive hearing loss
Research from Mass Eye and Ear demonstrates successful use of CRISPR/Cas9 to target and disrupt a genetic mutation causing hearing loss, offering hope for future treatments in humans.
A groundbreaking study led by researchers at Mass Eye and Ear has demonstrated the potential of genome editing to restore auditory function in mice with progressive hearing loss. The research, published in Science Translational Medicine [1], offers a promising pathway for developing treatments for various forms of genetic hearing loss in humans.
The study, headed by Zheng-Yi Chen, DPhil, from the Eaton-Peabody Laboratories at Mass Eye and Ear, focused on a specific mutation in the microRNA-96 (MiR-96) gene. This mutation causes progressive hearing loss in mice and is known to play a crucial role in regulating gene expression in mammalian hair cells, which are responsible for hearing.
Targeting the MiR-96 mutation
Researchers created a mouse model carrying the MiR-96 mutation, mirroring the progressive hearing loss observed in humans with DFNA50, a form of dominant inherited progressive hearing loss. By four weeks of age, these mice exhibited complete hearing loss at high frequencies.
The team employed a CRISPR/Cas9 genome editing approach to target and disrupt this mutation. The editing machinery was delivered to the inner ear through an injection of an adeno-associated virus (AAV). Injections were compared at two time points: during early development and in adult stages.
Promising results and safety profile
The study demonstrated robust preservation of auditory function in both cases long-term, with earlier intervention proving most optimal. Importantly, the AAV-mediated genome editing approach showed a good safety profile, including minimal off-target effects and no detectable long-term integration of the AAV vector in the genome.
“Our findings provide a promising pathway for developing treatments by editing for many forms of genetic hearing loss,” said Chen. “With further study, our intervention using genome editing could potentially halt or reverse hearing loss progression in affected individuals, including adults.”
Implications for human treatment
The research team has designed a construct to contain all known microRNA mutations to be used 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, hoping to move this treatment approach into first-in-human clinical trials.
Chen and his colleagues have also conducted clinical trials examining a different gene therapy approach for another form of deafness, DFNB9, caused by mutations in the OTOF gene. This trial in China has shown positive results in children treated in one or both ears.
Future directions
With more than 150 forms of genetic deafness identified, this research offers hope for patients who previously had limited options beyond cochlear implants. The findings suggest a need for more rigorous studies to build on these proof-of-concept results, with the ultimate goal of developing different treatment approaches to target each of these mutations.
“These findings suggest a need for more rigorous studies building on proof-of-concept papers like these, to achieve our goal of developing different treatment approaches to target every one of these mutations,” Chen concluded.
Reference:
- Zhu, W., Du, W., Rameshbabu, A. P., et. al. (2024). Targeted genome editing restores auditory function in adult mice with progressive hearing loss caused by a human microRNA mutation. Science Translational Medicine.
https://doi.org/10.1126/scitranslmed.adn0689
