In a landmark study, a group of researchers from Mass Eye and Ear has pioneered a groundbreaking method to restore hearing. Using a novel in vivo genome editing technique, they were able to successfully restore hearing in an adult mouse model suffering from a type of hereditary deafness. The deafness was due to aberrations in microRNA. Interestingly, mouse and human microRNAs share identical sequences, thus suggesting that this innovative study could lay the groundwork for further research into similar applications in humans.
The researchers focused on a particular mutation in the microRNA-96 (MiR-96) gene. This gene plays a vital role in the regulation of gene expression in hair cells, which are sensory cells responsible for hearing in mammals. In humans, this mutation is known to cause a form of dominant inherited progressive hearing loss named DFNA50. The researchers developed a mouse model that carried this mutation, mirroring the progressive hearing loss seen in humans with DFNA50. By the age of four weeks, these mice showed complete hearing loss at high frequencies.
In the new study, the team utilized 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). This intervention was performed during early development and adult stages, and both instances demonstrated successful, long-term preservation of auditory function.
The safety of the AAV-mediated genome editing approach was also assessed. The researchers found that it had a commendable safety profile, with negligible off-target effects and no detectable long-term integration of the AAV vector in the genome. This indicates a minimal potential risk and supports the feasibility of future clinical applications in humans.
Zheng-Yi Chen, DPhil, an associate scientist at Mass Eye and Ear, led this study. Chen, who also holds the Ines and Fredrick Yeatts Chair in Otolaryngology at Mass Eye and Ear and is an associate professor in Otolaryngology-Head and Neck Surgery at Harvard Medical School, stated, “Our findings provide a promising pathway for developing treatments by editing for many forms of genetic hearing loss.”
Chen and his team have designed a construct to contain all known microRNA mutations for use in humans. They plan to conduct additional preclinical studies in partnership with Mass General Brigham’s Gene and Cell Therapy Institute. The goal is to move this treatment approach into a first-in-human clinical trial.
This latest research marks a major advancement in gene therapy for hearing disorders. With the potential to restore auditory function in people with genetic forms of hearing impairment, it signals hope for future clinical trials. Chen and his team have also had positive results in clinical trials using a different gene therapy approach for another form of deafness, DFNB9 caused by mutations in the OTOF gene.
Chen expressed optimism about the future, saying, “With more than 150 forms of genetic deafness, our research offers further hope for patients that previously lacked any options beyond a cochlear implant.” He added that rigorous studies building on proof-of-concept papers like these are needed to develop different treatment approaches to target each of these mutations.
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