A novel CRISPR genome editing approach has shown promise in potentially reversing genetic hearing loss due to a certain type of mutation in microRNA.
Deafness
Mass Eye and Ear researchers have successfully restored hearing in preclinical adult mouse models having DFNA50, a type of genetic hearing loss linked to microRNA mutations, with the aid of a new in vivo genome editing approach. The findings of their study were reported in Science Translational Medicine.
“Our findings provide a promising pathway for developing treatments by editing for many forms of genetic hearing loss,” said lead researcher Zheng-Yi Chen, DPhil, the Ines and Fredrick Yeatts Chair in Otolaryngology at Mass Eye and Ear.
The CRISPR genome editing technique, which researchers say shows minimal risk, offers promise of potentially being used to treat inherited hearing loss in humans. Human and mouse microRNAs exhibit similar sequences.
Chen stated that the novel approach could potentially be used to treat hearing loss even in adults who are affected.
Studying progressive hearing loss
It is believed that around one in 500 newborn babies have genetic hearing loss. At present, there are no approved therapeutics for treating deafness.
Researchers have demonstrated in mice that replacing or modifying a gene could treat inherited deafness in baby mice. However, there was no study to show that the same can be done in the inner ear of adult animals.
Specifically, Mass Eye and Ear scientists honed in on a microRNA-96 (MiR-96) gene mutation in this research. This mutation, which is to blame for progressive hearing loss, is critical to the regulation of gene expression in mammals’ hair cells. These sensory cells enable hearing.
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The mutation of the microRNA-96 gene is linked to autosomal dominant deafness-50, shortened to DFNA50, a type of dominant genetic progressive hearing loss.
For their study, the researchers fashioned a mouse model with the mutation to imitate the progressive hearing loss observed in humans with DFNA50. The animals were completely deaf to high frequencies when they were four weeks old.
Genome editing approach and safety
The research team proceeded to use a CRISPR/Cas9 genome editing method to seek out and deal with the MiR-96 mutation. An adeno-associated virus (AAV) injection was used to convey the editing machinery to the inner ear of the animals.
Chen and his fellow researchers assessed injections during early development and in adulthood. They observed that auditory function was well preserved in both cases. Earlier intervention, however, proved to be most helpful.
What’s, perhaps, even more interesting was that the genome editing approach displayed an impressive safety profile. There were minimal off-target effects. Also, the team did not notice a permanent integration of the AAV vector into the genome.
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Researchers hope this study can be applied to humans sooner or later. Chen and his team are planning to carry out IND-enabling studies in more preclinical models to move the novel treatment method to testing in humans.
The researchers are working with the Gene and Cell Therapy Institute of Mass General Brigham to move their discoveries to first-in-human clinical trials. They hope these efforts will help develop highly impactful treatments for people with hearing challenges.
In a related development, Chen’s team has also carried out clinical trials for a different form of deafness known as DFNB9. Mutations in the OTOF gene are responsible for this form. Positive results were seen in children treated with their technology in a trial done in China.
References
Wenliang Zhu et al., Targeted genome editing restores auditory function in adult mice with progressive hearing loss caused by a human microRNA mutation.Sci. Transl. Med.16,eadn0689(2024). https://doi.org/10.1126/scitranslmed.adn0689
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