Laying the foundation for gene editing for inherited progressive deafness in adults

A study, published in the Journal of Clinical Investigation titled “Single Dose Genome Editing Therapy Rescues Auditory and Vestibular Functions in Adult Mice with DFNA41 Deafness,” provides an example of a successful use of gene-editing technology to treat a mouse model of human genetic hearing loss.

Zheng-Yi Chen, DPhil, associate scientist at the Eaton-Peabody Laboratories, and Ines and Fredrick Yeatts Chair in Otolaryngology, at Mass Eye and Ear, is the senior and co-corresponding author of the paper.

The researchers developed a one-time, gene-editing treatment that restored hearing and balance in adult mice with a genetic form of hearing loss called DFNA41, which is also found in humans.

They used a viral vector with a harmless adeno-associated virus (AAV) to deliver precise gene-editing tools into the mouse inner ear. This editing specifically removed the harmful genetic mutation while keeping the healthy gene intact.

As a result, the treated mice regained long-term hearing and balance. The gene-editing treatment further protected mice from hypersensitivity to noise-induced hearing loss.

In light of recent success using gene therapy to treat a different form of genetic hearing loss in children (in one and both ears), the researchers believe this work has the potential to become a treatment for patients with DFNA41.

In the study, the team investigated whether a single-dose, gene-editing therapy could safely and effectively correct a specific genetic mutation (P2RX2 V60L) that causes DFNA41, and whether this therapy could restore hearing in adult animal models, which better mimic human treatment conditions.

They aimed to find out if there is greater benefit if the intervention is carried out earlier and wanted to determine if this approach could protect against further damage from loud noise and vestibular dysfunction. These are crucial steps towards the ultimate goal of being able to safely translate this treatment to humans, say the researchers.

The researchers used a gene editing approach based on CRISPR-Cas9 technology, delivered by an AAV2 vector directly into the inner ear of an adult mouse model with DFNA41. The goal was to selectively disable the mutant copy of the P2RX2 gene without affecting the healthy one. This is very challenging to accomplish as there is only a single nucleotide difference between the normal and mutant gene sequences.

To achieve this, they designed highly specific gene-editing tools (SaCas9 with a mutation-targeting guide RNA) that they then delivered using a minimally invasive injection through the round window of the ear. This surgical delivery approach has been successfully used in humans.

The team verified editing accuracy and safety through genetic sequencing and tissue analysis by monitoring changes in hearing and balance over time using standard auditory and vestibular tests. They also compared the treatment effects from the interventions at different timepoints.

Lastly, the team sought to validate a similar editing strategy in human patient–derived stem cells to assess its potential for clinical translation.

The researchers found that a single injection of the gene-editing therapy into the inner ear of adult mice with DFNA41 successfully and specifically disabled the harmful mutation in the P2RX2 gene while preserving the normal gene. Treating this mutation led to restored long-term hearing and balance in adult mice.

The study also showed that this approach is safe by minimizing risk factors such as the off-target effect—or the therapy affecting genes other than the specific one it is targeting—or viral DNA integration.

They also found the therapy prevented further hearing loss caused by loud noise exposure. That finding is important because this increased hearing-loss risk from noise exposure is a known risk for DFNA41 patients.

The team say their research also demonstrated better treatment effects from early intervention, suggesting a similar strategy should be applied to humans. They say this approach may have promise as a human treatment, as they identified an effective and specific editing strategy in patient-derived stem cells carrying the same human mutation (P2RX2 V60L).

This study shows that gene editing can be used as a one-time, lasting treatment to rescue hearing and balance in adults with genetic inner ear disorders—something previously thought to be possible only during early development.

This finding has several key implications and may pave the way for future trials testing gene editing approaches for hearing and balance disorders.

First, there is potential for a therapeutic breakthrough, showing for the first time, that precise gene editing can effectively treat dominant, progressive hearing loss in fully mature ears—bringing us closer to real-world applications in humans.

Current trials have been in children born with deafness. The study showed that this approach can be applied to patients who develop delayed-onset hearing loss, from childhood to adulthood. The study also found a dual benefit of rescuing balance function and protecting against noise-induced hearing loss, offering additional protection for people with genetic susceptibility.

This work lays the groundwork for first-in-human trials for DFNA41, by showing safety, long-term benefit, and success in human stem cells carrying the same mutation. This foundation may also be feasible for other forms of inherited deafness in adults. The mutation-specific design of the therapy highlights the growing potential of precision medicine—tailoring treatments to an individual’s specific genetic mutation.

Building on proof‑of‑concept successes in mice and human stem cells, the researchers are now moving toward clinical translation through a series of IND‑enabling studies on editing therapy for genetic hearing loss, DFNA41 due to P2RX2 mutations and DFNA2 due to KCNQ4 mutations. They aim to complete the biodistribution and toxicity studies in order to initial clinical trials in a few years.

A study, published in the Journal of Clinical Investigation titled “Single Dose Genome Editing Therapy Rescues Auditory and Vestibular Functions in Adult Mice with DFNA41 Deafness,” provides an example of a successful use of gene-editing technology to treat a mouse model of human genetic hearing loss.

Zheng-Yi Chen, DPhil, associate scientist at the Eaton-Peabody Laboratories, and Ines and Fredrick Yeatts Chair in Otolaryngology, at Mass Eye and Ear, is the senior and co-corresponding author of the paper.

The researchers developed a one-time, gene-editing treatment that restored hearing and balance in adult mice with a genetic form of hearing loss called DFNA41, which is also found in humans.

They used a viral vector with a harmless adeno-associated virus (AAV) to deliver precise gene-editing tools into the mouse inner ear. This editing specifically removed the harmful genetic mutation while keeping the healthy gene intact.

As a result, the treated mice regained long-term hearing and balance. The gene-editing treatment further protected mice from hypersensitivity to noise-induced hearing loss.

In light of recent success using gene therapy to treat a different form of genetic hearing loss in children (in one and both ears), the researchers believe this work has the potential to become a treatment for patients with DFNA41.

In the study, the team investigated whether a single-dose, gene-editing therapy could safely and effectively correct a specific genetic mutation (P2RX2 V60L) that causes DFNA41, and whether this therapy could restore hearing in adult animal models, which better mimic human treatment conditions.

They aimed to find out if there is greater benefit if the intervention is carried out earlier and wanted to determine if this approach could protect against further damage from loud noise and vestibular dysfunction. These are crucial steps towards the ultimate goal of being able to safely translate this treatment to humans, say the researchers.

The researchers used a gene editing approach based on CRISPR-Cas9 technology, delivered by an AAV2 vector directly into the inner ear of an adult mouse model with DFNA41. The goal was to selectively disable the mutant copy of the P2RX2 gene without affecting the healthy one. This is very challenging to accomplish as there is only a single nucleotide difference between the normal and mutant gene sequences.

To achieve this, they designed highly specific gene-editing tools (SaCas9 with a mutation-targeting guide RNA) that they then delivered using a minimally invasive injection through the round window of the ear. This surgical delivery approach has been successfully used in humans.

The team verified editing accuracy and safety through genetic sequencing and tissue analysis by monitoring changes in hearing and balance over time using standard auditory and vestibular tests. They also compared the treatment effects from the interventions at different timepoints.

Lastly, the team sought to validate a similar editing strategy in human patient–derived stem cells to assess its potential for clinical translation.

The researchers found that a single injection of the gene-editing therapy into the inner ear of adult mice with DFNA41 successfully and specifically disabled the harmful mutation in the P2RX2 gene while preserving the normal gene. Treating this mutation led to restored long-term hearing and balance in adult mice.

The study also showed that this approach is safe by minimizing risk factors such as the off-target effect—or the therapy affecting genes other than the specific one it is targeting—or viral DNA integration.

They also found the therapy prevented further hearing loss caused by loud noise exposure. That finding is important because this increased hearing-loss risk from noise exposure is a known risk for DFNA41 patients.

The team say their research also demonstrated better treatment effects from early intervention, suggesting a similar strategy should be applied to humans. They say this approach may have promise as a human treatment, as they identified an effective and specific editing strategy in patient-derived stem cells carrying the same human mutation (P2RX2 V60L).

This study shows that gene editing can be used as a one-time, lasting treatment to rescue hearing and balance in adults with genetic inner ear disorders—something previously thought to be possible only during early development.

This finding has several key implications and may pave the way for future trials testing gene editing approaches for hearing and balance disorders.

First, there is potential for a therapeutic breakthrough, showing for the first time, that precise gene editing can effectively treat dominant, progressive hearing loss in fully mature ears—bringing us closer to real-world applications in humans.

Current trials have been in children born with deafness. The study showed that this approach can be applied to patients who develop delayed-onset hearing loss, from childhood to adulthood. The study also found a dual benefit of rescuing balance function and protecting against noise-induced hearing loss, offering additional protection for people with genetic susceptibility.

This work lays the groundwork for first-in-human trials for DFNA41, by showing safety, long-term benefit, and success in human stem cells carrying the same mutation. This foundation may also be feasible for other forms of inherited deafness in adults. The mutation-specific design of the therapy highlights the growing potential of precision medicine—tailoring treatments to an individual’s specific genetic mutation.

Building on proof‑of‑concept successes in mice and human stem cells, the researchers are now moving toward clinical translation through a series of IND‑enabling studies on editing therapy for genetic hearing loss, DFNA41 due to P2RX2 mutations and DFNA2 due to KCNQ4 mutations. They aim to complete the biodistribution and toxicity studies in order to initial clinical trials in a few years.