A team led by Mass Eye and Ear researchers has demonstrated for the first time successful hearing restoration using a novel, in vivo genome editing approach in an adult mouse model of a form of hereditary deafness caused by mutations in microRNA. The researchers note that microRNAs from mice and humans have identical sequences, and therefore hope that their new study will lay the foundation for translational research for applications in humans with deafness caused by these types of mutations.
The study also looked at the safety of the AAV-mediated genome editing approach and found that it had a good safety profile with little off-target effect and no detectable long-term integration of the AAV vector into the genome. “Our study suggested minimal potential risk and supports the feasibility of future clinical applications in humans,” said Wenliang Zhu, PhD, and physician-scientist Wan Du, MD, PhD, members of Chen’s laboratory at Mass Eye and Ear and first authors of the research. paper.
The study, led by Zheng-Yi Chen, DPhil, associate professor at the Eaton-Peabody Laboratories of Mass Eye and Ear (a member of the Mass General Brigham health care system), was published July 10 in Scientific translational medicine.
“Our findings provide a promising path for developing treatments through editing for many forms of genetic hearing loss,” said Chen, the Ines and Fredrick Yeatts Professor of Otolaryngology-Head and Neck Surgery at Mass Eye and Ear. at Harvard Medical School. “With further research, our intervention using genome editing could potentially halt or reverse the progression of hearing loss in affected individuals, including adults.”
Approximately one in 500 newborns suffers from genetic hearing loss and there are currently no approved therapies to treat deafness.
In the new study, researchers focused on a specific mutation in the microRNA-96 (MiR-96) gene that causes progressive hearing loss in mice and plays a crucial role in regulating gene expression in hair cells (sensory cells responsible for hearing) of mammals. In humans, this mutation has been identified as a cause of a form of dominant hereditary progressive hearing loss called DFNA50. The researchers created a mouse model with the mutation that reflected the progressive hearing loss in people with DFNA50; at four weeks old, these models showed complete hearing loss at high frequencies.
The team used a CRISPR/Cas9 genome editing approach to target and disrupt this mutation, which was delivered into the inner ear via an injection of an adeno-associated virus (AAV) that carries the editing machinery. They compared injections at two time points, during early developmental and adult stages, and demonstrated robust long-term maintenance of auditory function in both cases, with earlier intervention proving most optimal.
The study also looked at the safety of the AAV-mediated genome editing approach and found that it had a good safety profile with little off-target effect and no detectable long-term integration of the AAV vector into 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 containing all known microRNA mutations for use in humans and, in collaboration with Mass General Brigham’s Gene and Cell Therapy Institute, plan to conduct studies enabling IND in additional preclinical models, in the hope of continuing this process. treatment approach into a first-in-human clinical trial. Studies like these show the promise of gene therapy for treating conditions such as hearing loss. Mass General Brigham’s Gene and Cell Therapy Institute helps translate researchers’ scientific discoveries into first-in-human clinical trials and ultimately into life-changing treatments for patients.
This latest study by Chen and colleagues marks an important step forward in the field of gene therapy for hearing disorders and offers hope for future clinical trials aimed at restoring hearing function in people with genetic forms of hearing loss. Chen and his collaborators have also conducted clinical trials of another gene therapy approach for another form of deafness, DFNB9, caused by mutations in the OTOF gene. That clinical trial in China showed positive results in children treated in one or both ears. Chen hopes that the technology developed in the OTOF study, such as the minimally invasive delivery of AAV into human inner ears, will accelerate the development of editing therapy in the clinic.
“With more than 150 forms of genetic deafness, our study offers further hope for patients who previously had no options other than a cochlear implant,” said Chen. “These findings suggest that there is a need for more rigorous studies that build on proof-of-concept papers such as this, to achieve our goal of developing different treatment approaches to target each of these mutations.”
