Summary: Researchers successfully demonstrated the efficacy of adeno-associated virus (AAV) vectors in reversing genetic hearing loss in aged animal models. The scientists developed a mature mouse model with a mutation similar to the human TMPRSS3 gene defect, which typically results in progressive hearing loss.
Upon injecting these mice with an AAV carrying a healthy TMPRSS3 gene, a notable restoration of hearing was observed. This advancement suggests the potential of gene therapies to treat genetic hearing loss, even in advanced age.
- The study demonstrates for the first time the effectiveness of AAV vector-mediated gene therapy in reversing hearing loss in aged mice, opening possibilities for similar treatment in humans.
- This research successfully developed a mouse model with a mutation equivalent to the human TMPRSS3 gene defect, known to cause progressive hearing loss.
- The possibility of combining this gene therapy with cochlear implants could potentially treat genetic hearing loss.
Source: Mass Eye and Ear
By 2050, one in 10 individuals are expected to live with some form of hearing loss. Of the hundreds of millions of cases of hearing loss affecting individuals worldwide, genetic hearing loss is often the most difficult to treat.
While hearing aids and cochlear implants offer limited relief, no available treatment can reverse or prevent this group of genetic conditions, prompting scientists to evaluate gene therapies for alternative solutions.
One of the most promising tools used in these therapies—adeno associated virus (AAV) vectors—has galvanized the hearing-loss community in recent years.
One of the most promising tools used in these therapies—adeno associated virus (AAV) vectors—has galvanized the hearing-loss community in recent years. Credit: Neuroscience News
Despite having already rescued hearing in neonatal animals with genetic defects, the vectors have yet to demonstrate this ability in fully mature or aged animal models. Since humans are born with fully developed ears, this proof-of-concept is necessary before testing the intervention in humans with genetic hearing loss.
A team of researchers from Mass Eye and Ear, a member of Mass General Brigham, recently became the first to successfully demonstrate AAV vector efficacy in aged animal models when they developed a mature mouse model with a mutation equivalent to a defective TMPRSS3 human gene, which typically results in progressive hearing loss.
As reported in Molecular Therapy, researchers observed robust hearing rescue in the aged mice upon injecting the animals with an AAV carrying a healthy human TMPRSS3 gene.
“Our findings suggest that a virally mediated gene therapy, either by itself or in combination with a cochlear implant, could potentially treat genetic hearing loss,” said corresponding author Zheng Yi Chen, D.Phil., an investigator in the Eaton-Peabody Laboratories at Mass Eye and Ear.
“This was also the first study that has rescued hearing in aging mice, which points to the feasibility of treating DFNB8 patients with DFNB8 even at an advanced age. The study also establishes the feasibility of other gene therapies in the aged population.”
Rescue of auditory function by a single administration of AAV-TMPRSS3 gene therapy in aged mice of human recessive deafness DFNB8
Patients with mutations in the TMPRSS3 gene suffer from recessive deafness DFNB8/DFNB10. For these patients, cochlear implantation is the only treatment option. Poor cochlear implantation outcomes are seen in some patients.
To develop biological treatment for TMPRSS3 patients, we generated a knockin mouse model with a frequent human DFNB8 TMPRSS3 mutation.
The Tmprss3A306T/A306T homozygous mice display delayed onset progressive hearing loss similar to human DFNB8 patients. Using AAV2 as a vector to carry a human TMPRSS3 gene, AAV2-hTMPRSS3 injection in the adult knockin mouse inner ear results in TMPRSS3 expression in the hair cells and the spiral ganglion neurons.
A single AAV2-hTMPRSS3 injection in Tmprss3A306T/A306T mice of an average age of 18.5 months leads to sustained rescue of the auditory function to a level similar to wild-type mice. AAV2-hTMPRSS3 delivery rescues the hair cells and the spiral ganglions neurons.
This study demonstrates successful gene therapy in an aged mouse model of human genetic deafness.
It lays the foundation to develop AAV2-hTMPRSS3 gene therapy to treat DFNB8 patients, as a standalone therapy or in combination with cochlear implantation.