Background

Expected to afflict every one in ten individuals by 2050, hearing loss poses physiological, emotional, social and a growing worldwide annual economic toll. Although half of hearing loss cases are caused by genetic factors, there remains no available treatment to reverse or prevent genetic deafness.

In an effort to develop AAV therapy for hearing loss, researchers evaluated the efficacy of gene therapy to restore auditory function in a TMPRSS3-mutant mouse model. TMPRSS3, a type II transmembrane serine protease, is necessary for normal hearing and mutations in TMPRSS3 account for approximately 9% of autosomal recessive non-syndromic deafness. TMPRSS3 mutations affect the function and survival of hair cells and spiral ganglion neurons, the latter impacting the ability of TMPRSS3 patients to benefit from cochlear implants. As such, TMPRSS3 mutations account for an estimated 10% of cochlear implant failures.

Research Methods

To mimic post-lingual hearing loss in TMPRSS3 patients, researchers created a mouse model with the knock-in human mutation Ala306→Thr (c.916G→A). In humans, this mutation results in hearing loss that does not manifest until adulthood. Mice with the mutation develop delayed hearing loss starting at 12 months of age, making the model a valuable tool for the study of later intervention.

As AAV2 is widely used in clinical applications, the team constructed an AAV2-TMPRSS3 for inner ear delivery, injected via canalostomy into 12-month-old Tmprss3 (c.916G→A) mice, then monitored hearing in the following months.

Breakthrough Results

The study found significant hearing improvement in the injected inner ears compared to the contralateral uninjected control ears as shown by reduction in ABR and DPOAE threshold shifts. Further, researchers detected significantly larger wave 1 amplitudes in the treated inner ear, an indication of functional rescue of spiral ganglion neurons.

Analysis of the inner ear showed markedly improved hair cell survival in the injected vs. uninjected inner ear. To evaluate translational potential of TMPRSS3 gene therapy, human iPSCs carrying the Tmprss3 (c.916G→A) mutation were differentiated into a neuronal phenotype. Treatment with AAV2-TMPRSS3 was able to protect neuronal survival after repeated challenge with glutamate compared to untreated control cells.

“This groundbreaking research demonstrates the potential for gene therapy to not just prevent hearing deterioration but actually restore hearing function in patients with genetic mutations,” said Jim Ayala, CEO of Rescue Hearing Inc. “We’re excited about the clinical implications of these findings and what they mean for millions of people worldwide affected by genetic hearing loss.”

Conclusions and Clinical Implications

This is the first time that later intervention at 12 months by AAV-mediated gene delivery rescued hearing in a mouse model of human genetic hearing loss. Significantly, AAV delivery not only prevented continuous hearing loss, but also temporarily restored hearing.

AAV2-TMPRSS3 gene delivery is being developed into a clinical program as treatment for patients with TMPRSS3 mutations who otherwise lack treatment options. Evaluation of differentiated human iPSCs carrying the same mutation suggests that human cells may also be rescued by TMPRSS3 gene therapy.

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