Gene Therapy to Treat Mouse Model of Human Recessive Deafness Caused by a TMPRSS3 Mutation (ABSRTRACT)

Annual MidWinter Meeting

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, here we evaluate 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. 

Methods: To mimic post-lingual hearing loss in TMPRSS3 patients, we 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, we 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. 

Results: We 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, we 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 


44th Annual ARO MidWinter Virtual Meeting 

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. 

Conclusions: 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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gene therapy 


Non syndromic hearing loss 

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* Presenting Author 

First Name Last Name Affiliation Corena * Loeb * Harvard Medical School Wan Du Harvard Medical School Mingqian Huang Harvard Medical School 

Xiaoya Chen University of Miami Miller School of Medicine 

Katherina Walz University of Miami Miller School of Medicine 

Xuzhong Liu University of Miami Miller School of Medicine 

Hinrich Staecker University of Kansas Zheng-Yi Chen Harvard Medical School 

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44th Annual ARO MidWinter Virtual Meeting 

Signature Corena Loeb 

About Rescue Hearing Inc

Rescue Hearing Inc. combines the top physicians and researchers with cutting-edge technologies in gene therapy and diagnostics to develop a diversified asset portfolio for patients with hearing loss.


Jim Ayala