Genetic mutations are responsible for more than half of all congenital permanent hearing loss cases. The prevalence can be as high as 6 per 1,000 among school-age children. Mutations in the gap junction (GJ) proteins (e.g., GJB2) cause some of the most common forms of human congenital non-syndromic deafness. Genetic predisposition is also known to be an essential factor in age-dependent hearing loss (ADHL) and noise-induced hearing loss (NIHL), which affect tens of millions of patients. Today there is no biological treatment to correct the root cellular and genetic causes of inherited sensorineural hearing loss. Multiple research groups in the hearing field have worked for years to introduce gene therapy into clinical applications for the treatment of sensorineural deafness. Recent reports have yielded some promising results; however, the in vivo feasibility and reliability of virally mediated gene therapy in correcting the most common forms of non-syndromic human inherited deafness remain to be demonstrated. To date, gene therapy has not been successful at treating hearing loss in adult-stage mouse models. Moreover, none of the gene therapy studies for treating sensorineural hearing loss have advanced to the stage of systematic in vivo preclinical trials yet. The present project is the first to conduct major experiments required for n vivo preclinical studies of a gene therapy approach for treating the most common forms of non-syndromic deafness, as well as ADHL and NIHL, using mouse models. Studies will test the efficacy of gene therapy at both the postnatal and adult stages. We will study the feasibility and reliability of using a virally mediated gene replacement/augmentation therapy to prevent hearing loss in conditional Gjb2-/-, Gjb6-/-, and C57BL/6J (a popular mouse model for studying ADHL and NIHL) mice. We will also investigate the long-term efficacy and safety of the treatment in these mouse models. Carrying out the specific aims outlined here should fulfill some of the vital and necessary steps required for the translation of gene therapy into clinical applications.
This project performs major experiments required for in vivo preclinical studies into the treatment of human congenital and age-dependent hearing loss using a virally mediated gene therapy approach. Gjb6-/- and conditional Gjb2-/- (representing the most common human congenital non-syndromic deafness), and C57BL/6J (an age-dependent hearing loss mouse model), will be used. Carrying out the outlined specific aims should fulfill some of the vital and necessary steps for the translation of gene therapy into clinical applications.
|Chen, Bei; Wang, Yunfeng; Geng, Manying et al. (2018) Localization of Glucose Transporter 10 to Hair Cells' Cuticular Plate in the Mouse Inner Ear. Biomed Res Int 2018:7817453|
|Gao, Xue; Xu, Jin-Cao; Wang, Wei-Qian et al. (2018) A Missense Mutation in POU4F3 Causes Midfrequency Hearing Loss in a Chinese ADNSHL Family. Biomed Res Int 2018:5370802|
|Zhang, Wenjuan; Kim, Sun Myoung; Wang, Wenwen et al. (2018) Cochlear Gene Therapy for Sensorineural Hearing Loss: Current Status and Major Remaining Hurdles for Translational Success. Front Mol Neurosci 11:221|
|Mittal, Rahul; Grati, M'hamed; Sedlacek, Miloslav et al. (2016) Characterization of ATPase Activity of P2RX2 Cation Channel. Front Physiol 7:186|
|Wang, Yunfeng; Sun, Yu; Chang, Qing et al. (2013) Early postnatal virus inoculation into the scala media achieved extensive expression of exogenous green fluorescent protein in the inner ear and preserved auditory brainstem response thresholds. J Gene Med 15:123-33|