Min-A Kim1,2, Hyun-Ju Cho1, Seung-Hyun Bae1,2, Byeonghyeon Lee1,2, Se-Kyung Oh1,2,3, Tae-Jun Kwon4, Zae-Young Ryoo5, Hwa-Young Kim6, Jin-Ho Cho7, Un-Kyung Kim1,2, Kyu-Yup Lee8. 1. 1 Department of Biology, College of Natural Sciences, Kyungpook National University , Daegu, Republic of Korea. 2. 2 School of Life Sciences, KNU Creative BioResearch Group (BK21 plus project), Kyungpook National University , Daegu, Republic of Korea. 3. 3 Division of Life Sciences, Korea Polar Research Institute (KOPRI) , Incheon, Republic of Korea. 4. 4 Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF) , Daegu, Republic of Korea. 5. 5 School of Life Science and Biotechnology, College of Natural Sciences, Kyungpook National University , Daegu, Republic of Korea. 6. 6 Department of Biochemistry and Molecular Biology, Yeungnam University College of Medicine , Daegu, Republic of Korea. 7. 7 Department of Electronic Engineering, College of IT Engineering, Kyungpook National University , Daegu, Republic of Korea. 8. 8 Department of Otorhinolaryngology-Head and Neck Surgery, School of Medicine, Kyungpook National University , Daegu, Republic of Korea.
Abstract
AIMS: Methionine sulfoxide reductase B3 (MsrB3), which stereospecifically repairs methionine-R-sulfoxide, is an important Msr protein that is associated with auditory function in mammals. MsrB3 deficiency leads to profound congenital hearing loss due to the degeneration of stereociliary bundles and the apoptotic death of cochlear hair cells. In this study, we investigated a fundamental treatment strategy in an MsrB3 deficiency mouse model and confirmed the biological significance of MsrB3 in the inner ear using MsrB3 knockout (MsrB3(-/-)) mice. RESULTS: We delivered a recombinant adeno-associated virus encoding the MsrB3 gene directly into the otocyst at embryonic day 12.5 using a transuterine approach. We observed hearing recovery in the treated ears of MsrB3(-/-) mice at postnatal day 28, and we confirmed MsrB3 mRNA and protein expression in cochlear extracts. Additionally, we demonstrated that the morphology of the stereociliary bundles in the rescued ears of MsrB3(-/-) mice was similar to those in MsrB3(+/+) mice. INNOVATION: To our knowledge, this is the first study to demonstrate functional and morphological rescue of the hair cells of the inner ear in the MsrB3 deficiency mouse model of congenital genetic sensorineural hearing loss using an in utero, virus-mediated gene therapy approach. CONCLUSION: Our results provide insight into the role of MsrB3 in hearing function and bring us one step closer to hearing restoration as a fundamental therapy.
AIMS: Methionine sulfoxide reductase B3 (MsrB3), which stereospecifically repairs methionine-R-sulfoxide, is an important Msr protein that is associated with auditory function in mammals. MsrB3 deficiency leads to profound congenital hearing loss due to the degeneration of stereociliary bundles and the apoptotic death of cochlear hair cells. In this study, we investigated a fundamental treatment strategy in an MsrB3 deficiency mouse model and confirmed the biological significance of MsrB3 in the inner ear using MsrB3 knockout (MsrB3(-/-)) mice. RESULTS: We delivered a recombinant adeno-associated virus encoding the MsrB3 gene directly into the otocyst at embryonic day 12.5 using a transuterine approach. We observed hearing recovery in the treated ears of MsrB3(-/-) mice at postnatal day 28, and we confirmed MsrB3 mRNA and protein expression in cochlear extracts. Additionally, we demonstrated that the morphology of the stereociliary bundles in the rescued ears of MsrB3(-/-) mice was similar to those in MsrB3(+/+) mice. INNOVATION: To our knowledge, this is the first study to demonstrate functional and morphological rescue of the hair cells of the inner ear in the MsrB3 deficiency mouse model of congenital genetic sensorineural hearing loss using an in utero, virus-mediated gene therapy approach. CONCLUSION: Our results provide insight into the role of MsrB3 in hearing function and bring us one step closer to hearing restoration as a fundamental therapy.
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