{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T14:42:06Z","timestamp":1790174526133,"version":"4.1.0"},"reference-count":126,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2020,2,21]],"date-time":"2020-02-21T00:00:00Z","timestamp":1582243200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Over the last decade, pioneering molecular gene therapy for inner-ear disorders have achieved experimental hearing improvements after a single local or systemic injection of adeno-associated, virus-derived vectors (rAAV for recombinant AAV) encoding an extra copy of a normal gene, or ribozymes used to modify a genome. These results hold promise for treating congenital or later-onset hearing loss resulting from monogenic disorders with gene therapy approaches in patients. In this review, we summarize the current state of rAAV-mediated inner-ear gene therapies including the choice of vectors and delivery routes, and discuss the prospects and obstacles for the future development of efficient clinical rAAV-mediated cochlear gene medicine therapy.<\/jats:p>","DOI":"10.3390\/jcm9020589","type":"journal-article","created":{"date-parts":[[2020,2,25]],"date-time":"2020-02-25T08:12:22Z","timestamp":1582618342000},"page":"589","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["rAAV-Mediated Cochlear Gene Therapy: Prospects and Challenges for Clinical Application"],"prefix":"10.3390","volume":"9","author":[{"given":"Fabian","family":"Blanc","sequence":"first","affiliation":[{"name":"INSERM - UMR 1051, Institut des Neurosciences de Montpellier, H\u00f4pital Saint Eloi - B\u00e2timent INM, 80, rue Augustin Fliche - BP 74103, 34091 Montpellier, France"},{"name":"Universit\u00e9 de Montpellier, 163 rue Auguste Broussonnet, 34090 Montpellier, France"},{"name":"CHRU Montpellier\u2014Centre Hospitalier R\u00e9gional Universitaire, 34090 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"Mondain","sequence":"additional","affiliation":[{"name":"INSERM - UMR 1051, Institut des Neurosciences de Montpellier, H\u00f4pital Saint Eloi - B\u00e2timent INM, 80, rue Augustin Fliche - BP 74103, 34091 Montpellier, France"},{"name":"Universit\u00e9 de Montpellier, 163 rue Auguste Broussonnet, 34090 Montpellier, France"},{"name":"CHRU Montpellier\u2014Centre Hospitalier R\u00e9gional Universitaire, 34090 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7605-5225","authenticated-orcid":false,"given":"Alexis-Pierre","family":"Bemelmans","sequence":"additional","affiliation":[{"name":"Molecular Imaging Research Center, Institut de Biologie Fran\u00e7ois Jacob, Direction de la Recherche Fondamentale, CEA, 92265 Fontenay-aux-Roses, France"},{"name":"Universit\u00e9 Paris-Saclay, CEA, CNRS, UMR9199 Neurodegenerative Diseases Laboratory, 92265 Fontenay-aux-Roses, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3109-4575","authenticated-orcid":false,"given":"Corentin","family":"Affortit","sequence":"additional","affiliation":[{"name":"INSERM - UMR 1051, Institut des Neurosciences de Montpellier, H\u00f4pital Saint Eloi - B\u00e2timent INM, 80, rue Augustin Fliche - BP 74103, 34091 Montpellier, France"},{"name":"Universit\u00e9 de Montpellier, 163 rue Auguste Broussonnet, 34090 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3772-5190","authenticated-orcid":false,"given":"Jean-Luc","family":"Puel","sequence":"additional","affiliation":[{"name":"INSERM - UMR 1051, Institut des Neurosciences de Montpellier, H\u00f4pital Saint Eloi - B\u00e2timent INM, 80, rue Augustin Fliche - BP 74103, 34091 Montpellier, France"},{"name":"Universit\u00e9 de Montpellier, 163 rue Auguste Broussonnet, 34090 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2670-719X","authenticated-orcid":false,"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"INSERM - UMR 1051, Institut des Neurosciences de Montpellier, H\u00f4pital Saint Eloi - B\u00e2timent INM, 80, rue Augustin Fliche - BP 74103, 34091 Montpellier, France"},{"name":"Universit\u00e9 de Montpellier, 163 rue Auguste Broussonnet, 34090 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,2,21]]},"reference":[{"key":"ref_1","unstructured":"(2019, September 05). Deafness and Hearing Loss. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/deafness-and-hearing-loss."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.heares.2017.01.003","article-title":"Cochlear synaptopathy in acquired sensorineural hearing loss: Manifestations and mechanisms","volume":"349","author":"Liberman","year":"2017","journal-title":"Hear. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1812","DOI":"10.1002\/ar.22579","article-title":"Genetics of hearing and deafness","volume":"295","author":"Angeli","year":"2012","journal-title":"Anat. Rec. Adv. Integr. Anat. Evol. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4972","DOI":"10.2741\/3056","article-title":"Cochlear molecules and hereditary deafness","volume":"13","author":"Yan","year":"2008","journal-title":"Front. Biosci. J. Virtual Libr."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1159\/000380752","article-title":"Binaural integration of periodically alternating speech following cochlear implantation in subjects with profound sensorineural unilateral hearing loss","volume":"20","author":"Wesarg","year":"2015","journal-title":"Audiol. Neurootol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e240","DOI":"10.1097\/MAO.0000000000001448","article-title":"What Does Music Sound Like for a Cochlear Implant User?","volume":"38","author":"Jiam","year":"2017","journal-title":"Otol. Neurotol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1126\/science.8493530","article-title":"The basic science of gene therapy","volume":"260","author":"Mulligan","year":"1993","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Al-Moyed, H., Cepeda, A.P., Jung, S., Moser, T., K\u00fcgler, S., and Reisinger, E. (2019). A dual-AAV approach restores fast exocytosis and partially rescues auditory function in deaf otoferlin knock-out mice. EMBO Mol. Med., 11.","DOI":"10.15252\/emmm.201809396"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Akil, O., Dyka, F., Calvet, C., Emptoz, A., Lahlou, G., Nouaille, S., Boutet de Monvel, J., Hardelin, J.-P., Hauswirth, W.W., and Avan, P. (2019). Dual AAV-mediated gene therapy restores hearing in a DFNB9 mouse model. Proc. Natl. Acad. Sci. USA.","DOI":"10.1073\/pnas.1817537116"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1038\/nbt.3801","article-title":"Gene therapy restores auditory and vestibular function in a mouse model of Usher syndrome type 1c","volume":"35","author":"Pan","year":"2017","journal-title":"Nat. Biotechnol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.heares.2017.12.010","article-title":"Communication pathways to and from the inner ear and their contributions to drug delivery","volume":"362","author":"Salt","year":"2018","journal-title":"Hear. Res."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Ishiyama, G., Lopez, I.A., Ishiyama, P., Vinters, H.V., and Ishiyama, A. (2017). The blood labyrinthine barrier in the human normal and Meniere\u2019s disease macula utricle. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-00330-5"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1186\/s40463-017-0245-8","article-title":"Mannitol and the blood-labyrinth barrier","volume":"46","author":"Le","year":"2017","journal-title":"J. Otolaryngol. Head Neck Surg."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2477","DOI":"10.1152\/physrev.00053.2017","article-title":"Toward Cochlear Therapies","volume":"98","author":"Wang","year":"2018","journal-title":"Physiol. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1038\/gt.2012.51","article-title":"Gene transfer in inner ear cells: A challenging race","volume":"20","author":"Sacheli","year":"2013","journal-title":"Gene. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1038\/mt.2009.258","article-title":"Characterization of Genome Integrity for Oversized Recombinant AAV Vector","volume":"18","author":"Dong","year":"2010","journal-title":"Mol. Ther."},{"key":"ref_17","first-page":"317","article-title":"Adeno-Associated Virus (AAV) as a Vector for Gene Therapy","volume":"31","author":"Naso","year":"2017","journal-title":"BioDrugs Clin. Immunother. Biopharm. Gene Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.ymthe.2017.09.014","article-title":"Safety and Long-Term Efficacy of AAV4 Gene Therapy in Patients with RPE65 Leber Congenital Amaurosis","volume":"26","author":"Lebranchu","year":"2018","journal-title":"Mol. Ther. J. Am. Soc. Gene Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1016\/S0140-6736(16)30371-3","article-title":"Safety and durability of effect of contralateral-eye administration of AAV2 gene therapy in patients with childhood-onset blindness caused by RPE65 mutations: A follow-on phase 1 trial","volume":"388","author":"Bennett","year":"2016","journal-title":"Lancet Lond. Engl."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1089\/hum.2015.025","article-title":"Adeno-associated virus at 50: A golden anniversary of discovery, research, and gene therapy success\u2014A personal perspective","volume":"26","author":"Hastie","year":"2015","journal-title":"Hum. Gene Ther."},{"key":"ref_21","first-page":"49","article-title":"Viral expression cassette elements to enhance transgene target specificity and expression in gene therapy","volume":"19","author":"Powell","year":"2015","journal-title":"Discov. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1089\/hgtb.2015.140","article-title":"Expressing Transgenes That Exceed the Packaging Capacity of Adeno-Associated Virus Capsids","volume":"27","author":"Chamberlain","year":"2016","journal-title":"Hum. Gene Ther. Methods"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1128\/CMR.00008-08","article-title":"Gene Therapy Using Adeno-Associated Virus Vectors","volume":"21","author":"Daya","year":"2008","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.ymthe.2006.05.009","article-title":"Adeno-associated virus serotypes: Vector toolkit for human gene therapy","volume":"14","author":"Wu","year":"2006","journal-title":"Mol. Ther. J. Am. Soc. Gene Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1038\/mt.2011.287","article-title":"The AAV Vector Toolkit: Poised at the Clinical Crossroads","volume":"20","author":"Asokan","year":"2012","journal-title":"Mol. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"6947","DOI":"10.1128\/JVI.07232-11","article-title":"Structural Insight into the Unique Properties of Adeno-Associated Virus Serotype 9","volume":"86","author":"DiMattia","year":"2012","journal-title":"J. Virol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.jsb.2015.08.017","article-title":"Structure of neurotropic adeno-associated virus AAVrh.8","volume":"192","author":"Halder","year":"2015","journal-title":"J. Struct. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1038\/nature16465","article-title":"An essential receptor for adeno-associated virus infection","volume":"530","author":"Pillay","year":"2016","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1038\/4768","article-title":"\u03b1V\u03b25 integrin: A co-receptor for adeno-associated virus type 2 infection","volume":"5","author":"Summerford","year":"1999","journal-title":"Nat. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/4758","article-title":"Human fibroblast growth factor receptor 1 is a co-receptor for infection by adeno-associated virus 2","volume":"5","author":"Qing","year":"1999","journal-title":"Nat. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1128\/JVI.79.1.609-614.2005","article-title":"Hepatocyte Growth Factor Receptor Is a Coreceptor for Adeno-Associated Virus Type 2 Infection","volume":"79","author":"Kashiwakura","year":"2005","journal-title":"J. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"8961","DOI":"10.1128\/JVI.00843-06","article-title":"Adeno-Associated Virus Type 2 Contains an Integrin 5 1 Binding Domain Essential for Viral Cell Entry","volume":"80","author":"Asokan","year":"2006","journal-title":"J. Virol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"9831","DOI":"10.1128\/JVI.00878-06","article-title":"The 37\/67-Kilodalton Laminin Receptor Is a Receptor for Adeno-Associated Virus Serotypes 8, 2, 3, and 9","volume":"80","author":"Akache","year":"2006","journal-title":"J. Virol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"11040","DOI":"10.1128\/JVI.01056-06","article-title":"Adeno-Associated Virus Type 2 Capsids with Externalized VP1\/VP2 Trafficking Domains Are Generated prior to Passage through the Cytoplasm and Are Maintained until Uncoating Occurs in the Nucleus","volume":"80","author":"Sonntag","year":"2006","journal-title":"J. Virol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"10462","DOI":"10.1128\/JVI.00935-12","article-title":"Cytoplasmic Trafficking, Endosomal Escape, and Perinuclear Accumulation of Adeno-Associated Virus Type 2 Particles Are Facilitated by Microtubule Network","volume":"86","author":"Xiao","year":"2012","journal-title":"J. Virol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4132","DOI":"10.1128\/JVI.02660-13","article-title":"Recombinant Adeno-Associated Virus Utilizes Host Cell Nuclear Import Machinery To Enter the Nucleus","volume":"88","author":"Nicolson","year":"2014","journal-title":"J. Virol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"15047","DOI":"10.1038\/mtm.2015.47","article-title":"Super-resolution imaging of nuclear import of adeno-associated virus in live cells","volume":"2","author":"Kelich","year":"2015","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1038\/s41573-019-0012-9","article-title":"Adeno-associated virus vector as a platform for gene therapy delivery","volume":"18","author":"Wang","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1016\/j.celrep.2015.07.019","article-title":"In Silico Reconstruction of the Viral Evolutionary Lineage Yields a Potent Gene Therapy Vector","volume":"12","author":"Zinn","year":"2015","journal-title":"Cell Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"45524","DOI":"10.1038\/srep45524","article-title":"Cochlear gene therapy with ancestral AAV in adult mice: Complete transduction of inner hair cells without cochlear dysfunction","volume":"7","author":"Suzuki","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"16081","DOI":"10.1038\/mtm.2016.81","article-title":"Tailored transgene expression to specific cell types in the central nervous system after peripheral injection with AAV9","volume":"3","author":"Dashkoff","year":"2016","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1038\/sj.gt.3301529","article-title":"Quantitative comparison of expression with adeno-associated virus (AAV-2) brain-specific gene cassettes","volume":"8","author":"Xu","year":"2001","journal-title":"Gene Ther."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Gu, X., Chai, R., Guo, L., Dong, B., Li, W., Shu, Y., Huang, X., and Li, H. (2019). Transduction of Adeno-Associated Virus Vectors Targeting Hair Cells and Supporting Cells in the Neonatal Mouse Cochlea. Front. Cell Neurosci., 13.","DOI":"10.3389\/fncel.2019.00008"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/6185","article-title":"Targeted adeno-associated virus vector transduction of nonpermissive cells mediated by a bispecific F(ab\u2019\u03b3)2 antibody","volume":"17","author":"Bartlett","year":"1999","journal-title":"Nat. Biotechnol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.ymthe.2006.02.014","article-title":"Metabolic Biotinylation Provides a Unique Platform for the Purification and Targeting of Multiple AAV Vector Serotypes","volume":"14","author":"Arnold","year":"2006","journal-title":"Mol. Ther."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"9493","DOI":"10.1128\/JVI.75.19.9493-9501.2001","article-title":"Adeno-Associated Virus Type 2-Mediated Transduction of Human Monocyte-Derived Dendritic Cells: Implications for Ex Vivo Immunotherapy","volume":"75","author":"Ponnazhagan","year":"2001","journal-title":"J. Virol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1758","DOI":"10.1002\/jnr.21625","article-title":"Bone marrow-derived cells expressing Iba1 are constitutively present as resident tissue macrophages in the mouse cochlea","volume":"86","author":"Okano","year":"2008","journal-title":"J. Neurosci. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"76","DOI":"10.3109\/00016489009107417","article-title":"The role of macrophages in the disposal of degeneration products within the organ of corti after acoustic overstimulation","volume":"109","author":"Fredelius","year":"1990","journal-title":"Acta Otolaryngol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1007\/s00418-016-1436-5","article-title":"Characterisation of cochlear inflammation in mice following acute and chronic noise exposure","volume":"146","author":"Tan","year":"2016","journal-title":"Histochem. Cell Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1007\/s10162-007-0084-9","article-title":"Cisplatin Cytotoxicity of Auditory Cells Requires Secretions of Proinflammatory Cytokines via Activation of ERK and NF-\u03baB","volume":"8","author":"So","year":"2007","journal-title":"J. Assoc. Res. Otolaryngol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"4580","DOI":"10.1128\/JVI.76.9.4580-4590.2002","article-title":"Differential activation of innate immune responses by adenovirus and adeno-associated virus vectors","volume":"76","author":"Zaiss","year":"2002","journal-title":"J. Virol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2021","DOI":"10.1038\/mt.2011.81","article-title":"Capsid-specific T-cell responses to natural infections with adeno-associated viruses in humans differ from those of nonhuman primates","volume":"19","author":"Li","year":"2011","journal-title":"Mol. Ther. J. Am. Soc. Gene Ther."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1089\/hum.2009.182","article-title":"Prevalence of Serum IgG and Neutralizing Factors Against Adeno-Associated Virus (AAV) Types 1, 2, 5, 6, 8, and 9 in the Healthy Population: Implications for Gene Therapy Using AAV Vectors","volume":"21","author":"Boutin","year":"2010","journal-title":"Hum. Gene Ther."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1089\/hum.2011.031","article-title":"Impact of pre-existing immunity on gene transfer to nonhuman primate liver with adeno-associated virus 8 vectors","volume":"22","author":"Wang","year":"2011","journal-title":"Hum. Gene Ther."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1038\/nbt.3781","article-title":"A synthetic AAV vector enables safe and efficient gene transfer to the mammalian inner ear","volume":"35","author":"Landegger","year":"2017","journal-title":"Nat. Biotechnol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.1038\/mt.2009.159","article-title":"Impact of the underlying mutation and the route of vector administration on immune responses to factor IX in gene therapy for hemophilia B","volume":"17","author":"Cao","year":"2009","journal-title":"Mol. Ther. J. Am. Soc. Gene Ther."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2357","DOI":"10.1056\/NEJMoa1108046","article-title":"Adenovirus-associated virus vector-mediated gene transfer in hemophilia B","volume":"365","author":"Nathwani","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2077","DOI":"10.1182\/blood-2008-07-167510","article-title":"AAV-1-mediated gene transfer to skeletal muscle in humans results in dose-dependent activation of capsid-specific T cells","volume":"114","author":"Mingozzi","year":"2009","journal-title":"Blood"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1038\/gt.2010.175","article-title":"Adeno-associated virus-mediated gene delivery into the scala media of the normal and deafened adult mouse ear","volume":"18","author":"Kilpatrick","year":"2011","journal-title":"Gene Ther."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1002\/jgm.1189","article-title":"Gene transfer into guinea pig cochlea using adeno-associated virus vectors","volume":"10","author":"Konishi","year":"2008","journal-title":"J. Gene Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.omtm.2018.07.006","article-title":"Efficient Gene Transfer to the Central Nervous System by Single-Stranded Anc80L65","volume":"10","author":"Hudry","year":"2018","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"9609","DOI":"10.1038\/s41598-017-09805-x","article-title":"Intravenous rAAV2\/9 injection for murine cochlear gene delivery","volume":"7","author":"Shibata","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1089\/104303401300042465","article-title":"Cochlear gene delivery through an intact round window membrane in mouse","volume":"12","author":"Jero","year":"2001","journal-title":"Hum. Gene Ther."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.1097\/00005537-199910000-00021","article-title":"Cochlear Fluid Space Dimensions for Six Species Derived From Reconstructions of Three-Dimensional Magnetic Resonance Images","volume":"109","author":"Thorne","year":"1999","journal-title":"Laryngoscope"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2557","DOI":"10.1002\/lary.25317","article-title":"Cochlear gene transfer mediated by adeno-associated virus: Comparison of two surgical approaches","volume":"125","author":"Chien","year":"2015","journal-title":"Laryngoscope"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1159\/000449239","article-title":"Hearing Loss after Round Window Surgery in Mice Is due to Middle Ear Effusion","volume":"21","author":"Zhu","year":"2016","journal-title":"Audiol. Neurootol."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Xia, L., Yin, S., and Wang, J. (2012). Inner ear gene transfection in neonatal mice using adeno-associated viral vector: A comparison of two approaches. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0043218"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1080\/00016489.2017.1312015","article-title":"Adeno-associated virus transformation into the normal miniature pig and the normal guinea pigs cochlea via scala tympani","volume":"137","author":"Shi","year":"2017","journal-title":"Acta Otolaryngol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1016\/j.ymthe.2005.03.021","article-title":"Specific and efficient transduction of Cochlear inner hair cells with recombinant adeno-associated virus type 3 vector","volume":"12","author":"Liu","year":"2005","journal-title":"Mol. Ther. J. Am. Soc. Gene Ther."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1089\/hum.2011.086","article-title":"Hyaluronic acid enhances gene delivery into the cochlea","volume":"23","author":"Shibata","year":"2012","journal-title":"Hum. Gene Ther."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2980","DOI":"10.1038\/s41598-018-21233-z","article-title":"Enhanced viral-mediated cochlear gene delivery in adult mice by combining canal fenestration with round window membrane inoculation","volume":"8","author":"Yoshimura","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1007\/s10162-017-0628-6","article-title":"Rhesus Cochlear and Vestibular Functions Are Preserved After Inner Ear Injection of Saline Volume Sufficient for Gene Therapy Delivery","volume":"18","author":"Dai","year":"2017","journal-title":"J. Assoc. Res. Otolaryngol. JARO"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.omtm.2018.11.003","article-title":"Gene Transfer with AAV9-PHP.B Rescues Hearing in a Mouse Model of Usher Syndrome 3A and Transduces Hair Cells in a Non-human Primate","volume":"13","author":"Meijer","year":"2019","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.heares.2008.06.003","article-title":"Localized cell and drug delivery for auditory prostheses","volume":"242","author":"Hendricks","year":"2008","journal-title":"Hear. Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1038\/gt.2011.91","article-title":"Efficient cochlear gene transfection in guinea-pigs with adeno-associated viral vectors by partial digestion of round window membrane","volume":"19","author":"Wang","year":"2012","journal-title":"Gene Ther."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1097\/MOO.0000000000000296","article-title":"Principles of endoscopic ear surgery","volume":"24","author":"Tarabichi","year":"2016","journal-title":"Curr. Opin. Otolaryngol. Head Neck Surg."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1097\/MAO.0000000000001074","article-title":"Surgical Anatomy of the Human Round Window Region: Implication for Cochlear Endoscopy Through the External Auditory Canal","volume":"37","author":"Fujita","year":"2016","journal-title":"Otol. Neurotol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1097\/MAO.0000000000000629","article-title":"Microperforations significantly enhance diffusion across round window membrane","volume":"36","author":"Kelso","year":"2015","journal-title":"Otol. Neurotol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1006\/mthe.2001.0490","article-title":"The functional and structural outcome of inner ear gene transfer via the vestibular and cochlear fluids in mice","volume":"4","author":"Kawamoto","year":"2001","journal-title":"Mol. Ther. J. Am. Soc. Gene Ther."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Guo, J.-Y., He, L., Qu, T.-F., Liu, Y.-Y., Liu, K., Wang, G.-P., and Gong, S.-S. (2018). Canalostomy As a Surgical Approach to Local Drug Delivery into the Inner Ears of Adult and Neonatal Mice. J. Vis. Exp. JoVE.","DOI":"10.3791\/57351"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1038\/gt.2014.73","article-title":"Adeno-associated virus-mediated gene transfer targeting normal and traumatized mouse utricle","volume":"21","author":"Wang","year":"2014","journal-title":"Gene Ther."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1038\/s41467-018-08243-1","article-title":"AAV2.7m8 is a powerful viral vector for inner ear gene therapy","volume":"10","author":"Isgrig","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1089\/hum.2017.120","article-title":"Delivery of Adeno-Associated Virus Vectors in Adult Mammalian Inner-Ear Cell Subtypes Without Auditory Dysfunction","volume":"29","author":"Tao","year":"2018","journal-title":"Hum. Gene Ther."},{"key":"ref_84","unstructured":"De Morgon, A., Aran, J.M., Collet, L., Dauman, R., Fraysse, B., Freyss, G., Pujol, R., Sens, A., Serkers, O., and Tran Ba Huy, P. (1990). Donn\u00e9es Actuelles sur la Pathologie et la Physiologie de l\u2019oreille Interne, Arnette. Edition Arnette."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Ekdale, E.G. (2013). Comparative Anatomy of the Bony Labyrinth (Inner Ear) of Placental Mammals. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0066624"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"233ra54","DOI":"10.1126\/scitranslmed.3008177","article-title":"Close-Field Electroporation Gene Delivery Using the Cochlear Implant Electrode Array Enhances the Bionic Ear","volume":"6","author":"Pinyon","year":"2014","journal-title":"Sci. Transl. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.heares.2007.02.010","article-title":"Cochlear implants and ex vivo BDNF gene therapy protect spiral ganglion neurons","volume":"228","author":"Rejali","year":"2007","journal-title":"Hear. Res."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1097\/MAO.0000000000001273","article-title":"History of the Endolymphatic Sac: From Anatomy to Surgery","volume":"38","author":"Corrales","year":"2017","journal-title":"Otol. Neurotol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.amjoto.2017.01.023","article-title":"Long-term outcomes of endolymphatic sac shunting with local steroids for Meniere\u2019s disease","volume":"38","author":"Wick","year":"2017","journal-title":"Am. J. Otolaryngol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.heares.2003.12.018","article-title":"Responses of the endolymphatic sac to perilymphatic injections and withdrawals: Evidence for the presence of a one-way valve","volume":"191","author":"Salt","year":"2004","journal-title":"Hear. Res."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1177\/000348941011901207","article-title":"Mutations in TMC1 are a Common Cause of DFNB7\/11 Hearing Loss in the Iranian Population","volume":"119","author":"Hildebrand","year":"2010","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"295ra108","DOI":"10.1126\/scitranslmed.aab1996","article-title":"Tmc gene therapy restores auditory function in deaf mice","volume":"7","author":"Askew","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1002\/dneu.20771","article-title":"Deafness and retinal degeneration in a novel USH1C knock-in mouse model","volume":"70","author":"Lentz","year":"2010","journal-title":"Dev. Neurobiol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/s00439-004-1217-4","article-title":"The USH1C 216G?A splice-site mutation results in a 35-base-pair deletion","volume":"116","author":"Lentz","year":"2005","journal-title":"Hum. Genet."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1016\/j.ymthe.2017.01.007","article-title":"Gene Therapy Restores Balance and Auditory Functions in a Mouse Model of Usher Syndrome","volume":"25","author":"Isgrig","year":"2017","journal-title":"Mol. Ther. J. Am. Soc. Gene Ther."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"9695","DOI":"10.1073\/pnas.1708894114","article-title":"Local gene therapy durably restores vestibular function in a mouse model of Usher syndrome type 1G","volume":"114","author":"Emptoz","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/7693","article-title":"A mutation in OTOF, encoding otoferlin, a FER-1-like protein, causes DFNB9, a nonsyndromic form of deafness","volume":"21","author":"Yasunaga","year":"1999","journal-title":"Nat. Genet."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1016\/j.ajhg.2008.07.008","article-title":"Impairment of SLC17A8 Encoding Vesicular Glutamate Transporter-3, VGLUT3, Underlies Nonsyndromic Deafness DFNA25 and Inner Hair Cell Dysfunction in Null Mice","volume":"83","author":"Ruel","year":"2008","journal-title":"Am. J. Hum. Genet."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.neuron.2012.05.019","article-title":"Restoration of Hearing in the VGLUT3 Knockout Mouse Using Virally Mediated Gene Therapy","volume":"75","author":"Akil","year":"2012","journal-title":"Neuron"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1641","DOI":"10.1093\/hmg\/ddi172","article-title":"In vitro and in vivo suppression of GJB2 expression by RNA interference","volume":"14","author":"Maeda","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1038\/nm.3106","article-title":"Rescue of hearing and vestibular function by antisense oligonucleotides in a mouse model of human deafness","volume":"19","author":"Lentz","year":"2013","journal-title":"Nat. Med."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/nature25164","article-title":"Treatment of autosomal dominant hearing loss by in vivo delivery of genome editing agents","volume":"553","author":"Gao","year":"2018","journal-title":"Nature"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1038\/s41591-019-0500-9","article-title":"Allele-specific gene editing prevents deafness in a model of dominant progressive hearing loss","volume":"25","author":"Pan","year":"2019","journal-title":"Nat. Med."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.molcel.2015.04.028","article-title":"Choosing the Right Tool for the Job: RNAi, TALEN, or CRISPR","volume":"58","author":"Boettcher","year":"2015","journal-title":"Mol. Cell"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1038\/mt.2013.285","article-title":"Recombinant AAV as a platform for translating the therapeutic potential of RNA interference","volume":"22","author":"Borel","year":"2014","journal-title":"Mol. Ther. J. Am. Soc. Gene Ther."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1007\/978-1-62703-119-6_3","article-title":"Designing functional siRNA with reduced off-target effects","volume":"942","author":"Naito","year":"2013","journal-title":"Methods Mol. Biol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1007\/s00441-014-2029-z","article-title":"Connexins and gap junctions in the inner ear--it\u2019s not just about K+ recycling","volume":"360","author":"Jagger","year":"2015","journal-title":"Cell Tissue Res."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1002\/cmdc.201000156","article-title":"Off-target effects related to the phosphorothioate modification of nucleic acids","volume":"5","author":"Winkler","year":"2010","journal-title":"ChemMedChem"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1016\/j.cell.2013.02.022","article-title":"Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression","volume":"152","author":"Qi","year":"2013","journal-title":"Cell"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/j.cell.2014.09.029","article-title":"Genome-Scale CRISPR-Mediated Control of Gene Repression and Activation","volume":"159","author":"Gilbert","year":"2014","journal-title":"Cell"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.cr.2019.08.001","article-title":"Methods and applications of CRISPR\/Cas system for genome editing in stem cells","volume":"8","author":"Yang","year":"2019","journal-title":"Cell Regen."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1038\/s41592-019-0508-6","article-title":"Multiplexed genome engineering by Cas12a and CRISPR arrays encoded on single transcripts","volume":"16","author":"Campa","year":"2019","journal-title":"Nat. Methods"},{"key":"ref_113","doi-asserted-by":"crossref","unstructured":"Xu, C.L., Ruan, M.Z.C., Mahajan, V.B., and Tsang, S.H. (2019). Viral Delivery Systems for CRISPR. Viruses, 11.","DOI":"10.3390\/v11010028"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1038\/cdd.2016.16","article-title":"Effects of genetic correction on the differentiation of hair cell-like cells from iPSCs with MYO15A mutation","volume":"23","author":"Chen","year":"2016","journal-title":"Cell Death Differ."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1089\/hum.2018.028","article-title":"Virally Mediated Overexpression of Glial-Derived Neurotrophic Factor Elicits Age- and Dose-Dependent Neuronal Toxicity and Hearing Loss","volume":"30","author":"Akil","year":"2019","journal-title":"Hum. Gene Ther."},{"key":"ref_116","first-page":"588","article-title":"Development of in vivo gene therapy for hearing disorders: Introduction of adeno-associated virus into the cochlea of the guinea pig","volume":"3","author":"Lalwani","year":"1996","journal-title":"Gene Ther."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1080\/00016480117641","article-title":"Dynamics of inner ear pressure change caused by intracranial pressure manipulation in the guinea pig","volume":"121","author":"Thalen","year":"2001","journal-title":"Acta Otolaryngol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/0378-5955(94)90236-4","article-title":"Apical cochlear nerve exposed to perilymph in the gerbil and rat","volume":"73","author":"Tinling","year":"1994","journal-title":"Hear. Res."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1002\/rmv.1762","article-title":"Adeno-associated virus (AAV) vectors in gene therapy: Immune challenges and strategies to circumvent them","volume":"23","author":"Hareendran","year":"2013","journal-title":"Rev. Med. Virol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/S0378-5955(97)00017-8","article-title":"Anatomy of the normal human cochlear aqueduct with functional implications","volume":"107","author":"Gopen","year":"1997","journal-title":"Hear. Res."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1177\/019459989310900104","article-title":"Enlargement of the cochlear aqueduct: Fact or fiction?","volume":"109","author":"Jackler","year":"1993","journal-title":"Otolaryngol. Head Neck Surg."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.anl.2011.05.005","article-title":"A perspective from magnetic resonance imaging findings of the inner ear: Relationships among cerebrospinal, ocular and inner ear fluids","volume":"39","author":"Nakashima","year":"2012","journal-title":"Auris Nasus Larynx"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1017\/S0022215100068833","article-title":"Distribution pattern of blood in the inner ear following spontaneous subarachnoid haemorrhage","volume":"82","author":"Holden","year":"1968","journal-title":"J. Laryngol. Otol."},{"key":"ref_124","first-page":"171","article-title":"Inner ear and subarachnoid spaces: Relations and diseases","volume":"118","author":"Djouhri","year":"2001","journal-title":"Ann. Oto Laryngol. Chir. Cervico Faciale Bull. Soc. Oto Hopitaux Paris"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"83","DOI":"10.3109\/00016487009181863","article-title":"Cochlear aqueduct in infants","volume":"70","author":"Palva","year":"1970","journal-title":"Acta Otolaryngol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"18","DOI":"10.3389\/fnins.2018.00018","article-title":"Assessment of Cochlear Function during Cochlear Implantation by Extra- and Intracochlear Electrocochleography","volume":"12","author":"Dalbert","year":"2018","journal-title":"Front. Neurosci."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/9\/2\/589\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T08:59:44Z","timestamp":1760173184000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/9\/2\/589"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,21]]},"references-count":126,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2020,2]]}},"alternative-id":["jcm9020589"],"URL":"https:\/\/doi.org\/10.3390\/jcm9020589","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,21]]}}}