title: Identification of Adeno-Associated Viral Vectors That Target Neonatal and Adult Mammalian Inner Ear Cell Subtypes.
abstract: The mammalian inner ear consists of diverse cell types with important functions. Gene mutations in these diverse cell types have been found to underlie different forms of genetic hearing loss. Targeting these mutations for gene therapy development represents a future therapeutic strategy to treat hearing loss. Adeno-associated viral (AAV) vectors have become the vector of choice for gene delivery in animal models in vivo. To identify AAV vectors that target inner ear cell subtypes, we systemically screened 12 AAV vectors with different serotypes (AAV1, 2, 5, 6, 6.2, 7, 8, 9, rh.8, rh.10, rh.39, and rh.43) that carry a reporter gene GFP in neonatal and adult mice by microinjection in vivo. We found that most AAVs infect both neonatal and adult inner ear, with different specificities and expression levels. The inner ear cochlear sensory epithelial region, which includes auditory hair cells and supporting cells, is most frequently targeted for gene delivery. Expression of the transgene is sustained, and neonatal inner ear delivery does not adversely affect hearing. Adult inner ear injection of AAV has a similar infection pattern as the younger inner ear, with the exception that outer hair cell death caused by the injection procedure can lead to hearing loss. In the adult, more so than in the neonatal mice, cell types infected and efficiency of infection are correlated with the site of injection. Most infected cells survive in neonatal and adult inner ears. The study adds to the list of AAV vectors that transduce the mammalian inner ear efficiently, providing the tools that are important to study inner ear gene function and for the development of gene therapy to treat hearing loss.
authors.affiliation: 1 Department of Otolaryngology, Harvard Medical School and Eaton-Peabody Laboratories, Massachusetts Eye & Ear Infirmary, Boston, Massachusetts.|2 Department of Otolaryngology-Head and Neck Surgery, Eye and ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China .|3 Key Laboratory of Hearing Medicine, National Health and Family Planning Commission, Shanghai, China .
authors.forename: Yilai
authors.initials: Y
authors.lastname: Shu
authors.affiliation: 1 Department of Otolaryngology, Harvard Medical School and Eaton-Peabody Laboratories, Massachusetts Eye & Ear Infirmary, Boston, Massachusetts.
authors.forename: Yong
authors.initials: Y
authors.lastname: Tao
authors.affiliation: 2 Department of Otolaryngology-Head and Neck Surgery, Eye and ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China .|3 Key Laboratory of Hearing Medicine, National Health and Family Planning Commission, Shanghai, China .
authors.forename: Zhengmin
authors.initials: Z
authors.lastname: Wang
authors.affiliation: 1 Department of Otolaryngology, Harvard Medical School and Eaton-Peabody Laboratories, Massachusetts Eye & Ear Infirmary, Boston, Massachusetts.|4 Department of Ear, Nose and Throat, People's Hospital of Jilin Province, Changchun, Jilin Province, China .
authors.forename: Yong
authors.initials: Y
authors.lastname: Tang
authors.affiliation: 2 Department of Otolaryngology-Head and Neck Surgery, Eye and ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China .|3 Key Laboratory of Hearing Medicine, National Health and Family Planning Commission, Shanghai, China .
authors.forename: Huawei
authors.initials: H
authors.lastname: Li
authors.affiliation: 5 Department of Otolaryngology, Chinese PLA General Hospital, Beijing, People's Republic of China .
authors.forename: Pu
authors.initials: P
authors.lastname: Dai
authors.affiliation: 6 Horae Gene Therapy Center and Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts.|7 State Key Laboratory of Biotherapy, West China Hospital, Sichuan University , Chengdu, Sichuan, China .
authors.forename: Guangping
authors.initials: G
authors.lastname: Gao
authors.affiliation: 1 Department of Otolaryngology, Harvard Medical School and Eaton-Peabody Laboratories, Massachusetts Eye & Ear Infirmary, Boston, Massachusetts.
authors.forename: Zheng-Yi
authors.initials: ZY
authors.lastname: Chen
mesh_terms: D000328:Adult; D000818:Animals; D000831:Animals, Newborn; D003051:Cochlea / Q000378:metabolism* / Q000473:pathology; D000229:Dependovirus / Q000145:classification / Q000235:genetics*; D007758:Ear, Inner / Q000378:metabolism* / Q000473:pathology; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D034381:Hearing Loss / Q000235:genetics / Q000628:therapy*; D006801:Humans; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D014161:Transduction, Genetic; D019076:Transgenes / Q000235:genetics
chemical_list: D049452:Green Fluorescent Proteins