GJB2 gene therapy and conditional deletion reveal developmental stage-dependent effects on inner ear structure and function
Pathogenic variants in GJB2, the gene encoding connexin 26, are the most common cause of autosomal-recessive hereditary deafness. Despite this high prevalence, pathogenic mechanisms leading to GJB2-related deafness are not well understood, and cures are absent. Humans with GJB2-related deafness reta...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-12-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050121001479 |
| _version_ | 1818573825968701440 |
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| author | Jingying Guo Xiaobo Ma Jennifer M. Skidmore Jelka Cimerman Diane M. Prieskorn Lisa A. Beyer Donald L. Swiderski David F. Dolan Donna M. Martin Yehoash Raphael |
| author_facet | Jingying Guo Xiaobo Ma Jennifer M. Skidmore Jelka Cimerman Diane M. Prieskorn Lisa A. Beyer Donald L. Swiderski David F. Dolan Donna M. Martin Yehoash Raphael |
| author_sort | Jingying Guo |
| collection | DOAJ |
| description | Pathogenic variants in GJB2, the gene encoding connexin 26, are the most common cause of autosomal-recessive hereditary deafness. Despite this high prevalence, pathogenic mechanisms leading to GJB2-related deafness are not well understood, and cures are absent. Humans with GJB2-related deafness retain at least some auditory hair cells and neurons, and their deafness is usually stable. In contrast, mice with conditional loss of Gjb2 in supporting cells exhibit extensive loss of hair cells and neurons and rapidly progress to profound deafness, precluding the application of therapies that require intact cochlear cells. In an attempt to design a less severe Gjb2 animal model, we generated mice with inducible Sox10iCreERT2-mediated loss of Gjb2. Tamoxifen injection led to reduced connexin 26 expression and impaired function, but cochlear hair cells and neurons survived for 2 months, allowing phenotypic rescue attempts within this time. AAV-mediated gene transfer of GJB2 in mature mutant ears did not demonstrate threshold improvement and in some animals exacerbated hearing loss and resulted in hair cell loss. We conclude that Sox10iCreERT2;Gjb2flox/flox mice are valuable for studying the biology of connexin 26 in the cochlea. In particular, these mice may be useful for evaluating gene therapy vectors and development of therapies for GJB2-related deafness. |
| first_indexed | 2024-12-15T00:18:05Z |
| format | Article |
| id | doaj.art-fa3d714e52b744348ecd08e357da7134 |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-12-15T00:18:05Z |
| publishDate | 2021-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-fa3d714e52b744348ecd08e357da71342022-12-21T22:42:25ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012021-12-0123319333GJB2 gene therapy and conditional deletion reveal developmental stage-dependent effects on inner ear structure and functionJingying Guo0Xiaobo Ma1Jennifer M. Skidmore2Jelka Cimerman3Diane M. Prieskorn4Lisa A. Beyer5Donald L. Swiderski6David F. Dolan7Donna M. Martin8Yehoash Raphael9Kresge Hearing Research Institute, Otolaryngology, Head and Neck Surgery, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA; Department of Otolaryngology Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, ChinaDepartment of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, ChinaDepartment of Pediatrics, Michigan Medicine, University of Michigan, Ann Arbor, MI, USADepartment of Pediatrics, Michigan Medicine, University of Michigan, Ann Arbor, MI, USAKresge Hearing Research Institute, Otolaryngology, Head and Neck Surgery, Michigan Medicine, University of Michigan, Ann Arbor, MI, USAKresge Hearing Research Institute, Otolaryngology, Head and Neck Surgery, Michigan Medicine, University of Michigan, Ann Arbor, MI, USAKresge Hearing Research Institute, Otolaryngology, Head and Neck Surgery, Michigan Medicine, University of Michigan, Ann Arbor, MI, USAKresge Hearing Research Institute, Otolaryngology, Head and Neck Surgery, Michigan Medicine, University of Michigan, Ann Arbor, MI, USADepartment of Pediatrics, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA; Department of Human Genetics, Michigan Medicine, University of Michigan, Ann Arbor, MI, USAKresge Hearing Research Institute, Otolaryngology, Head and Neck Surgery, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA; Corresponding author: Yehoash Raphael, Kresge Hearing Research Institute, Otolaryngology, Head and Neck Surgery, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA.Pathogenic variants in GJB2, the gene encoding connexin 26, are the most common cause of autosomal-recessive hereditary deafness. Despite this high prevalence, pathogenic mechanisms leading to GJB2-related deafness are not well understood, and cures are absent. Humans with GJB2-related deafness retain at least some auditory hair cells and neurons, and their deafness is usually stable. In contrast, mice with conditional loss of Gjb2 in supporting cells exhibit extensive loss of hair cells and neurons and rapidly progress to profound deafness, precluding the application of therapies that require intact cochlear cells. In an attempt to design a less severe Gjb2 animal model, we generated mice with inducible Sox10iCreERT2-mediated loss of Gjb2. Tamoxifen injection led to reduced connexin 26 expression and impaired function, but cochlear hair cells and neurons survived for 2 months, allowing phenotypic rescue attempts within this time. AAV-mediated gene transfer of GJB2 in mature mutant ears did not demonstrate threshold improvement and in some animals exacerbated hearing loss and resulted in hair cell loss. We conclude that Sox10iCreERT2;Gjb2flox/flox mice are valuable for studying the biology of connexin 26 in the cochlea. In particular, these mice may be useful for evaluating gene therapy vectors and development of therapies for GJB2-related deafness.http://www.sciencedirect.com/science/article/pii/S2329050121001479transgenic mouseconnexin 26gap junctioncochlear GJB-2DFNB1 deafnesshearing loss |
| spellingShingle | Jingying Guo Xiaobo Ma Jennifer M. Skidmore Jelka Cimerman Diane M. Prieskorn Lisa A. Beyer Donald L. Swiderski David F. Dolan Donna M. Martin Yehoash Raphael GJB2 gene therapy and conditional deletion reveal developmental stage-dependent effects on inner ear structure and function Molecular Therapy: Methods & Clinical Development transgenic mouse connexin 26 gap junction cochlear GJB-2 DFNB1 deafness hearing loss |
| title | GJB2 gene therapy and conditional deletion reveal developmental stage-dependent effects on inner ear structure and function |
| title_full | GJB2 gene therapy and conditional deletion reveal developmental stage-dependent effects on inner ear structure and function |
| title_fullStr | GJB2 gene therapy and conditional deletion reveal developmental stage-dependent effects on inner ear structure and function |
| title_full_unstemmed | GJB2 gene therapy and conditional deletion reveal developmental stage-dependent effects on inner ear structure and function |
| title_short | GJB2 gene therapy and conditional deletion reveal developmental stage-dependent effects on inner ear structure and function |
| title_sort | gjb2 gene therapy and conditional deletion reveal developmental stage dependent effects on inner ear structure and function |
| topic | transgenic mouse connexin 26 gap junction cochlear GJB-2 DFNB1 deafness hearing loss |
| url | http://www.sciencedirect.com/science/article/pii/S2329050121001479 |
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