Luoying Jiang, Shao Wei Hu, Zijing Wang, Yi Zhou, Honghai Tang, Yuxin Chen, Daqi Wang, Xintai Fan, Lei Han, Huawei Li, Dazhi Shi, Yingzi He, Yilai Shu
{"title":"在人类 DFNB111 耳聋小鼠模型中通过多位点表达基因的基因替代疗法恢复听力。","authors":"Luoying Jiang, Shao Wei Hu, Zijing Wang, Yi Zhou, Honghai Tang, Yuxin Chen, Daqi Wang, Xintai Fan, Lei Han, Huawei Li, Dazhi Shi, Yingzi He, Yilai Shu","doi":"10.1016/j.ajhg.2024.08.008","DOIUrl":null,"url":null,"abstract":"<p><p>Gene therapy has made significant progress in the treatment of hereditary hearing loss. However, most research has focused on deafness-related genes that are primarily expressed in hair cells with less attention given to multisite-expressed deafness genes. MPZL2, the second leading cause of mild-to-moderate hereditary deafness, is widely expressed in different inner ear cells. We generated a mouse model with a deletion in the Mpzl2 gene, which displayed moderate and slowly progressive hearing loss, mimicking the phenotype of individuals with DFNB111. We developed a gene replacement therapy system mediated by AAV-ie for efficient transduction in various types of cochlear cells. AAV-ie-Mpzl2 administration significantly lowered the auditory brainstem response and distortion product otoacoustic emission thresholds of Mpzl2<sup>-/-</sup> mice for at least seven months. AAV-ie-Mpzl2 delivery restored the structural integrity in both outer hair cells and Deiters cells. This study suggests the potential of gene therapy for MPZL2-related deafness and provides a proof of concept for gene therapy targeting other deafness-related genes that are expressed in different cell populations in the cochlea.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2253-2264"},"PeriodicalIF":8.1000,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11480802/pdf/","citationCount":"0","resultStr":"{\"title\":\"Hearing restoration by gene replacement therapy for a multisite-expressed gene in a mouse model of human DFNB111 deafness.\",\"authors\":\"Luoying Jiang, Shao Wei Hu, Zijing Wang, Yi Zhou, Honghai Tang, Yuxin Chen, Daqi Wang, Xintai Fan, Lei Han, Huawei Li, Dazhi Shi, Yingzi He, Yilai Shu\",\"doi\":\"10.1016/j.ajhg.2024.08.008\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Gene therapy has made significant progress in the treatment of hereditary hearing loss. However, most research has focused on deafness-related genes that are primarily expressed in hair cells with less attention given to multisite-expressed deafness genes. MPZL2, the second leading cause of mild-to-moderate hereditary deafness, is widely expressed in different inner ear cells. We generated a mouse model with a deletion in the Mpzl2 gene, which displayed moderate and slowly progressive hearing loss, mimicking the phenotype of individuals with DFNB111. We developed a gene replacement therapy system mediated by AAV-ie for efficient transduction in various types of cochlear cells. AAV-ie-Mpzl2 administration significantly lowered the auditory brainstem response and distortion product otoacoustic emission thresholds of Mpzl2<sup>-/-</sup> mice for at least seven months. AAV-ie-Mpzl2 delivery restored the structural integrity in both outer hair cells and Deiters cells. This study suggests the potential of gene therapy for MPZL2-related deafness and provides a proof of concept for gene therapy targeting other deafness-related genes that are expressed in different cell populations in the cochlea.</p>\",\"PeriodicalId\":7659,\"journal\":{\"name\":\"American journal of human genetics\",\"volume\":\" \",\"pages\":\"2253-2264\"},\"PeriodicalIF\":8.1000,\"publicationDate\":\"2024-10-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11480802/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"American journal of human genetics\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1016/j.ajhg.2024.08.008\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/9/5 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"GENETICS & HEREDITY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"American journal of human genetics","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.ajhg.2024.08.008","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/9/5 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
Hearing restoration by gene replacement therapy for a multisite-expressed gene in a mouse model of human DFNB111 deafness.
Gene therapy has made significant progress in the treatment of hereditary hearing loss. However, most research has focused on deafness-related genes that are primarily expressed in hair cells with less attention given to multisite-expressed deafness genes. MPZL2, the second leading cause of mild-to-moderate hereditary deafness, is widely expressed in different inner ear cells. We generated a mouse model with a deletion in the Mpzl2 gene, which displayed moderate and slowly progressive hearing loss, mimicking the phenotype of individuals with DFNB111. We developed a gene replacement therapy system mediated by AAV-ie for efficient transduction in various types of cochlear cells. AAV-ie-Mpzl2 administration significantly lowered the auditory brainstem response and distortion product otoacoustic emission thresholds of Mpzl2-/- mice for at least seven months. AAV-ie-Mpzl2 delivery restored the structural integrity in both outer hair cells and Deiters cells. This study suggests the potential of gene therapy for MPZL2-related deafness and provides a proof of concept for gene therapy targeting other deafness-related genes that are expressed in different cell populations in the cochlea.
期刊介绍:
The American Journal of Human Genetics (AJHG) is a monthly journal published by Cell Press, chosen by The American Society of Human Genetics (ASHG) as its premier publication starting from January 2008. AJHG represents Cell Press's first society-owned journal, and both ASHG and Cell Press anticipate significant synergies between AJHG content and that of other Cell Press titles.