Hair cell-specific Myo15 promoter-mediated gene therapy rescues hearing in DFNB9 mouse model

被引:12
作者
Wang, Hui [1 ,2 ,3 ,4 ,5 ]
Xun, Mengzhao [1 ,2 ,3 ,4 ,5 ]
Tang, Honghai [1 ,2 ,3 ,4 ,5 ]
Zhao, Jingjing [1 ,2 ,3 ,4 ,5 ]
Hu, Shaowei [1 ,2 ,3 ,4 ,5 ]
Zhang, Longlong [1 ,2 ,3 ,4 ,5 ]
Lv, Jun [1 ,2 ,3 ,4 ,5 ]
Wang, Daqi [1 ,2 ,3 ,4 ,5 ]
Chen, Yuxin [1 ,2 ,3 ,4 ,5 ]
Liu, Jianping [1 ,2 ,3 ,4 ,5 ]
Li, Geng-lin [1 ,2 ,3 ,4 ,5 ]
Wang, Wuqing [1 ,2 ,3 ,4 ,5 ,6 ]
Shu, Yilai [1 ,2 ,3 ,4 ,5 ,6 ]
Li, Huawei [1 ,2 ,3 ,4 ,5 ,6 ]
机构
[1] Fudan Univ, ENT Inst, Shanghai 200031, Peoples R China
[2] Fudan Univ, Otorhinolaryngol Dept, State Key Lab Med Neurobiol, Eye & ENT Hosp, Shanghai 200031, Peoples R China
[3] Fudan Univ, MOE Frontiers Ctr Brain Sci, Shanghai 200031, Peoples R China
[4] Fudan Univ, Inst Biomed Sci, Shanghai 200032, Peoples R China
[5] Fudan Univ, NHC Key Lab Hearing Med, Shanghai 200031, Peoples R China
[6] Fudan Univ, State Key Lab Med Neurobiol, Shanghai 200031, Peoples R China
来源
MOLECULAR THERAPY NUCLEIC ACIDS | 2024年 / 35卷 / 01期
基金
国家重点研发计划; 中国国家自然科学基金;
关键词
ADENOASSOCIATED VIRAL VECTOR; COCHLEAR AQUEDUCT; INNER-EAR; EXPRESSION; OTOFERLIN; PROTEIN; TRANSDUCTION; FORM;
D O I
10.1016/j.omtn.2024.102135
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Adeno-associated viral (AAV) vectors are increasingly used as vehicles for gene delivery to treat hearing loss. However, lack of specificity of the transgene expression may lead to overexpression of the transgene in nontarget tissues. In this study, we evaluated the expression efficiency and specificity of transgene delivered by AAV-PHP.eB under the inner ear sensory cell -specific Myo15 promoter. Compared with the ubiquitous CAG promoter, the Myo15 promoter initiates efficient expression of the GFP fluorescence reporter in hair cells, while minimizing non-specific expression in other cell types of the inner ear and CNS. Furthermore, using the Myo15 promoter, we constructed an AAV-mediated therapeutic system with the coding sequence of OTOF gene. After inner ear injection, we observed apparent hearing recovery in Otof -/- mice, highly efficient expression of exogenous otoferlin, and significant improvement in the exocytosis function of inner hair cells. Overall, our results indicate that gene therapy mediated by the hair cell -specific Myo15 promoter has potential clinical application for the treatment of autosomal recessive deafness and yet for other hereditary hearing loss related to dysfunction of hair cells.
引用
收藏
页数:12
相关论文
共 52 条
[1]   Emerging Gene Therapies for Genetic Hearing Loss [J].
Ahmed, Hena ;
Shubina-Oleinik, Olga ;
Holt, Jeffrey R. .
JARO-JOURNAL OF THE ASSOCIATION FOR RESEARCH IN OTOLARYNGOLOGY, 2017, 18 (05) :649-670
[2]   Dual AAV-mediated gene therapy restores hearing in a DFNB9 mouse model [J].
Akil, Omar ;
Dyka, Frank ;
Calvet, Charlotte ;
Emptoz, Alice ;
Lahlou, Ghizlene ;
Nouaille, Sylvie ;
de Monvel, Jacques Boutet ;
Hardelin, Jean-Pierre ;
Hauswirth, William W. ;
Avan, Paul ;
Petit, Christine ;
Safieddine, Saaid ;
Lustig, Lawrence R. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2019, 116 (10) :4496-4501
[3]   A dual-AAV approach restores fast exocytosis and partially rescues auditory function in deaf otoferlin knock-out mice [J].
Al-Moyed, Hanan ;
Cepeda, Andreia P. ;
Jung, SangYong ;
Moser, Tobias ;
Kuegler, Sebastian ;
Reisinger, Ellen .
EMBO MOLECULAR MEDICINE, 2019, 11 (01)
[4]  
Bachor E, 1999, AM J OTOL, V20, P612
[5]   A specific promoter of the sensory cells of the inner ear defined by transgenesis [J].
Boëda, B ;
Weil, D ;
Petit, C .
HUMAN MOLECULAR GENETICS, 2001, 10 (15) :1581-1589
[6]   Usher type 1G protein sans is a critical component of the tip-link complex, a structure controlling actin polymerization in stereocilia [J].
Caberlotto, Elisa ;
Michel, Vincent ;
Foucher, Isabelle ;
Bahloul, Amel ;
Goodyear, Richard J. ;
Pepermans, Elise ;
Michalski, Nicolas ;
Perfettini, Isabelle ;
Alegria-Prevot, Olinda ;
Chardenoux, Sebastien ;
Do Cruzeiro, Marcio ;
Hardelin, Jean-Pierre ;
Richardson, Guy P. ;
Avan, Paul ;
Weil, Dominique ;
Petit, Christine .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2011, 108 (14) :5825-5830
[7]   Engineered AAVs for efficient noninvasive gene delivery to the central and peripheral nervous systems [J].
Chan, Ken Y. ;
Jang, Min J. ;
Yoo, Bryan B. ;
Greenbaum, Alon ;
Ravi, Namita ;
Wu, Wei-Li ;
Sanchez-Guardado, Luis ;
Lois, Carlos ;
Mazmanian, Sarkis K. ;
Deverman, Benjamin E. ;
Gradinaru, Viviana .
NATURE NEUROSCIENCE, 2017, 20 (08) :1172-+
[8]   Barhl1 regulatory sequences required for cell-specific gene expression and autoregulation in the inner ear and central nervous system [J].
Chellappa, Ramesh ;
Li, Shengguo ;
Pauley, Sarah ;
Jahan, Israt ;
Jin, Kangxin ;
Xiang, Mengqing .
MOLECULAR AND CELLULAR BIOLOGY, 2008, 28 (06) :1905-1914
[9]   Genetic etiology of non-syndromic hearing loss in Europe [J].
del Castillo, Ignacio ;
Morin, Matias ;
Dominguez-Ruiz, Maria ;
Moreno-Pelayo, Miguel A. .
HUMAN GENETICS, 2022, 141 (3-4) :683-696
[10]   Cre-dependent selection yields AAV variants for widespread gene transfer to the adult brain [J].
Deverman, Benjamin E. ;
Pravdo, Piers L. ;
Simpson, Bryan P. ;
Kumar, Sripriya Ravindra ;
Chan, Ken Y. ;
Banerjee, Abhik ;
Wu, Wei-Li ;
Yang, Bin ;
Huber, Nina ;
Pasca, Sergiu P. ;
Gradinaru, Viviana .
NATURE BIOTECHNOLOGY, 2016, 34 (02) :204-+