Selection of viral capsids and promoters affects the efficacy of rescue of Tmprss3-deficient cochlea.
Selection of viral capsids and promoters affects the efficacy of rescue of Tmprss3-deficient cochlea.
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DOI：
10.1016/j.omtm.2023.08.004
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发表时间：
2023-09-14
期刊：
影响因子：
--
通讯作者：
Cheng, Alan G.
中科院分区：
文献类型：
--
作者：
Aaron, Ksenia A.;Pekrun, Katja;Atkinson, Patrick J.;Billings, Sara E.;Abitbol, Julia M.;Lee, Ina A.;Eltawil, Yasmin;Chen, Yuan-Siao;Dong, Wuxing;Nelson, Rick F.;Kay, Mark A.;Cheng, Alan G.
Adeno-associated virus (AAV)-mediated gene transfer has shown promise in rescuing mouse models of genetic hearing loss, but how viral capsid and promoter selection affects efficacy is poorly characterized. Here, we tested combinations of AAVs and promoters to deliver Tmprss3, mutations in which are associated with hearing loss in humans. Tmprss3tm1/tm1 mice display severe cochlear hair cell degeneration, loss of auditory brainstem responses, and delayed loss of spiral ganglion neurons. Under the ubiquitous CAG promoter and AAV-KP1 capsid, Tmprss3 overexpression caused striking cytotoxicity in vitro and in vivo and failed to rescue degeneration or dysfunction of the Tmprss3tm1/tm1 cochlea. Reducing the dosage or using AAV-DJ-CAG-Tmprss3 diminished cytotoxicity without rescue of the Tmprss3tm1/tm1 cochlea. Finally, the combination of AAV-KP1 capsid and the EF1α promoter prevented cytotoxicity and reduced hair cell degeneration, loss of spiral ganglion neurons, and improved hearing thresholds in Tmprss3tm1/tm1 mice. Together, our study illustrates toxicity of exogenous genes and factors governing rescue efficiency, and suggests that cochlear gene therapy likely requires precisely targeted transgene expression. Cheng and colleagues show that selection of viral capsids and promoters can affect the toxicity of exogenous gene transfer of mouse Tmprss3 and its efficacy of rescue of hair cell loss and hearing loss caused by Tmprss3 deficiency. Tmprss3 deficiency causes hair cell loss and hearing loss in humans.
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DOI：
10.1016/j.omtm.2021.03.005
发表时间：
2021-06-11
期刊：
Molecular therapy. Methods & clinical development
影响因子：
--
作者：
Bankoti K;Generotti C;Hwa T;Wang L;O'Malley BW Jr;Li D
通讯作者：
Li D
影响因子：
12.4
作者：
Isgrig, Kevin;Shteamer, Jack W.;Chien, Wade W.
通讯作者：
Chien, Wade W.
影响因子：
16.6
作者：
Isgrig, Kevin;McDougald, Devin S.;Chien, Wade W.
通讯作者：
Chien, Wade W.
影响因子：
5.4
作者：
Grimm, Dirk;Lee, Joyce S.;Kay, Mark A.
通讯作者：
Kay, Mark A.
病毒介导的 Kcnq1 基因替代疗法在未成熟的 scala 介质中恢复了人类 Jervell 和 Lange-Nielsen 耳聋综合征小鼠模型的听力
影响因子：
11.1
作者：
Chang, Qing;Wang, Jianjun;Lin, Xi
通讯作者：
Lin, Xi