Tmc gene therapy restores auditory function in deaf mice.
Tmc gene therapy restores auditory function in deaf mice.
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DOI：
10.1126/scitranslmed.aab1996
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发表时间：
2015-07-08
影响因子：
17.1
通讯作者：
Holt JR
中科院分区：
文献类型：
--
作者：
Askew C;Rochat C;Pan B;Asai Y;Ahmed H;Child E;Schneider BL;Aebischer P;Holt JR
遗传性听力损失占全球语前耳聋的50%，但目前还没有生物治疗方法。为了研究基因治疗作为恢复遗传性听力损失患者听觉功能的潜在生物学策略，我们在遗传性耳聋小鼠模型中测试了基因增强方法。我们重点研究了DFNB 7/11和DFNA 36，这两种基因分别是由跨膜通道样蛋白1（TMC 1）突变引起的常染色体隐性和显性遗传。携带靶向Tmc 1缺失或显性Tmc 1点突变（称为Beethoven）的小鼠是人类DFNB 7/11和DFNA 36的良好模型。我们筛选了几种腺相关病毒（AAV）血清型和启动子，并鉴定了AAV 2/1和鸡b-肌动蛋白（Cba）启动子作为驱动外源Tmc 1在内毛细胞中体内表达的有效组合。外源性Tmc 1或其密切相关的直系同源物，Tmc 2，能够恢复感觉转导，听觉脑干反应，和声学惊吓反射，在其他耳聋小鼠，这表明基因增强与Tmc 1或Tmc 2是非常适合进一步发展为一种策略，恢复听力功能的耳聋患者携带TMC 1突变。
Genetic hearing loss accounts for up to 50% of prelingual deafness worldwide, yet there are no biologic treatments currently available. To investigate gene therapy as a potential biologic strategy for restoration of auditory function in patients with genetic hearing loss, we tested a gene augmentation approach in mouse models of genetic deafness. We focused on DFNB7/11 and DFNA36, which are autosomal recessive and dominant deafnesses, respectively, caused by mutations in transmembrane channel–like 1 (TMC1). Mice that carry targeted deletion of Tmc1 or a dominant Tmc1 point mutation, known as Beethoven, are good models for human DFNB7/11 and DFNA36. We screened several adeno- associated viral (AAV) serotypes and promoters and identified AAV2/1 and the chicken b-actin (Cba) promoter as an efficient combination for driving the expression of exogenous Tmc1 in inner hair cells in vivo. Exogenous Tmc1 or its closely related ortholog, Tmc2, were capable of restoring sensory transduction, auditory brainstem responses, and acoustic startle reflexes in otherwise deaf mice, suggesting that gene augmentation with Tmc1 or Tmc2 is well suited for further development as a strategy for restoration of auditory function in deaf patients who carry TMC1 mutations.
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影响因子：
1.7
作者：
Nakanishi, Hiroshi;Kurima, Kiyoto;Kawashima, Yoshiyuki;Griffith, Andrew J.
通讯作者：
Griffith, Andrew J.
影响因子：
25
作者：
Géléoc, GSG;Holt, JR
通讯作者：
Holt, JR
影响因子：
15.9
作者：
Kawashima, Yoshiyuki;Geleoc, Gwenaelle S. G.;Griffith, Andrew J.
通讯作者：
Griffith, Andrew J.
影响因子：
5.1
作者：
Kohrman, D. C.;Raphael, Y.
通讯作者：
Raphael, Y.
DOI：
10.1126/science.1241062
发表时间：
2014-05-09
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Géléoc GS;Holt JR
通讯作者：
Holt JR