Delivery of Adeno-Associated Virus Vectors in Adult Mammalian Inner-Ear Cell Subtypes Without Auditory Dysfunction
Delivery of Adeno-Associated Virus Vectors in Adult Mammalian Inner-Ear Cell Subtypes Without Auditory Dysfunction
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DOI：
10.1089/hum.2017.120
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发表时间：
2018-01-22
影响因子：
4.2
通讯作者：
Chen, Zheng-Yi
中科院分区：
文献类型：
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作者：
Tao, Yong;Huang, Mingqian;Chen, Zheng-Yi
听力损失，包括遗传性听力损失，是人类最常见的感觉缺陷形式之一，治疗选择有限。腺相关病毒（AAV）介导的基因转移已被证明可以在新生儿阶段分娩的遗传性耳聋小鼠模型中有效恢复听觉功能。然而，小鼠的耳蜗在这些时间点仍在发育，而在人类中，新生的内耳已经完全成熟。对于治疗遗传性耳聋的有效基因疗法，有必要确定AAV介导的疗法是否可以在完全成熟的小鼠内耳中同样有效，而不会对内耳造成损害。这项研究通过成年小鼠的管造口术测试了几种 AAV 血清型。结果表明，大多数 AAV 可以有效地转导感觉内毛细胞，但转导外毛细胞的效率较低。 AAV 的一个子集还可以转导非感觉耳蜗细胞类型。耳管造口术和 AAV 血清型均不会损害毛细胞或损害正常听力。研究表明，耳管造口术可能是安全有效的基因传递的可行途径，并且它们扩展了 AAV 的功能，以针对成人内耳中的不同细胞类型。
Hearing loss, including genetic hearing loss, is one of the most common forms of sensory deficits in humans with limited options of treatment. Adeno-associated virus (AAV)-mediated gene transfer has been shown to recover auditory functions effectively in mouse models of genetic deafness when delivered at neonatal stages. However, the mouse cochlea is still developing at those time points, whereas in humans, the newborn inner ears are already fully mature. For effective gene therapy to treat genetic deafness, it is necessary to determine whether AAV-mediated therapy can be equally effective in the fully mature mouse inner ear without causing damage to the inner ear. This study tested several AAV serotypes by canalostomy in adult mice. It is shown that most AAVs transduce the sensory inner hair cells efficiently, but are less efficient at transducing outer hair cells. A subset of AAVs also transduces non-sensory cochlear cell types. Neither the surgical procedure of canalostomy nor the AAV serotypes damage hair cells or impair normal hearing. The studies indicate that canalostomy can be a viable route for safe and efficient gene delivery, and they expand the repertoire of AAVs to target diverse cell types in the adult inner ear.