Delivery of Channel Rhodopsin for Optogenetic Control of Neurons in the Cochlea

描述（由申请人提供）：人工耳蜗植入体（CI）为大多数重度至极重度感音神经性听力损失患者提供有意义的声音和言语感知。CI电极绕过耳聋内耳的有缺陷或缺失的毛细胞，以电刺激螺旋神经节细胞（SGCs），即听觉系统的一级神经元。虽然大多数CI用户都能获得听觉上的好处，但在类似的受试者中，结果差异很大。此外，许多患者没有超过50%的开放式单词识别分数，几乎所有CI患者都报告在嘈杂环境和音乐欣赏中存在困难。一种解释可能是当前系统使用的电刺激范例对听觉性能设置了根本限制。具体地说，虽然言语感知已被证明随着电极的数量而增加，但有效通道的数量会因电的纵向传播而减少。这导致通道交叉和远离电极位置的神经元群的激活。为了解决当前植入技术的这些局限性，我们将使用一种令人兴奋的新方法，称为光遗传学，用光刺激内耳的神经元。光比电有一个关键的优势，因为它可以聚焦，理论上可以选择性激活数百个独立的声道。视紫红质-2（ChR 2）是一种光敏蛋白，可以使用病毒载体递送到神经元中，并已成功用于许多系统，包括CNS和视觉通路。通过SGCs转导的听觉通路的光遗传学控制尚未报道。我们的假设是，使用直接病毒载体转导或干细胞介导的体内ChR 2转移的内耳神经元的修饰是可行的，并且ChR 2表达神经元能够产生光学诱发的听觉反应。我们提出，SGCs的光敏化和插入光学电极用于内耳的受控刺激可能为未来基于光的CI技术提供基础。

DESCRIPTION (provided by applicant): The cochlear implant (CI) provides meaningful sound and speech perception to the majority of patients with severe to profound sensorineural hearing loss. The CI electrode bypasses the defective or absent hair cells of the deaf inner ear to electrically stimulate the spiral ganglion cells (SGCs), the first order neurons of the auditory system. Although most CI users receive auditory benefits, outcomes vary widely across similar subjects. In addition, a number of patients do not have open set word recognition scores that exceed 50% and virtually all CI patients report difficulty in noisy environments and musical appreciation. One explanation may be that the electrical stimulation paradigm used by current systems sets fundamental limits on auditory performance. Specifically, although speech perception has been shown to increase with the number of electrodes, the number of effective channels is diminished by the longitudinal spread of electricity. This results in channel cross-tal and the activation of neuronal populations remote from the site of the electrode. In order to address these limitations of current implant technology, we will use an exciting new approach called optogenetics to stimulate neurons of the inner ear with light. Light offers a key advantage over electricity because it can be focused and allows, in theory, the selective activation of hundreds of independent acoustic channels. Channelrhodopsin-2 (ChR2) is a light-sensitive protein that can be delivered into neurons using a viral vector and has been used successfully in many systems, including the CNS and in the visual pathways. Optogenetic control of auditory pathways through transduction of SGCs has not yet been reported. Our hypothesis is that modification of inner ear neurons using direct viral vector transduction or stem cell-mediated transfer of ChR2 in vivo is feasible and that ChR2-expressing neurons are capable of generating an optically-evoked auditory response. We propose that photosensitization of SGCs and insertion of an optical electrode for controlled stimulation of the inner ear may provide the basis for future CI technology based on light.