Acoustic and electrical hearing after Atoh1 treatment

我们最近证明了哺乳动物体内产生了新的内毛细胞。 基因治疗后的科尔蒂器官。具体地说，这些实验涉及体内接种一种 携带Atohl基因的腺病毒载体(M.Atohl)插入耳蜗腺病毒载体。 我们还证明了新的毛细胞可以吸引神经元。耳聋的治疗方法 Atohl表现出由Preyer反射和听觉诱发确定的部分功能恢复 听性脑干反应(ABR)阈值。在当前的应用中，我们建议使用动物- 确定修复的性质和程度的心理物理技术和生理测量 声学听力。我们还将进行与使用这种Atohl疗法相关的实验 配合人工耳蜗植入物。 对于前两个具体目标，我们将用耳毒性药物使豚鼠耳聋，用Atohl治疗它们 和测量心理物理检测(目标1)和辨别(目标2)以及ABR和失真 产品耳声发射(DPOAE)。在目标3中，我们将评估M.Atohl 接种、人工耳蜗植入和人工耳蜗电刺激。在《目标4》中我们将 在接种的耳朵内植入人工耳蜗，并评估对电的心理物理反应 电刺激和电诱发复合动作电位(ECAP)，有和没有恢复的IHC。 将使用一些存活毛细胞(即植入但未致聋的动物)作为对照。 用于与毛细胞恢复的动物进行比较。 我们提议的实验涉及使用我们的 实验室。这项工作得到了强大的初步数据的支持，并代表了 风险相对较低，影响非常大。建议中的实验将加深我们对 毛细胞再生在哺乳动物耳蜗中的功能意义 耳蜗术联合应用治疗感音神经性耳聋的临床研究 植入细胞替代疗法。

We have recently demonstrated that new inner hair cells (IHCs) are generated in the mammalian organ of Corti following gene therapy. Specifically, the experiments involve in vivo inoculation of an adenovirus vector with the Atohl gene insert (M.Atohl) into the mature predeafened guinea pig cochlea. We have also demonstrated that the new hair cells can attract neurons. Predeafened ears treated with Atohl exhibit partial restoration of function as determined by Preyer's reflex and acoustically-evoked auditory brainstem response (ABR) thresholds. In the current application we propose to use animal- psychophysics techniques and physiological measures to define the nature and extent of the restored acoustic hearing. We will also conduct experiments relevant to the use of this Atohl therapy in conjunction with cochlear implants. For the first two specific aims we will deafen guinea pigs with ototoxic drugs, treat them with Atohl and measure psychophysical detection (Aim 1) and discrimination (Aim 2) as well as ABRs and distortion product otoacoustic emissions (DPOAEs). In Aim 3, we will assess the interaction between M.Atohl inoculation, cochlear implantation, and electrical stimulation of the cochlear implant. In Aim 4 we will place a cochlear implant in the inoculated ear and assess psychophysical responses to electrical stimulation and electrically evoked compound action potentials (ECAPs) with and without restored IHCs. Controls with some surviving hair cells (i.e., animals that are implanted but not predeafened) will be used for comparison to animals with restored hair cells. The experiments we propose involve the use of techniques that are already in place in our laboratories. The work is backed by strong preliminary data, and represents an ideal combination of relatively low-risk with very high impact. The proposed experiments will enhance our understanding of the functional significance of hair cell regeneration in the mammalian cochlea and contribute to the development of a clinical therapy for sensorineural deafness involving the combined use of cochlear implantation with cell replacement therapy.