Acoustic and electrical hearing after Atoh1 treatment

Atoh1 治疗后的声学和电学听力

• 批准号: 7792310
• 负责人: BRYAN E PFINGST
• 金额: $ 29.25万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7792310
• 关键词: Acoustic Nerve; Acoustic Stimulation; Acoustics; Action Potentials; Adenovirus Vector; Aminoglycosides; Animals; Apical; Area; Audiometry; Auditory; Auditory Brainstem Responses; Back; Behavioral; Cavia; Cell Survival; Cells; Clinical; Cochlea; Cochlear Implants; Cochlear implant procedure; Combined Modality Therapy; Complement; Control Animal; Control Groups; Cues; Data; Detection; Development; Differential Threshold; Discrimination; Ear; Electric Stimulation; Esthesia; Ethacrynic Acid; Evoked Potentials, Auditory, Brain Stem; Exhibits; Frequencies; Genes; Hair Cells; Health; Hearing; Histology; Implant; Injection of therapeutic agent; Inner Hair Cells; Kanamycin; Laboratories; Lead; Left; Lesion; Location; Measures; Morphology; Nature; Neurons; Noise; Organ of Corti; Performance; Peripheral; Pharmaceutical Preparations; Physiological; Population; Positioning Attribute; Procedures; Process; Psychophysics; Psychophysiology; Recovery; Reflex action; Relative (related person); Replacement Therapy; Risk; Sensorineural Hearing Loss; Site; Stereocilium; Stimulus; System; Techniques; Testing; Time; Tissues; Viral Vector; Visual; Work; auditory pathway; base; combination gene therapy; comparison group; ganglion cell; gene therapy; hair cell regeneration; implantation; improved; in vivo; nerve supply; otoacoustic emission; relating to nervous system; research study; response; restoration; spiral ganglion; tectorial membrane; visual stimulus

DESCRIPTION (provided by applicant): 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 Atoh1 gene insert (Ad.Atoh1) into the mature predeafened guinea pig cochlea. We have also demonstrated that the new hair cells can attract neurons. Predeafened ears treated with Atoh1 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 Atoh1 therapy in conjunction with cochlear implants. For the first two specific aims we will deafen guinea pigs with ototoxic drugs, treat them with Atohl1 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 Ad.Atoh1 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.

描述（由申请人提供）：我们最近证明，在基因治疗后，哺乳动物的柯蒂氏器官中会产生新的内毛细胞（IHC）。具体来说，实验涉及将带有 Atoh1 基因插入片段 (Ad.Atoh1) 的腺病毒载体体内接种到成熟的预聋豚鼠耳蜗中。我们还证明新的毛细胞可以吸引神经元。根据 Preyer 反射和声诱发听觉脑干反应 (ABR) 阈值确定，用 Atoh1 治疗的预耳聋耳朵表现出部分功能恢复。在当前的应用中，我们建议使用动物心理物理学技术和生理测量来定义恢复听觉的性质和程度。我们还将进行与 Atoh1 疗法与人工耳蜗结合使用相关的实验。对于前两个具体目标，我们将用耳毒性药物使豚鼠致聋，用 Atohl1 治疗它们，并测量心理物理检测（目标 1）和歧视（目标 2）以及 ABR 和失真产物耳声发射 (DPOAE)。在目标 3 中，我们将评估 Ad.Atoh1 接种、人工耳蜗植入和人工耳蜗电刺激之间的相互作用。在目标 4 中，我们将在接种的耳朵中放置人工耳蜗，并评估在有或没有恢复 IHC 的情况下对电刺激和电诱发复合动作电位 (ECAP) 的心理物理反应。具有一些幸存毛细胞的对照（即植入但未预耳聋的动物）将用于与具有恢复毛细胞的动物进行比较。我们建议的实验涉及使用我们实验室中已有的技术。这项工作得到了强有力的初步数据的支持，代表了相对低风险与极高影响力的理想组合。拟议的实验将增强我们对哺乳动物耳蜗毛细胞再生功能意义的理解，并有助于开发感音神经性耳聋的临床疗法，包括耳蜗植入与细胞替代疗法的联合使用。