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; 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）：我们最近证明了基因治疗后，在Corti的哺乳动物器官中产生了新的内毛细胞（IHC）。具体而言，实验涉及将腺病毒载体与ATOH1基因插入物（AD.ATOH1）进行体内接种，以成熟的前衰落的豚鼠耳蜗。我们还证明了新的毛细胞可以吸引神经元。用ATOH1处理的预性耳朵表现出部分恢复功能的部分恢复，这是由猎物的反射和声学诱发的听觉脑干响应（ABR）阈值确定的。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措施来定义恢复的声学听力的性质和程度。我们还将进行与该ATOH1治疗与人工耳蜗植入物结合使用的实验。对于前两个具体目的，我们将用耳毒性药物对豚鼠倾斜，用ATOHL1对其进行治疗，并测量心理物理检测（AIM 1）和歧视（AIM 2）以及ABR和ABR和失真产物耳声发射（DPOAES）。在AIM 3中，我们将评估AD.ATOH1接种，人工耳蜗植入和对耳蜗植入物的电刺激之间的相互作用。在AIM 4中，我们将在接种的耳朵中放置一个耳蜗植入物，并评估对电刺激的心理物理反应以及具有和没有恢复IHC的电诱发的复合动作电位（ECAP）。具有某些存活的毛细胞（即，植入但不淡化的动物）的对照将与具有恢复毛细胞的动物进行比较。我们提出的实验涉及我们实验室中已经存在的技术的使用。这项工作得到了强大的初步数据的支持，代表了相对较低风险和影响很高的理想组合。提出的实验将增强我们对哺乳动物耳蜗中毛细胞再生的功能意义的理解，并有助于开发一种临床治疗，以进行感觉神经性耳聋，涉及与细胞替代治疗的耳蜗植入的联合使用。