Acoustic and electrical hearing after Math1 treatment

我们最近证明，在基因治疗后，哺乳动物的Corti器官中产生了新的内毛细胞(IHC)。具体地说，这些实验包括将带有Math 1基因的腺病毒载体体内接种到成熟的预聋豚鼠耳蜗中。我们还证明了新的毛细胞可以吸引神经元。经Maath 1治疗的前聋耳表现出部分功能恢复，如Preyer‘s Refex所确定的，以及听觉诱发听性脑干反应(ABR)阈值的显著改善。在目前的应用中，我们建议使用动物心理物理学技术来定义恢复的声学听力的性质和范围。我们还将进行有关将这种基因疗法与人工耳蜗术结合使用的实验。具体地说，在目标1和目标2中，我们将用耳毒性药物使豚鼠耳聋，用数学1治疗它们，并测量心理物理检测和辨别阈值以及ABR。在目标3中，我们将评估Ad.Math1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植入人工耳蜗，并评估在有和没有恢复IHC的情况下对电刺激的心理物理反应。 我们提议的实验涉及使用我们实验室中已经到位的技术。这项工作得到了强劲的初步数据的支持，代表了相对低风险和非常高影响的理想组合。拟议中的实验将使这种基因疗法的应用更接近临床应用。

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 Math 1 gene insert into the mature predeafened guinea pig cochlea. We have also demonstrated that the new hair cells can attract neurons. Predeafend ears treated with Math 1 exhibit partial restoration of function as determined by Preyer's refex and significant improvement in acoustically-evoked auditory brainstem response (ABR) threshods. In the current application we propose to use animal-psychophysics techniques to define the nature and extent of the restored acoustic hearing. We will also conduct experiments relevant to the use of this gene therapy in conjunction with cochlear implants. Specifically, in Aims 1 and 2 we will deafen guinea pigs with ototoxic drugs, treat them with Math 1 and measure psychophysical detection and discrimination thresholds as well as ABRs. In Aim 3, we will assess the interaction between Ad.Math 1 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 with and without restored IHCs. 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 bring this gene therapy application closer to clinical use.