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Auditory Neuroprotection by Small Molecule Agonists of the TrkB Receptor

TrkB 受体小分子激动剂的听觉神经保护作用

基本信息

批准号：
8494606
负责人：
XI LIN
金额：
$ 29.99万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8494606
关键词：
Adverse effects Agonist Animal Model Animals Auditory Basic Science Blood - brain barrier anatomy Brain-Derived Neurotrophic Factor Cavia Clinical Clinical Trials Cochlea Cochlear Implants Data Drug Delivery Systems Drug Kinetics Funding Goals Grant Hair Cells Human In Vitro Infusion procedures Intraperitoneal Injections Investigational New Drug Application Knockout Mice Modeling Mus Mutation Nerve Degeneration Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Organ Paper Patients Performance Pharmaceutical Preparations Phase Property Publishing Research Residual state Sensorineural Hearing Loss Series Structure Testing Time Toxic effect Translations United States Food and Drug Administration Wallerian Degeneration Work base deafness dosage drug discovery effective therapy efficacy testing in vitro Assay in vitro testing in vivo in vivo Model interest mimetics mouse model neuroprotection neurotrophic factor patch clamp pre-clinical preclinical study prevent small molecule spiral ganglion

项目摘要

DESCRIPTION (provided by applicant): Exogenous application of neurotrophins rescues spiral ganglion (SG) neurons from degeneration resulted from the loss of cochlear hair cells. Since the survival of SG neurons is the basis for cochlear implants to work, these encouraging results have stimulated enormous interest in translation-oriented research aiming at applying exogenous neurotrophin(s) to the human cochlea to promote the survival of residual SG neurons in the cochlea of severe sensorineural hearing loss patients. However, none of these studies have advanced to the phase of clinical trials twelve years after the first series of papers were published. One of the major hurdles hindering the clinical translation is how to achieve long-term, recurring and safe deliveries at desired dosage into the cochlea. We have recently identified a number of high-potency small mimetic molecules of brain derived neurotrophic factor. These compounds readily crossed the blood brain barrier and into the cochlea. They activated TrkB receptors at extremely low concentrations. One of the most potent compounds, 7,8- dihydroxyflavone (7,8-DHF), effectively activated the TrkB receptor at less than 100 nM. The compound also demonstrated effective neuroprotective effects in a number of in vivo models. Most relevant to this project, we have obtained preliminary data showing that systemic application of 7,8-DHF by intraperitoneal injections dramatically protected SG neurons from degeneration without any obvious side effects in mice. The data were acquired from a mouse model of human deafness caused by connexin26 (Cx26) mutations, which is the most common cause of prelingual non-syndromic deafness in humans. These results raise the hope of overcoming the major hurdle of drug delivery for the translation of the auditory neuroprotective effect to benefit patients. This grant seeks support to test the efficacy of 7,8-DHF in both in vitro assay and in vivo animal models, and to conduct preclinical trials for the compound to determine its toxicity and pharmacokinetics. By finishing the specific aims proposed in the project, we will be able to collect crucial preclinical data required for filing an investigational new drug (IND) application with the food and drug administration (FDA) at the end of the funding period. This grant seeks support to test the efficacy of 7,8-DHF in both in vitro assay and in vivo animal models, and to conduct preclinical trials for the compound to determine its toxicity and pharmacokinetics. Our specific aims are: Specific aim 1: We will perform in vitro tests of 7,8-DHF to determine its efficacy in promoting the survival of SG neurons cultured in defined media. We will also test whether 7,8-DHF and depolarization have synergistic effects on the survival of SG neurons in vitro. Specific aim 2: Test the efficacy of 7,8-DHF in vivo for protecting SG neurons against degeneration in conditional Cx26 null mouse models. Specific aim 3: Test the efficacy of 7,8-DHF in vivo for protecting SG neurons against degeneration in a guinea pig model deafened by ototoxic drugs. Specific aim 4: In this specific aim we will perform FDA required preclinical trials for the compound, 7,8-DHF, to obtain organ targeting, toxicity, systemic side effects and pharmacokinetic information for the drug. By finishing these specific aims, we will be able to collect crucial preclinical data required for filing an investigational new drug (IND) application with the food and drug administration (FDA) at the end of the funding period.

描述(申请人提供)：外源性应用神经营养因子可使螺旋神经节(SG)神经元免于因耳蜗毛细胞的丧失而变性。由于SG神经元的存活是人工耳蜗植入物发挥作用的基础，这些令人鼓舞的结果激发了人们对翻译导向研究的极大兴趣，该研究旨在将外源性神经营养因子(S)应用于人耳蜗组织，以促进重度感音神经性耳聋患者耳蜗中残留的SG神经元的存活。然而，在第一系列论文发表12年后，这些研究都没有进入临床试验阶段。阻碍临床翻译的主要障碍之一是如何以所需的剂量实现长期、反复和安全的耳蜗腔内给药。我们最近发现了一些高效的脑源性神经营养因子的小分子模拟分子。这些化合物很容易穿过血脑屏障，进入耳蜗。他们在极低浓度下激活了TrkB受体。其中最有效的化合物之一，7，8-二羟基黄酮(7，8-DHF)，能在不到100 nM的范围内有效地激活TrkB受体。该化合物在许多体内模型中也显示了有效的神经保护作用。与这个项目最相关的是，我们已经获得了初步数据，表明通过腹膜腔注射全身应用7，8-DHF可以显著保护小鼠脑海马神经元免于变性，而没有任何明显的副作用。这些数据是从连接蛋白26(Cx26)突变引起的人类耳聋的小鼠模型中获得的，连接蛋白26(Cx26)突变是人类语前非综合征耳聋的最常见原因。这些结果带来了克服药物传递的主要障碍，将听觉神经保护作用转化为造福患者的希望。这笔赠款寻求支持，以测试7，8-DHF在体外和体内动物模型中的有效性，并对该化合物进行临床前试验，以确定其毒性和药代动力学。通过完成项目中提出的具体目标，我们将能够收集在资助期结束时向食品和药物管理局(FDA)提交研究用新药(IND)申请所需的关键临床前数据。这笔赠款寻求支持，以测试7，8-DHF在体外和体内动物模型中的有效性，并对该化合物进行临床前试验，以确定其毒性和药代动力学。我们的具体目标是：特定目标1：我们将进行7，8-DHF的体外实验，以确定其促进在特定介质中培养的SG神经元存活的有效性。我们还将测试7，8-DHF和去极化是否对体外培养的SG神经元的存活有协同作用。具体目的2：检测7，8-DHF对条件性Cx26缺失型小鼠海马神经元变性的保护作用。具体目的3：在耳毒性药物致聋的豚鼠模型上，检测7，8-DHF对SG神经元变性的保护作用。具体目标4：在这个特定目标中，我们将对化合物7，8-DHF进行FDA要求的临床前试验，以获得该药物的器官靶向性、毒性、全身副作用和药代动力学信息。通过完成这些具体目标，我们将能够收集在资助期结束时向食品和药物管理局(FDA)提交研究新药(IND)申请所需的关键临床前数据。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Optimization of a small tropomyosin-related kinase B (TrkB) agonist 7,8-dihydroxyflavone active in mouse models of depression.

DOI：
10.1021/jm301099x
发表时间：
2012-10-11
期刊：
JOURNAL OF MEDICINAL CHEMISTRY
影响因子：
7.3
作者：
Liu, Xia;Chan, Chi-Bun;Qi, Qi;Xiao, Ge;Luo, Hongbo R.;He, Xiaolin;Ye, Keqiang
通讯作者：
Ye, Keqiang

Novel small molecule activators of the Trk family of receptor tyrosine kinases.