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.

Public Health Relevance

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. 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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC010204-04
Application #
8288297
Study Section
Special Emphasis Panel (ZDC1-SRB-R (23))
Program Officer
Freeman, Nancy
Project Start
2009-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$315,647
Indirect Cost
$112,004
Name
Emory University
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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Yuan, Yongyi; Zhang, Jianguo; Chang, Qing et al. (2014) De novo mutation in ATP6V1B2 impairs lysosome acidification and causes dominant deafness-onychodystrophy syndrome. Cell Res 24:1370-3
Zhang, Zhentao; Liu, Xia; Schroeder, Jason P et al. (2014) 7,8-dihydroxyflavone prevents synaptic loss and memory deficits in a mouse model of Alzheimer's disease. Neuropsychopharmacology 39:638-50
Liu, Xia; Qi, Qi; Xiao, Ge et al. (2013) O-methylated metabolite of 7,8-dihydroxyflavone activates TrkB receptor and displays antidepressant activity. Pharmacology 91:185-200
Obianyo, Obiamaka; Ye, Keqiang (2013) Novel small molecule activators of the Trk family of receptor tyrosine kinases. Biochim Biophys Acta 1834:2213-8
Uluc, Kutluay; Kendigelen, Pýýnar; Fidan, Emin et al. (2013) TrkB receptor agonist 7, 8 dihydroxyflavone triggers profound gender- dependent neuroprotection in mice after perinatal hypoxia and ischemia. CNS Neurol Disord Drug Targets 12:360-70
Yu, Qing; Chang, Qing; Liu, Xia et al. (2013) Protection of spiral ganglion neurons from degeneration using small-molecule TrkB receptor agonists. J Neurosci 33:13042-52
Johnson, Rebecca A; Lam, Maxine; Punzo, Antonio M et al. (2012) 7,8-dihydroxyflavone exhibits therapeutic efficacy in a mouse model of Rett syndrome. J Appl Physiol 112:704-10
Qu, Yan; Tang, Wenxue; Zhou, Binfei et al. (2012) Early developmental expression of connexin26 in the cochlea contributes to its dominate functional role in the cochlear gap junctions. Biochem Biophys Res Commun 417:245-50
Lin, Xi (2011) Perception of sound and gravity by TMC1 and TMC2. J Clin Invest 121:4633-6