权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Preclinical evaluation of an otoprotectant TT002

耳保护剂 TT002 的临床前评估

基本信息

批准号：
10671525
负责人：
Yunlong Huang
金额：
$ 56.58万
依托单位：
TING THERAPEUTICS LLC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10671525
关键词：
Adult Aftercare Animal Model Animals Anthelmintics Antineoplastic Agents Antioxidants Attenuated Audiology Auditory Auditory Brainstem Responses Authorization documentation Benchmarking Blood Cancer Patient Cancer cell line Cavia Cell Line Cestoda Chemicals Cisplatin Clinical Clinical Treatment Clinical Trials Cochlea Contracts Data Detection Dose Drug Interactions Drug Kinetics Drug Screening Drug usage FDA approved FVB Mouse Food and Drug Administration Drug Approval Freedom Future Germany Glutathione Metabolism Pathway Goals Hair Cells Hearing Protection Human Immunohistochemistry In Vitro International Investigational Drugs Investments Knowledge Labyrinth Legal patent Liquid Chromatography Malignant Neoplasms Malignant neoplasm of testis Measures Morphology Mus New Drug Approvals Observational Study Oral Administration Outcome Patients Performance Perilymph Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Phase Procedures Protocols documentation Publishing Quality of life Regimen Research Contracts Rights Rodent Model Safety Small Business Innovation Research Grant Sodium Chloride Testing Therapeutic Therapeutic Index Time Toxic effect Toxicology Treaty United States Food and Drug Administration Western Blotting Work Xenograft Model Zebrafish anticancer activity authority chemotherapy cisplatin induced hearing loss commercial application commercialization design drug testing efficacy study experimental study good laboratory practice guinea pig model healthy volunteer hearing impairment hearing preservation in silico in vitro activity in vivo intraperitoneal manufacture mouse model neoplastic cell novel therapeutics otoacoustic emission otoprotectant ototoxicity pharmacokinetics and pharmacodynamics pharmacologic phase 1 study preclinical development preclinical evaluation preclinical study preclinical trial prevent prevent hearing loss research clinical testing safety and feasibility sodium thiosulfate technological innovation tumor tumor xenograft virtual vitamin metabolism webinar

项目摘要

Project Summary Ting Therapeutics LLC is a pharmaceutical company developing drugs to prevent and treat hearing loss. Cisplatin is one of the most widely used drugs to treat cancers. However, cisplatin therapy causes hearing loss in 40-60% of the patients. To date, no drugs have been approved by the Food and Drug Administration for protection from cisplatin-induced hearing loss (CIHL). Most candidate compounds currently in pre-clinical and clinical trials are related to antioxidants, vitamins, and glutathione metabolism, many of which, such as sodium thiosulfate, interfere with cisplatin’s ability to kill the tumor cells. We have performed unbiased in silico virtual screens for otoprotectants against CIHL and identified 20 FDA-approved drugs including TT002, known as niclosamide, an anthelmintic (gut worm) drug used in humans world-wide for nearly four decades. In vitro: TT002 showed a comparable level of protection against cisplatin damage in a cochlear cell line to kenpaullone, with an IC50 of 0.17 μM, substantially (>10X) lower and better than four other benchmark otoprotectants. Moreover, TT002 did not interfere with cisplatin anti-cancer activity in vitro. In vivo: TT002 attenuates hearing loss in adult mice treated with cisplatin (30 mg/kg once) when delivered intraperitoneally (IP) at 10 mg/kg/day for 4 consecutive days. Interestingly, TT002 also protects against NIHL (100 dB SPL 8-16 kHz for 2 hrs) in adult FVB mice when delivered IP at 10 mg/kg/day for 4 consecutive days. In this SBIR Phase II, we will perform Investigational New Drug-enabling experiments to test TT002’s effect on cisplatin’s tumor killing efficacy in vivo and to conduct efficacy studies to define an optimal dosing regimen and therapeutic index. The long-term goal is for TT002 to become a standard otoprotective drug of cisplatin-based therapies. For this purpose, we will demonstrate TT002’s efficacy in a mouse model of cisplatin ototoxicity that mimics the administration protocol in cancer patients (Aim 1). We will determine pharmacokinetics and pharmacodynamics profiles in blood and perilymph, as well as efficacy, in a guinea pig model for cisplatin-induced hearing loss (Aim 2). This Aim will be performed under contract with an independent and reputable Contract Research Organization, Turner Scientific LLC. Finally, we will test drug-drug interactions in vitro and we will verify, in vivo, that TT002 does not interfere with cisplatin’s anti-cancer activity in mouse model xenografts (Aim 3). By successfully completing these studies, Ting Therapeutics will obtain critical data necessary for the initiation of Investigational New Drug enabling complaint preclinical studies and subsequent clinical trials. Ting Therapeutics has filed a Patent Cooperation Treaty (PCT) for both the US and international rights. The completion of this proposal will allow Ting Therapeutics to initiate conversations with pharmaceutical companies and venture investments for the commercialization of TT002.

项目总结