Preclinical evaluation of an otoprotectant TT002

项目摘要 Ting Therapeutics LLC是一家开发预防和治疗听力损失药物的制药公司。 顺铂是治疗癌症最广泛使用的药物之一。然而，顺铂治疗会导致听力损失， 40-60%的患者。到目前为止，食品和药物管理局还没有批准用于 预防顺铂引起的听力损失（CIHL）。大多数候选化合物目前处于临床前和 临床试验涉及抗氧化剂，维生素和谷胱甘肽代谢，其中许多，如钠 硫代硫酸盐，干扰顺铂杀死肿瘤细胞的能力。我们在计算机虚拟环境中进行了无偏测试 筛选针对CIHL的耳保护剂，并确定了20种FDA批准的药物，包括TT 002，称为 氯硝柳胺，一种在世界范围内用于人类近四十年的驱虫药（肠道蠕虫）。体外：TT 002 在耳蜗细胞系中显示出与kenpaullone相当的对顺铂损伤的保护水平， IC 50为0.17 μM，比其他四种基准耳保护剂低得多（> 10倍）。此外，委员会认为， TT 002不干扰顺铂的体外抗癌活性。在体内：TT 002减轻成人听力损失 当以10 mg/kg/天腹膜内（IP）递送顺铂（30 mg/kg，一次）4 连续几天。有趣的是，TT 002还可以保护成人FVB免受NIHL（100 dB SPL 8-16 kHz，2小时） 以10 mg/kg/天IP给药，连续4天。在SBIR第二阶段，我们将执行 用于测试TT 002对顺铂体内肿瘤杀伤效力的影响的研究性新药使能实验 并进行功效研究以确定最佳给药方案和治疗指数。远景目标 TT 002成为顺铂类药物治疗的标准耳保护药物。为此，我们将 证明了TT 002在顺铂耳毒性小鼠模型中的疗效，该模型模拟了 癌症患者（目标1）。我们将确定血液中的药代动力学和药效学特征， 外淋巴液，以及疗效，在豚鼠模型顺铂诱导的听力损失（目的2）。这一目标将是 根据与独立且信誉良好的合同研究组织Turner Scientific签订的合同进行 LLC.最后，我们将在体外测试药物-药物相互作用，并在体内验证TT 002不会干扰 在小鼠模型异种移植物中具有顺铂的抗癌活性（Aim 3）。通过成功完成这些研究， Ting Therapeutics将获得启动研究性新药启用所需的关键数据 投诉临床前研究和后续临床试验。Ting Therapeutics已申请专利合作 PCT条约（PCT）适用于美国和国际权利。该提案的完成将使汀治疗 启动与制药公司和风险投资的对话， TT002。

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.