Preclinical evaluation of an otoprotectant TT002

项目摘要 Ting Treateutics LLC是一家制药公司，开发预防和治疗听力损失的药物。 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。 在40%-60%的患者中。到目前为止，还没有药物被食品和药物管理局批准用于 预防顺铂所致听力损失(CIHL)。大多数候选化合物目前处于临床前和 临床试验与抗氧化剂、维生素和谷胱甘肽代谢有关，其中许多是钠 硫代硫酸盐，干扰顺铂杀死肿瘤细胞的能力。我们已经不偏不倚地在Silico Virtual. 筛选针对CIHL的耳保护剂，并确定了20种FDA批准的药物，包括TT002，被称为 氯硝柳胺，一种驱虫药(肠道蠕虫)，在世界各地的人类使用了近40年。体外：TT002 在耳蜗细胞系中对顺铂损伤的保护水平与坎帕隆相当， 0.17μM的IC50值，大大(&gt；10倍)低于并好于其他四种基准耳保护剂。此外， TT002不干扰顺铂的体外抗癌活性。体内：TT002减轻成人听力损失 顺铂(30 mg/kg，1次，10 mg/kg/d，ip，共4次)处理小鼠 连续几天。有趣的是，TT002对成人FVB的NIHL(100dBSPL 8-16 kHz持续2小时)也有保护作用 小鼠连续4d ip 10 mg/kg/d。在此SBIR第二阶段中，我们将执行 TT002TT002‘S对顺铂体内杀伤作用的新药使能实验研究 并进行疗效研究，以确定最佳给药方案和治疗指数。长期目标 TT002将成为以顺铂为基础的治疗的标准耳保护药物。为此，我们将 在顺铂耳毒性小鼠模型中展示TT002的S疗效，该模型模仿给药方案 癌症患者(目标1)。我们将测定血液中的药代动力学和药效学特征 外淋巴，以及对顺铂致聋豚鼠模型的疗效(目标2)。这一目标将是 根据与独立和声誉良好的合同研究机构特纳科学公司的合同执行 有限责任公司最后，我们将在体外测试药物与药物的相互作用，并在体内验证TT002不会干扰 顺铂在小鼠模型异种移植瘤中的抗癌活性(目标3)。通过成功完成这些研究， Ting Treateutics将获得启动研究性新药使能所需的关键数据 投诉临床前研究和随后的临床试验。Ting治疗公司已提交专利合作申请 美国和国际权利的条约(PCT)。这项提案的完成将使Ting Treeutics 启动与制药公司和风险投资公司的谈判，以实现其商业化 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.