Development of Kv1.3 channel blocker ShK-186 as a therapy for multiple sclerosis

多发性硬化症(MS)影响着大约400,000美国人，构成了一种进行性的、致残的 目前的治疗方法不足以治疗的疾病。这项申请描述了非临床的发展 Shk-186，一种新的Kv1.3钾通道抑制剂，靶向效应记忆T细胞(TEM)群体 透射电子显微镜细胞在与自身免疫性疾病相关的组织损伤中发挥着重要作用，并且 在中枢神经系统、滑液和外周血中发现了依赖于Kv1.3的自身反应性的TEM细胞。 MS、类风湿性关节炎和1型糖尿病患者。Shk-186是由乔治博士发现的 钱迪(合作者)和他的团队在加州大学欧文分校工作。这种药物正在开发中。 由华盛顿州西雅图的Kineta Inc.商业使用。ShK-186通过抑制Kv1.3钾通道功能 皮摩尔效应和减少有丝分裂原刺激的细胞因子的产生，[~3H]-胸腺嘧啶核苷掺入，细胞 运动，和抗原提呈细胞之间的相互作用的透射电镜细胞。此外，ShK-186及其密切相关的 类似物ShK-170已经在许多自身免疫动物模型中被证明可以预防和治疗疾病 包括过继转移实验性自身免疫性脑炎(EAE)、免疫介导、慢性 复发性EAE(CR-EAE)和Pristane诱导的关节炎。SHK-186表现出极好的耐受性和 在临床前动物模型中的安全性，包括在大鼠28天重复剂量毒性研究中。这种药 Kv1.3在受体图谱研究中表现出极好的特异性，而没有证据表明心脏 毒性，包括清醒大鼠的心电遥测研究。本申请将承担：(1)进一步 CR-EAE模型的临床前研究，以更好地确定剂量、剂量频率和 治疗周期对药物疗效的影响；(2)大鼠对GLP的耐受性和毒理学研究以支持研究 向食品药品监督管理局提交ShK-186新药申请，以及(3)前IND和 IND提交文件。这一为期两年的计划的主要里程碑是向FDA提交了IND 应用程序旨在支持ShK-186的首个人体临床试验。

Multiple sclerosis (MS) affects approximately 400,000 Americans and constitutes a progressive, disabling disease for which current therapies are inadequate. This application describes the nonclinical development of ShK-186, a novel Kv1.3 potassium channel inhibitor that targets the effector memory T cell (TEM) population in MS. TEM cells play a prominent role in the tissue damage associated with autoimmune disease, and autoreactive Kv1.3-dependent TEM cells have been identified in the CNS, synovial fluid, and peripheral blood of MS, rheumatoid arthritis, and type 1 diabetes mellitus patients. ShK-186 was discovered by Dr. George Chandy (co-PI) and his group at the University of California at Irvine. The drug is being developed commercially by KINETA Inc. of Seattle, WA. ShK-186 inhibits Kv1.3 potassium channel function with picomolar potency and reduces mitogen-stimulated cytokine production, [3H]-thymidine incorporation, cell motility, and antigen-presenting cell interaction by TEM cells. In addition, ShK-186 and its closely-related analog, ShK-170 have been shown to prevent and treat disease in a number of autoimmune animal models including adoptive-transfer experimental autoimmune encephalitis (EAE), immunization-mediated, chronic relapsing EAE (CR-EAE), and pristane-induced arthritis. ShK-186 has demonstrated excellent tolerability and safety in preclinical animal models including in a 28-day, repeat dose toxicity study in rat. The drug demonstrates excellent specificity for Kv1.3 in receptor profiling studies, and there is no evidence for cardiac toxicity including in ECG telemetry studies of conscious rats. The present application will undertake: (1) further preclinical studies in the CR-EAE model to better define the relationship between dose, dose frequency, and treatment period on drug efficacy, (2) GLP tolerability and toxicology studies in rat to support an Investigational New Drug application for ShK-186 to the Food and Drug Administration, and (3) preparation of the pre-IND and IND submission documents. The major milestone of this two-year program is the submission to FDA of an IND application intended to support first-in-human clinical trials of ShK-186.