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

开发 Kv1.3 通道阻滞剂 ShK-186 作为多发性硬化症的治疗方法

• 批准号: 7801083
• 负责人: Shawn Patrick Iadonato
• 金额: $ 29.94万
• 依托单位: KINETA, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7801083
• 关键词: Acute; Adoptive Transfer; Affect; American; Animal Behavior; Animal Model; Antibodies; Antibody Formation; Antigen-Presenting Cells; Arthritis; Autoimmune Diseases; Autoimmune Process; Biological Assay; Bone Resorption; Calcium Signaling; California; Cardiotoxicity; Caribbean region; Cell Communication; Cell Enlargement; Cells; Cheilitis Granulomatosa; Chemistry; Chronic; Clinical Trials; Conscious; Contact Dermatitis; Delayed Hypersensitivity; Development; Disease; Dose; Drug Delivery Systems; Electrocardiogram; Enzyme-Linked Immunosorbent Assay; Exhibits; Experimental Autoimmune Encephalomyelitis; Frequencies; Goals; Helianthus; Hematology; Histology; Human; Immune; Immune response; Immune system; Immunization; In Vitro; Individual; Insulin-Dependent Diabetes Mellitus; Investigational Drugs; Investigational New Drug Application; Kv1.3 potassium channel; Length; Maintenance; Maximum Tolerated Dose; Mediating; Mediator of activation protein; Memory; Mitogens; Modeling; Multiple Sclerosis; NOEL; Nervous System Trauma; Neurologic; No-Observed-Adverse-Effect Level; Organ; Patients; Peptides; Periodontitis; Pharmaceutical Preparations; Physiologic pulse; Play; Population; Potassium Channel Blockers; Preparation; Pristane; Production; Property; Publishing; Pustular psoriasis; Rattus; Relapse; Relapsing-Remitting Multiple Sclerosis; Reporting; Research Design; Rheumatoid Arthritis; Role; Safety; Schedule; Sea Anemones; Serum; Severities; Specificity; Sprague-Dawley Rats; Synovial Fluid; T memory cell; T-Lymphocyte Subsets; Telemetry; Therapeutic; Thymidine; Time; Tissues; Toxic effect; Toxicology; United States Food and Drug Administration; Universities; Viral; Weight; analog; base; cell motility; channel blockers; chronic graft versus host disease; chronic-relapsing EAE; cytokine; design; disabling disease; disorder later incidence prevention; drug candidate; drug efficacy; food consumption; in vivo; inhibitor/antagonist; lupus cutaneous; meetings; migration; neutralizing antibody; novel; patch clamp; pathogen; patient population; peptide analog; peripheral blood; pre-clinical; preclinical study; prevent; programs; public health relevance; receptor; small molecule; treatment duration

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: This project involves the development of a drug, ShK-186, to treat multiple sclerosis and other autoimmune diseases. The drug targets a specific population of immune cells termed "effector memory T cells".

描述（由申请人提供）：多发性硬化症 (MS) 影响着大约 400,000 名美国人，是一种进行性、致残性疾病，目前的治疗方法不足以治疗这种疾病。该申请描述了 ShK-186 的非临床开发，ShK-186 是一种新型 Kv1.3 钾通道抑制剂，针对 MS 中的效应记忆 T 细胞 (TEM) 群体。 TEM 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，并且已在 MS、类风湿性关节炎和 1 型糖尿病患者的中枢神经系统、滑液和外周血中发现了自身反应性 Kv1.3 依赖性 TEM 细胞。 ShK-186 是由加州大学欧文分校的 George Chandy 博士（联合 PI）和他的团队发现的。该药物由华盛顿州西雅图的 KINETA Inc. 进行商业开发。 ShK-186 以皮摩尔效力抑制 Kv1.3 钾通道功能，并减少有丝分裂原刺激的细胞因子产生、[3H]-胸苷掺入、细胞运动和 TEM 细胞与抗原呈递细胞的相互作用。此外，ShK-186 及其密切相关的类似物 ShK-170 已被证明可以预防和治疗多种自身免疫动物模型中的疾病，包括过继转移实验性自身免疫性脑炎 (EAE)、免疫介导的慢性复发性 EAE (CR-EAE) 和降植烷诱导的关节炎。 ShK-186 在临床前动物模型中（包括在大鼠中进行的 28 天重复剂量毒性研究）表现出出色的耐受性和安全性。该药物在受体分析研究中表现出对 Kv1.3 优异的特异性，并且没有证据表明存在心脏毒性，包括在意识大鼠的心电图遥测研究中。本申请将进行：(1) CR-EAE 模型中的进一步临床前研究，以更好地确定剂量、剂量频率和治疗周期与药物疗效之间的关系，(2) 大鼠 GLP 耐受性和毒理学研究，以支持 ShK-186 向食品和药物管理局提交研究性新药申请，以及 (3) 准备 IND 前和 IND 提交文件。这个为期两年的计划的主要里程碑是向 FDA 提交了 IND 申请，旨在支持 ShK-186 的首次人体临床试验。 公共健康相关性：该项目涉及开发一种药物 ShK-186，用于治疗多发性硬化症和其他自身免疫性疾病。该药物针对称为“效应记忆 T 细胞”的特定免疫细胞群。