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: 8053763
• 负责人: Shawn Patrick Iadonato
• 金额: $ 30万
• 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 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8053763
• 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; Lead; 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; receptor; small molecule; terminally differentiated effector memory (TEM) T cells; treatment duration

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.

多发性硬化症（MS）影响大约40万美国人，并构成一个渐进的，致残的， 目前的治疗方法不足以治疗的疾病。本申请描述了 ShK-186，一种新型Kv1.3钾通道抑制剂，靶向效应记忆T细胞（TEM）群体， 女士TEM细胞在与自身免疫性疾病相关的组织损伤中起着重要作用， 已在CNS、滑液和外周血中鉴定出自身反应性Kv1.3依赖性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PI）和他的团队在欧文的加州大学。这种药物正在研制中 由基内塔Inc.来自华盛顿州西雅图。ShK-186抑制Kv1.3钾通道功能， 皮摩尔效力，并减少促分裂原刺激的细胞因子产生，[3 H]-胸苷掺入，细胞 运动性和TEM细胞的抗原呈递细胞相互作用。此外，ShK-186及其密切相关的 类似物ShK-170已显示在许多自身免疫动物模型中预防和治疗疾病 包括过继性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已显示出极好的耐受性， 在临床前动物模型中的安全性，包括在大鼠中进行的28天重复给药毒性研究。药物 在受体分析研究中显示出对Kv1.3的极好特异性，并且没有证据表明心脏 毒性，包括在清醒大鼠的ECG遥测研究中。本申请将承担：（1）进一步 CR-EAE模型中的临床前研究，以更好地定义剂量、给药频率和 （2）大鼠GLP耐受性和毒理学研究，以支持研究性研究 ShK-186向美国食品药品监督管理局提交新药申请，以及（3）准备pre-IND和 IND提交文件。这个为期两年的项目的主要里程碑是向FDA提交IND 该应用旨在支持ShK-186的首次人体临床试验。