Therapeutic Potential of the Potassium Channel Inhibitor SHK-186 for Pediatric Lupus

钾通道抑制剂 SHK-186 对小儿狼疮的治疗潜力

• 批准号: 9046007
• 负责人: Peter Probst
• 金额: $ 22.5万
• 依托单位: KINETA, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-10 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9046007
• 关键词: Adverse effects; Affect; Animal Model; Antibodies; Antigen-Antibody Complex; Atopic Dermatitis; Atypical lymphocyte; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Biological Assay; Biopsy; Blood Circulation; Blood specimen; CD28 gene; CD3 Antigens; CD8B1 gene; Calcium; Cells; Chronic; Clinical Trials; Complication; Data; Defect; Dependence; Deposition; Disease; Etiology; Evaluation; Female; Flow Cytometry; Frequencies; Generic Drugs; Glomerulonephritis; Goals; Human; Immune Cell Activation; Immune response; Immune system; Immunohistochemistry; Infection; Infiltration; Inflammation; Inflammatory; Interleukin-2; Intestines; Ion Channel; Ionophores; Kidney; Left; Life; Lupus; Lupus Nephritis; Malignant Neoplasms; Measurement; Mononuclear; Names; Nature; Organ; Organ failure; Pathogenesis; Patients; Pattern; Peptides; Peripheral Blood Mononuclear Cell; Personal Communication; Play; Potassium Channel; Prevention; Production; Proteins; Protocols documentation; Psoriasis; Psoriatic Arthritis; Regulatory T-Lymphocyte; Role; Signal Transduction; Staining method; Stains; Systemic Lupus Erythematosus; T memory cell; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Urine; autoreactive T cell; base; chemokine; cytokine; drug candidate; inhibitor/antagonist; macrophage; novel; novel therapeutics; patient population; pediatric lupus; peripheral blood; pre-clinical; public health relevance; release of sequestered calcium ion into cytoplasm; response; targeted biomarker

 DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease with poorly understood etiology and pathogenesis and for which adequate treatment options are limited. Although dysregulated production of autoantibodies and immune complex deposition are considered hallmarks of SLE, considerable evidence supports the hypothesis that auto reactive lymphocytes are implicated in disease. SLE patients have several T cell defects including aberrant signaling, suboptimal IL-2 production, lower regulatory T cell frequencies, high CD4-/CD8- Th17 T cells, and sustained abnormally high intracellular calcium. Effector memory T cells (TEMs) decrease in circulation and increase in the kidneys and urine of lupus nephritis patients, suggesting that renal infiltration of this T ell subtype contributes to disease. Activation and inflammatory cytokine production by effector memory T cells requires expression of Kv1.3, a potassium channel needed for sustained intracellular calcium levels in effector memory T cells that have been found to be autoreactive and pathogenic in several autoimmune diseases. Here we propose to evaluate the levels of expression of Kv1.3 in SLE T cells in peripheral blood of inactive and active SLE patients compared to normal healthy controls, and test the functional effect of blocking the Kv1.3 channels in these cells with Kineta's drug candidate Kv1.3 specific peptide blocker ShK-186 (dalazatide) in terms of calcium flux and cytokine production ex vivo. In addition, we will evaluate Kv1.3 expression in kidney biopsies from patients with lupus nephritis and correlate expression to disease activity. This study will inform our hypothesis that Kv1.3 expressing T cells are pathogenic in SLE and may support considering evaluation of ShK- 186 in SLE patient populations in clinical trials.

 描述（由适用提供）：全身性红斑狼疮（SLE）是一种慢性多系统自身免疫性疾病，病因学和发病机理知之甚少，适当的治疗方案受到限制。尽管自身抗体和免疫复合物沉积的产生失调被认为是SLE的标志，但大量证据支持了以下假设：疾病中实施了自身反应性淋巴细胞。 SLE患者有几个T细胞缺陷，包括异常信号，IL-2产生次优，调节性T细胞频率较低，CD4-/CD8-TH17 T细胞以及细胞内钙的持续高度。效应子记忆T细胞（TEMS）循环减少并增加狼疮肾炎患者的肾脏和尿液，这表明该亚型的肾脏浸润会导致疾病。通过效应记忆T细胞的激活和炎症性细胞因子的产生需要KV1.3的表达，KV1.3是效应记忆T细胞中持续细胞内钙水平所需的钾通道，在几种自身免疫性疾病中发现具有自动反应性和致病性。 Here we propose to evaluate the levels of expression of Kv1.3 in SLE T cells in peripheral blood of inactive and active SLE patients compared to normal healthy controls, and test the functional effect of blocking the Kv1.3 channels in these cells with Kineta's drug candidate Kv1.3 specific peptide blocker ShK-186 (dalazatide) in terms of calcium flux and cytokine production ex vivo.此外，我们将评估狼疮肾炎患者的肾脏活检中的KV1.3表达，并将其与疾病活性相关。这项研究将告知我们的假设，即KV1.3表达T细胞在SLE中是致病性的，并且可以在临床试验中考虑对SLE患者种群评估SHK-186。