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

 描述(申请人提供)：系统性红斑狼疮(SLE)是一种慢性多系统自身免疫性疾病，病因和发病机制知之甚少，适当的治疗选择有限。尽管自身抗体的异常产生和免疫复合体的沉积被认为是系统性红斑狼疮的特征，但相当多的证据支持自身反应性淋巴细胞与疾病有关的假设。SLE患者存在多种T细胞缺陷，包括信号异常、IL-2分泌不足、调节性T细胞频率降低、高CD4-/CD8-Th17T细胞和持续异常高的细胞内钙。狼疮性肾炎患者循环中效应记忆T细胞减少，肾脏和尿液中的效应记忆T细胞增多，提示该T细胞亚型的肾脏浸润参与了疾病的发生。效应记忆T细胞的激活和炎性细胞因子的产生需要Kv1.3的表达，Kv1.3是维持效应记忆T细胞内钙水平所必需的钾通道，已被发现在几种自身免疫性疾病中具有自身反应和致病作用。本研究旨在检测静止期和活动期SLE患者外周血中Kv1.3的表达水平，并检测Kineta的候选药物Kv1.3特异性多肽阻滞剂ShK-186(达拉扎肽)对这些细胞中Kv1.3通道的阻断作用及其对钙离子流量和细胞因子产生的影响。此外，我们还将评估Kv1.3在狼疮性肾炎患者肾活检组织中的表达及其与疾病活动性的相关性。这项研究将提供我们的假设，即表达Kv1.3的T细胞在SLE中是致病的，并可能支持在临床试验中评估ShK-186在SLE患者群体中的应用。

 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.