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

 描述（由申请人提供）：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，充分的治疗选择有限。尽管自身抗体和免疫复合物沉积的失调被认为是SLE的标志，但大量证据支持自身反应性淋巴细胞与疾病有关的假设。SLE患者有几种T细胞缺陷，包括异常信号传导、次优IL-2产生、较低的调节性T细胞频率、高CD 4-/CD 8-Th 17 T细胞和持续异常高的细胞内钙。效应记忆T细胞（TEM）在狼疮性肾炎患者的循环中减少，而在肾脏和尿液中增加，表明这种T细胞亚型的肾脏浸润有助于疾病。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是效应记忆T细胞中维持细胞内钙水平所需的钾通道，已发现其在几种自身免疫性疾病中具有自身反应性和致病性。在这里，我们建议评估与正常健康对照相比，非活动性和活动性SLE患者外周血中SLE T细胞中Kv1.3的表达水平，并测试用基内塔的候选药物Kv1.3特异性肽阻断剂ShK-186（达拉奉）阻断这些细胞中Kv1.3通道在离体钙通量和细胞因子产生方面的功能效果。此外，我们将评估狼疮性肾炎患者肾活检组织中Kv1.3的表达，并将其与疾病活动性相关。这项研究将告知我们的假设，即表达Kv1.3的T细胞在SLE中是致病性的，并可能支持在临床试验中考虑在SLE患者群体中评估ShK- 186。

 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.