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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

基本信息

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
项目类别：
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

项目摘要

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.