Novel Therapy for Pemphigus Vulgaris by Treatment with a Cholinergic Agonist

胆碱能激动剂治疗寻常型天疱疮的新疗法

• 批准号: 7749075
• 负责人: SUSAN C WRIGHT
• 金额: $ 17.54万
• 依托单位: PANORAMA RESEARCH, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-06 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7749075
• 关键词: Acantholysis; Adrenal Cortex Hormones; Adverse effects; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Autoantibodies; Biological Assay; Biological Models; Bulla; Cessation of life; Cholinergic Agonists; Clinical; Clinical Trials; Cytokine Suppression; Development; Disease; Evaluation; Event; Future; GTS-21; Goals; Homeostasis; Immunoglobulin G; Immunosuppression; In Vitro; Interleukin-11; Lead; Life; Mediating; Mucous Membrane; Neonatal; Nicotinic Receptors; Pathway interactions; Patients; Pemphigus; Pemphigus Vulgaris; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phosphorylation; Process; Production; Refractory; Research; Sepsis; Serum; Signal Transduction; Signal Transduction Pathway; Skin; Specialist; Stratum Basale; System; Testing; Work; acetylcholine receptor agonist; base; cholinergic; chronic autoimmune disease; cohesion; commercialization; cytokine; in vitro Model; intraepithelial; keratinocyte; mouse model; nervous system disorder; novel; novel strategies; novel therapeutic intervention; pre-clinical; preclinical study; prevent; public health relevance; skin disorder; standard care; theories

DESCRIPTION (provided by applicant): Pemphigus vulgaris (PV) is a chronic autoimmune disease targeting skin and mucous membranes, characterized by intraepithelial aphlegmasic flaccid blisters and erosions. It is caused by pathogenic autoantibodies that induce the separation of keratinocytes (KC) from one another, a process known as acantholysis, and leads to the formation of blisters just above the basal layer (Bystryn, 2005). The natural course of the disease is progressive with death occurring within a few years of onset due to sepsis in untreated patients (Veldman, 2008). The standard therapy (glucocorticosteroids) can have severe side effects, and some patients do not respond. Therefore there is a great need for new therapeutic approaches for this serious skin disease. The goal of this application is to develop a novel approach to PV therapy based on the 17 nicotinic acetylcholine receptor selective agonist, GTS-21. This agonist is predicted to promote stable KC cohesion and reverse acantholysis, based on the known function of the cholinergic system to maintain epidermal homeostasis. GTS-21 is also expected to mediate anti-inflammatory and immunosuppressive effects in part due to its well-documented suppression of cytokine synthesis in various model systems. We will test the hypothesis that GTS-21 will block phosphorylation signaling events that lead to acantholysis in KCs stimulated with autoantibodies derived from PV patient serum (PV IgG). We will also test a new theory that GTS-21 will inhibit PV IgG-induced production of cytokines (TNF-1 and IL-11) from cultured KCs that normally promote the acantholytic process. The ability of GTS-21 to prevent IV IgG-induced loss of KC cohesion will be tested in an in vitro acantholysis assay. A neonatal mouse model of PV will be used to evaluate the efficacy of GTS-21 to prevent IV-IgG-induced skin blistering and acantholysis. The findings of these studies will provide the basis for future commercialization of this drug, ultimately leading to clinical trials in PV patients. GTS-21 has a unique mechanism of action compared to standard therapies for PV and may be especially useful for patients refractory to standard therapies. PUBLIC HEALTH RELEVANCE: The goal of this project is to develop a novel therapy for the life-threatening skin disease, pemphigus vulgarus.

描述（由申请人提供）：寻常天疱疮（PV）是一种以皮肤和粘膜为靶点的慢性自身免疫性疾病，其特征为上皮内无光泽性弛缓性水疱和糜烂。它是由致病性自身抗体引起的，这些抗体诱导角质形成细胞（KC）彼此分离，这一过程称为棘层松解，并导致在基底层上方形成水泡（Bystryn，2005）。疾病的自然病程是进行性的，未接受治疗的患者在发病后几年内因败血症死亡（Veldman，2008）。标准治疗（糖皮质激素）可能有严重的副作用，有些患者没有反应。因此，非常需要新的治疗方法来治疗这种严重的皮肤病。本申请的目的是开发一种基于17烟碱乙酰胆碱受体选择性激动剂GTS-21的PV治疗新方法。基于胆碱能系统维持表皮稳态的已知功能，预测这种激动剂可促进稳定的KC凝聚力和逆转棘层松解。GTS-21还预期介导抗炎和免疫抑制作用，部分原因是其在各种模型系统中对细胞因子合成的抑制得到充分证实。我们将检验GTS-21将阻断磷酸化信号传导事件的假设，该磷酸化信号传导事件导致用来自PV患者血清的自身抗体（PV IgG）刺激的KC中的棘层松解。我们还将测试一种新的理论，即GTS-21将抑制PV IgG诱导的细胞因子（TNF-1和IL-11）从培养的KC中产生，这些细胞因子通常促进棘层松解过程。将在体外棘层松解试验中检测GTS-21预防IV IgG诱导的KC凝聚力丧失的能力。PV的新生小鼠模型将用于评价GTS-21预防IV-IgG诱导的皮肤起泡和棘层松解的功效。这些研究的结果将为该药物的未来商业化提供基础，最终导致PV患者的临床试验。与PV的标准疗法相比，GTS-21具有独特的作用机制，可能对标准疗法难治性患者特别有用。公共卫生相关性：该项目的目标是开发一种新的治疗危及生命的皮肤病，寻常天疱疮。