Pharmacology and Bioengineering of New Treatment of ITP

描述(申请人提供)：免疫性血小板减少性紫癜(ITP)是一种常见的自身免疫性疾病，在美国每年约有50,000例新病例。大约25%-30%的慢性ITP患者对标准治疗(皮质类固醇免疫抑制和脾切除术)无效，并面临致命出血的高风险。目前还没有可行的替代疗法，由于缺乏合适的动物模型，新疗法的开发进展缓慢。然而，在这个项目上进行的工作导致了新的、可重复的、定量的ITP大鼠和小鼠模型的开发，现在可以对新的治疗策略进行系统的评估。本实验旨在探讨大剂量静脉注射免疫球蛋白(IVIG)治疗ITP的机制。这项工作表明，静脉注射免疫球蛋白的大部分益处来自于对FcRN的竞争性抑制，FcRN保护免疫球蛋白免于降解。此外，我们启动了三种新的ITP治疗策略的开发和评估(即，应用特定的FcRN抑制剂来增加病原性抗血小板抗体的清除，用抗原特异性体外生物反应器去除抗血小板抗体，以及通过使用抗体包裹的脂质体作为“诱饵颗粒”来抑制血小板破坏)。在最初的筹资期间，每一项具体目标都产生了非常有希望的成果。这项竞争性的更新将建立在这些结果的基础上，在ITP的脾切除小鼠模型中测试拟议的IVIG作用机制(Aim#1)，优化抗体包衣脂质体的配方以增强药代动力学和药效学特性，并测试与抗体包衣脂质体在ITP中作用机制相关的假设(Aim#2)。目的#3将开发和评估一种治疗ITP的新免疫复合疗法，目的#4将优化中空纤维生物反应器的结构，以高效和选择性地体外去除致病的抗血小板抗体。从拟议的研究中收集的结果有望导致难治性ITP的新治疗方法的开发。此外，在这个项目上进行的工作可能为设计治疗所有自身免疫性疾病的有效策略提供洞察力，这些疾病总共影响到1400-2200万美国人。

DESCRIPTION (provided by applicant): Immune thrombocytopenic purpura (ITP) is a common autoimmune disease that is associated with ~50,000 new cases each year in the United States. Approximately 25-30% of chronic ITP patients are refractory to standard therapy (corticosteroid immunosuppression and splenectomy) and are at high risk for fatal hemorrhage. No feasible alternative therapies are presently available, and progress toward the development of new treatments had been slowed be the lack of suitable animal models of the disease. However, work conducted on this project has led to the development of new, reproducible, quantitative rat and mouse models of ITP, which now allow the systematic evaluation of new treatment strategies. Experiments have been conducted to probe the mechanisms responsible for the effects of high-dose intravenous immunoglobulin (IVIG) therapy of ITP. This work demonstrated that much of the benefit provided by IVIG results from the competitive inhibition of the FcRn, which protects IgG from degradation. Additionally, we initiated the development and evaluation of three new therapeutic strategies for ITP (i.e., application of specific FcRn-inhibitors to increase the elimination of pathogenic antiplatelet antibodies, removal of antiplatelet antibodies with an antigen-specific extracorporeal bioreactor, and inhibition of platelet destruction through the use of antibody-coated liposomes as "decoy particles"). Extremely promising results were generated from each specific aim during the initial funding period. This competing renewal will build upon these results, testing proposed mechanisms of IVIG action in a splenectomized-mouse model of ITP (Aim #1), optimizing the formulation of antibody-coated liposomes for enhanced pharmacokinetic and pharmacodynamic properties, and testing hypotheses related to the mechanisms of effect of antibody-coated liposomes in ITP (Aim #2). Aim #3 will develop and evaluate a new immune complex therapy for ITP, and Aim #4 will optimize the construction of hollow fiber bioreactors for efficient and selective extracorporeal removal of pathogenic, antiplatelet antibodies. Findings gathered from the proposed studies are expected to lead toward the development of new treatments for refractory ITP. Additionally, work conducted on this project may offer insight in the design of effective strategies for the treatment of all autoimmune conditions, which collectively affect 14-22 million Americans.