Pharmacology and Bioengineering of New Treatment of ITP

ITP新疗法的药理学和生物工程

基本信息

批准号：
7629755
负责人：
Joseph P Balthasar
金额：
$ 35.32万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-04-11 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7629755
关键词：
Active Immunization Acute Adrenal Cortex Hormones Affect Alternative Therapies American Animal Disease Models Animal Model Animals Antibodies Antigen-Antibody Complex Antigens Autoantibodies Autoimmune Diseases Autoimmune Process Biomedical Engineering Bioreactors Blood Circulation Blood Platelets Canis familiaris Catabolism Chronic Classification Complement Receptor Development Disease Dose Drug Formulations Drug Kinetics Epistaxis Evaluation Excision Fc Receptor Fiber Funding Grant Hemorrhage Immune Immunization Immunoglobulin G Immunoglobulin Therapy Immunoglobulins Immunosuppression Immunotherapy In Vitro Incidence Individual Intracranial Hemorrhages Intravenous Immunoglobulins Investigation Knockout Mice Laboratories Lead Liposomes Mediating Modeling Pathway interactions Patients Petechiae Pharmacodynamics Pharmacology Property Rattus Refractory Research Personnel Rodent Model Series Splenectomy System Test Result Testing Thrombocytopenia Thrombocytopenic Purpura Time United States Work attenuation design high risk in vivo inhibitor/antagonist insight mouse model neonatal Fc receptor novel strategies novel therapeutics particle prevent programs research study scale up small molecule treatment strategy

项目摘要

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.

描述（由申请人提供）：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）难以治疗，并且发生致命性出血的风险很高。目前还没有可行的替代疗法，并且由于缺乏合适的疾病动物模型，新疗法的开发进展已经放缓。然而，该项目的工作已导致开发出新的、可重复的、定量的 ITP 大鼠和小鼠模型，现在可以对新的治疗策略进行系统评估。已经进行了实验来探讨高剂量静脉注射免疫球蛋白 (IVIG) 治疗 ITP 的作用机制。这项工作证明 IVIG 提供的大部分益处来自 FcRn 的竞争性抑制，从而保护 IgG 免遭降解。此外，我们还启动了三种新的 ITP 治疗策略的开发和评估（即应用特异性 FcRn 抑制剂来增加致病性抗血小板抗体的消除、使用抗原特异性体外生物反应器去除抗血小板抗体以及抑制血小板破坏）通过使用抗体包被的脂质体作为“诱饵颗粒”）。在最初的资助期间，每个具体目标都产生了非常有希望的结果。这一竞争性更新将建立在这些结果的基础上，在 ITP 脾切除小鼠模型中测试 IVIG 的作用机制（目标#1），优化抗体包被脂质体的配方以增强药代动力学和药效学特性，并测试与抗体包被的脂质体在 ITP 中的作用机制（目标#2）。目标 #3 将开发和评估一种新的 ITP 免疫复合物疗法，目标 #4 将优化中空纤维生物反应器的结构，以高效、选择性地体外去除致病性抗血小板抗体。从拟议研究中收集的结果预计将有助于开发难治性 ITP 的新疗法。此外，该项目开展的工作可能会为治疗所有自身免疫性疾病的有效策略的设计提供见解，这些疾病总共影响着 14-2200 万美国人。