Pharmacology and Bioengineering of New Treatment of ITP

ITP新疗法的药理学和生物工程

• 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
• 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

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）：免疫血小板减少紫癜（ITP）是一种常见的自身免疫性疾病，每年与美国约50,000例新病例有关。大约25-30％的慢性ITP患者对标准疗法（皮质类固醇免疫抑制和脾切除术）具有难治性，并且致命出血的风险很高。目前没有可行的替代疗法可用，并且缺乏适当的疾病动物模型，促进新疗法的进展已减慢。但是，该项目进行的工作导致了新的，可再现的，定量的大鼠和ITP的老鼠模型的发展，现在可以系统地评估新的治疗策略。已经进行了实验，以探测负责高剂量静脉免疫球蛋白（IVIG）ITP治疗的作用的机制。这项工作表明，IVIG提供的许多好处是由于FCRN的竞争抑制作用，从而保护IgG免于降解。另外，我们启动了ITP的三种新治疗策略的开发和评估（即，应用特定的FCRN抑制剂以增加消除致病性抗血小板抗体的消除，用抗原特异性的体外生物反应器和抑制deStrose的抗体和抑制作用来消除抗血小板抗体，并将其作为destrapion抑制作用，以及destrosem destrains destrain contrauction and deStrains''粒子”）。在初始资金期间，每个特定目标都产生了极其有希望的结果。这种竞争性更新将基于这些结果，测试IVIG动作的拟议机制在脾脏化的ITP模型中（AIM＃1）（目标＃1），优化了抗体涂层脂质体的配方，以增强药代动力学和药物动力学特性，并测试与抗体效应相关的效应的机制（AIM），以供应2个抗体效应（AIM）。 AIM＃3将开发和评估针对ITP的新免疫复合疗法，AIM＃4将优化空心纤维生物反应器的构建，以有效且有选择性的体外去除致病性抗血小板抗体。预计从拟议的研究中收集的发现将导致制定难治性ITP的新疗法。此外，对该项目进行的工作可能会为设计有效的所有自身免疫性条件的有效策略提供见解，这共同影响了14-2200万美国人。