Multiplex treatment outcomes test for Chagas disease

恰加斯病多重治疗结果测试

• 批准号: 9305839
• 负责人: Rick L Tarleton
• 金额: $ 100.08万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9305839
• 关键词: Aftercare; Algorithms; Antibodies; Antibody Response; Antibody titer measurement; Antigen Targeting; Antigens; Argentina; B-Lymphocytes; Benznidazole; Biological Assay; Blood; Brazil; Carbohydrates; Chagas Disease; Characteristics; Communicable Diseases; Counseling; Data; Development; Diagnostic; Disease; Effectiveness; Enrollment; Exposure to; Failure; Geographic Locations; Goals; Human; Immune response; Immunologic Markers; Immunosuppression; Individual; Infection; Latin America; Length; Macaca; Measurement; Measures; Methods; Monitor; Muscle; Outcome Assessment; Parasites; Patients; Pattern; Persons; Pharmaceutical Preparations; Plasmablast; Polysaccharides; Population Heterogeneity; Process; Protein Array; Protein Microchips; Proteins; Recombinants; Research Personnel; Risk; Sampling; Serologic tests; Serological; Serum; Site; Slide; Speed; Technology; Testing; Therapeutic; Time; Treatment Efficacy; Treatment outcome; Trypanosoma cruzi; United States; Work; assay development; base; candidate selection; clinical development; cost; curative treatments; design; diagnostic panel; drug candidate; drug development; effective therapy; expectation; follow-up; improved; indexing; neonate; nonhuman primate; novel therapeutics; outcome forecast; patient population; prevent; prospective test; response; screening; seropositive; success; tool; transmission process; treatment program

Abstract Infection with the protozoan parasite Trypanosoma cruzi is generally controlled but often not eliminated by host immune responses. In humans and many other hosts, this persistent infection ultimately results in muscle tissue damage known as Chagas disease. Although several partially effective drugs exist to treat the infection, it is estimated that only ~1% of infected subjects receive treatment. The main barrier to the wider use of current drugs and the development of better therapeutics in Chagas disease is the absence of reliable methods to definitively determine the efficacy of treatment. The goal of this project is to validate and improve tests of cure for T. cruzi infection, relying primarily on the changing pattern of antibody responses to a panel of defined T. cruzi antigens following effective treatment. Our previous ~10 year have validated this approach using a limited set of antigens using a robust, but expensive Luminex bead-based approach. In this project, we will use protein and glycan microarrays to select additional high quality targets for measurement of anti-T. cruzi antibodies, expanding from the current 15 parameters in the Luminex assay to 50 or more parameters. This increase in target number and diversity will improve the quality and the speed of determination of treatment efficacy and assure that all exposed subjects are identified. Using this expanded panel of T. cruzi antigens and the much reduced cost of testing provided by an array format, we will develop and validate a test of cure. The initial test parameters (e.g. the number and selection of target antigens, proteins and/or glycans, and number of serial samples required and over what follow-up period) will be established using sera from long-term infected macaques treated with benznidazole and sampled multiple times before and at 6 week intervals after treatment for up to a year post-treatment, at which time the cure status is definitively determined as assisted by immunosuppression. These parameters will be validated using sera serially sampled from humans for up to 15 years post-treatment wherein the conversion to negative conventional serology, the currently accepted measure of cure, will be applied. Finally, we will apply the validated test prospectively to subjects newly enrolled in treatment programs in 2 sites in Argentina and 1 in Brazil. The overall goal of this process will be to identify the fewest number of samples collected per patient over the shortest period of time post- treatment that are needed to discriminate between treatment success and failure using the fewest number of target antigens. Using a combination of historical stored samples and recent samples from the same subjects and the test of cure, we will also assess the rate of spontaneous cure in untreated subjects. Identification of seropositive persons who have spontaneously resolved the infection is important for prognosis /counseling and to prevent their exposure to treatment and its common accompanying adverse complications. Completion of these studies will allow improved selection of candidates for treatment, assessment of outcomes in those subjects who receive treatment, and provide the critical tool needed to identify candidate drugs that perform better and are safer than the currently available, but underutilized compounds.

抽象的 普遍控制了原生动物寄生虫锥虫锥虫的感染，但通常不会被宿主免疫消除 回答。在人类和许多其他宿主中，这种持续感染最终导致肌肉组织损害已知 作为查加斯病。尽管存在几种部分有效的药物来治疗感染，但据估计只有约1％ 受感染受试者接受治疗。广泛使用当前药物的主要障碍和更好的发展 Chagas疾病中的治疗方法是没有可靠的方法来确定治疗的疗效。 该项目的目的是验证和改善Cruzi感染的治疗测试，主要依赖于变化 有效治疗后，抗体对定义的克鲁兹抗原的抗体反应模式。我们以前的〜10 使用有限但昂贵的Luminex珠子使用有限的抗原验证了这种方法 方法。在这个项目中，我们将使用蛋白质和聚糖微阵列选择其他高质量目标 抗T的测量。克鲁兹抗体，从Luminex分析中的当前15个参数扩展到50或更多 参数。目标数量和多样性的增加将提高质量和确定速度 治疗功效并确保确定所有暴露的受试者。使用此扩展的Cruzi抗原和 阵列格式提供的测试成本大大降低，我们将开发并验证治疗测试。初始测试 参数（例如，靶抗原，蛋白质和/或聚糖的数量和选择，以及串行样品的数量 需要使用长期感染猕猴的血清建立必需的和在什么后续期间） 苯甲酸唑和治疗后的6周间隔多次进行处理，最多可在治疗后一年 当时，治愈状态被确定为免疫抑制的辅助确定。这些参数将是 使用从人类的血清进行验证，最多15年，其中转换为负 常规血清学是当前接受的治疗方法。最后，我们将应用经过验证的测试 前瞻性地参加了在阿根廷2个地点和巴西1个地点的治疗计划的受试者。总体目标 此过程将是确定在 - 使用最少数量的目标来区分治疗成功和失败所需的治疗 抗原。结合了历史存储的样本和来自同一受试者的最新样本以及测试 治愈，我们还将评估未经治疗受试者的自发治疗率。识别血清阳性的人 自发解决感染对于预后 /咨询很重要，并防止其暴露 治疗及其常见的不良并发症。这些研究的完成将允许改进 选择治疗的候选人，评估接受治疗的受试者的结果，并提供 确定比目前可用的候选药物所需的关键工具，但是 未充分利用的化合物。