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.

摘要 原生动物寄生虫克氏锥虫的感染通常被控制，但通常不能通过宿主免疫消除。 应答在人类和许多其他宿主中，这种持续感染最终导致已知的肌肉组织损伤。 恰加斯病虽然存在几种部分有效的药物来治疗感染，但据估计， 受感染者接受治疗。更广泛地使用当前药物和开发更好的药物的主要障碍是 恰加斯病治疗的一个障碍是缺乏可靠的方法来明确确定治疗效果。 本项目的目标是验证和改进T.克鲁兹感染，主要依靠不断变化的 对一组确定的T.有效治疗后的Cruzi抗原。我们以前的~10 一年来，我们使用一组有限的抗原，使用一种稳健但昂贵的基于Luminex珠粒的 approach.在这个项目中，我们将使用蛋白质和聚糖微阵列来选择额外的高质量目标， 抗T. cruzi抗体，从目前Luminex检测中的15个参数扩展到50个或更多 参数目标数量和多样性的增加将提高确定目标的质量和速度。 治疗有效性，并确保识别所有暴露受试者。使用T.克氏抗原和 由于阵列格式提供的测试成本大大降低，我们将开发并验证治愈测试。初试 参数（例如靶抗原、蛋白质和/或聚糖的数量和选择，以及连续样品的数量 所需的和在什么随访期内）将使用来自长期感染的猕猴的血清建立，所述猕猴用 并在治疗前和治疗后6周间隔多次取样，直至治疗后一年， 此时，在免疫抑制的辅助下明确确定治愈状态。这些参数将 使用治疗后长达15年从人连续采样的血清进行验证，其中转化为阴性 将采用目前公认的治疗措施-常规血清学。最后，我们将应用经过验证的测试 在阿根廷的2家研究中心和巴西的1家研究中心，对新入组治疗项目的受试者进行前瞻性研究。的总目标 这一过程将确定在最短的时间内从每位患者采集的最少数量的样本， 使用最少数量的靶点区分治疗成功和失败所需的治疗 抗原使用来自相同受试者的历史存储样本和最近样本的组合， 治愈，我们还将评估未经治疗受试者的自发治愈率。确定血清反应阳性者， 自发解决感染是重要的预后/咨询，并防止他们暴露于 治疗及其常见的不良并发症。这些研究的完成将有助于改善 选择治疗候选人，评估接受治疗的受试者的结局，并提供 这是一个关键的工具，需要确定候选药物，表现更好，比目前可用的更安全，但 未充分利用的化合物。