Biomarker-Based Test of Cure for Chagas Disease

基于生物标记的恰加斯病治愈测试

• 批准号: 9978716
• 负责人: Andrew E. Levin
• 金额: $ 30万
• 依托单位: KEPHERA DIAGNOSTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-16 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978716
• 关键词: Acute; Address; Adverse effects; Aftercare; Age; Antibody Response; Antibody titer measurement; Antigens; Benznidazole; Biological Assay; Biological Markers; Blood Screening; Blood Transfusion; Blood donor; Brazil; Cardiac; Cardiomyopathies; Centers for Disease Control and Prevention (U.S.); Chagas Disease; Characteristics; Child; Chronic; Chronic Phase; Clinical; Clinical Management; Clinical Research; Clinical Trials; Collection; Controlled Environment; Data; Development; Diagnosis; Disease; Enzyme-Linked Immunosorbent Assay; Epitopes; FDA approved; Goals; Human; Immigrant; Immune response; Immunoglobulin G; Immunologics; Individual; Infection; Insect Vectors; International; Investigation; Laboratories; Lateral; Latin America; Literature; Logistic Regressions; Measurement; Measures; Methodology; Methods; Monitor; Morbidity - disease rate; Nifurtimox; Organ Transplantation; Outcome; Output; Parasites; Parasitic Diseases; Parasitic infection; Pathologic; Patient-Focused Outcomes; Patients; Peptides; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Population; Predictive Value; Preparation; Prevalence; Public Health; Publishing; Reader; Reproducibility; Research; Resources; Risk; Rural; Sampling; Serologic tests; Serum; Specificity; Standardization; Test Result; Testing; Time; Toxic effect; Transfusion; Treatment Failure; Trypanosoma cruzi; Validation; Vascular blood supply; aged; assay development; base; chronic infection; cohort; cost; cost effective; cross reactivity; curative treatments; drug testing; gastrointestinal; health organization; immunoreactivity; individual patient; innovation; mortality; novel therapeutics; performance tests; point of care; potential biomarker; prediction algorithm; prevent; prototype; research study; response; scale up; screening panel; statistics; synthetic peptide; time interval; tool; transmission process; validation studies

Project Summary Chagas disease, caused by infection with the parasite Trypanosoma cruzi, is the most prevalent parasitic disease in the western hemisphere, infecting 8-11 million individuals and with over 70 million at risk. The infection is transmitted by an insect vector, but can also be acquired through blood transfusion, organ transplant, or congenitally. Following a brief acute phase, the parasite persists for years as a chronic, but often asymptomatic infection, which may progress to cardiomyopathy and other pathological conditions leading to severe morbidity and mortality. In the U.S., the prevalence of T. cruzi infection in immigrant populations has led to the implementation of blood screening assays to prevent transfusion transmission. Autochthonous transmission can be expected based on the gradual encroachment of the insect vector into the southernmost regions of the U.S. Treatment for Chagas disease currently relies on two drugs, benznidazole and nifurtimox. While these drugs are highly effective if used during the acute phase, their efficacy in the chronic phase varies significantly, decreasing with increasing duration of infection. Moreover, due to their known toxicity, both drugs are known to have frequent adverse effects, which intensify with patient age. Benznidazole has been approved by FDA only for use on children aged 2-12, while nifurtimox is not FDA-approved; both drugs can only be obtained in the U.S. from CDC for use outside the approved indication. Accordingly, a variety of efforts are underway to develop new drugs to treat Chagas disease, supported by public health organizations and pharmaceutical companies. However, a major limitation is the lack of a reliable, standardized and validated test of cure to measure the efficacy of Chagas drugs and to establish whether treatment has successfully eradicated an individual patient’s infection for purposes of clinical management. The aim of this project is the development of a test of cure for Chagas disease that will address these needs. Of the methodologies that have been evaluated for measuring drug effects on T. cruzi infection, serology and PCR have been the mainstays. A decrease in antibody titer to one or another T. cruzi antigen over a period of time following treatment has been used in various studies as a de factor test of cure, but the in-house assays used have not been standardized or validated and are not commercially available. PCR offers high positive predictive value, but its low negative predictive value excludes it as a methodology for a bona fide test of cure. Approach to assay development will be on the measurement of antibody response to a set of T. cruzi peptide antigens selected based on immunological characteristics. Assays will be developed first in ELISA and subsequently in point-of-care formats to address the needs of drug trials and individual patient management. Performance of the test-of-cure assays will be evaluated on available sets of well-characterized serum samples obtained at time intervals pre- and post-treatment from prior Chagas studies. In Phase II, broader validation studies will be carried out leading to introduction of the first commercially available test-of-cure for Chagas disease.

项目概要 查加斯病是由寄生虫克氏锥虫感染引起的，是最常见的寄生虫 该疾病在西半球感染了 8-1100 万人，并且有超过 7000 万人面临感染风险。 通过昆虫媒介传播，但也可以通过输血、器官移植或 先天性的，在短暂的急性期之后，寄生虫会以慢性方式持续数年，但通常无症状。 感染，可能发展为心肌病和其他导致严重发病的病理状况 在美国，克氏锥虫感染在移民人群中的流行导致了 实施血液筛查可以预防输血传播。 基于昆虫媒介逐渐侵入美国最南端地区，预计这种情况将会发生。 恰加斯病的治疗目前依赖两种药物：苯硝唑和硝呋莫司。 如果在急性期使用非常有效，但在慢性期疗效差异很大，会降低 此外，由于已知的毒性，这两种药物都会随着感染持续时间的增加而频繁发生。 苯硝唑已被 FDA 批准仅用于以下人群。 2-12 岁儿童，而硝呋莫司未获得 FDA 批准；这两种药物只能在美国从 CDC 获得 因此，正在努力开发新药以用于批准的适应症之外。 在公共卫生组织和制药公司的支持下治疗南美锥虫病。 主要限制是缺乏可靠、标准化和经过验证的治疗测试来衡量恰加斯的功效 确定治疗药物是否已成功根除个别患者的感染 临床管理的目的。 该项目的目的是开发一种治疗恰加斯病的方法来满足这些需求。 已评估药物测量对克氏锥虫感染的影响的方法、血清学和 PCR 在一段时间内，针对一种或另一种克氏锥虫抗原的抗体滴度下降是主要因素。 以下治疗已在各种研究中用作治愈的实际测试，但使用的内部测定 PCR 尚未标准化或验证，并且无法在商业上提供高阳性预测。 值，但其较低的阴性预测值使其无法作为真正的治愈方法测试。 检测开发的重点是测量对一组克氏锥虫肽抗原的抗体反应 根据免疫学特征选择的检测方法将首先在 ELISA 中开发，随后在 ELISA 中开发。 床旁护理模式，以满足药物试验和个体患者管理的需求。 将根据当时获得的一组已充分表征的血清样本来评估治愈试验 在第二阶段，将进行更广泛的验证研究。 导致推出第一个商业化的恰加斯病治愈测试。