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: 10761244
• 负责人: Andrew E. Levin
• 金额: $ 101.5万
• 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 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10761244
• 关键词: Acute; Address; Adherence; Adult; Adverse effects; Aftercare; Age; Antibody titer measurement; Antigens; Benznidazole; Biological Assay; Biological Markers; Blood Screening; Blood Transfusion; Brazil; Cardiac; Cardiomyopathies; Chagas Disease; Characteristics; Child; Chronic; Chronic Phase; Clinical; Clinical Management; Clinical Research; Clinical Trials; Controlled Environment; Data; Dedications; Detection; Development; Diagnosis; Disease; Enzyme-Linked Immunosorbent Assay; Epitopes; Evaluation; FDA approved; Immigrant; Immune response; Immunoglobulin G; Individual; Infection; Insect Vectors; International; Label; Laboratories; Lateral; Latin America; Length; Malabsorption Syndromes; Measures; Methodology; Methods; Morbidity - disease rate; Newly Diagnosed; Nifurtimox; Organ Transplantation; Outcome; Parasites; Parasitic Diseases; Parasitic infection; Pathologic; Patients; Peptides; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Phase; Population; Preparation; Prevalence; Process; Prospective cohort; Proteins; Protocols documentation; Public Health; Reproducibility; Research; Retrospective cohort; Risk; Rural; Sampling; Serodiagnoses; Serology; Serology test; Serum; Services; Standardization; Testing; Time; Toxic effect; Training; Transfusion; Treatment Failure; Trypanosoma cruzi; Validation; Vascular blood supply; aged; chronic infection; clinical prognosis; cohort; commercial launch; commercialization; curative treatments; design; detection method; diagnostic assay; dosage; drug testing; gastrointestinal; health organization; individual patient; lateral flow assay; manufacture; manufacturing scale-up; mortality; novel; novel therapeutics; patient response; point of care; prevent; prospective; prototype; research and development; research study; response; scale up; synthetic peptide; time interval; transmission process; treatment response; validation studies

Project Summary Chagas disease, caused by infection with 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, 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 has been approved for children up to age 18; adults are currently treated off-label. 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 to measure the efficacy of Chagas drugs and to establish whether treatment is successfully eliminating an individual patient’s infection for purposes of clinical management. The aim of this project is the development of a test that measures the response to treatment in Chagas disease patients that will address these needs. Of the methodologies that have been evaluated for measuring effects of drug treatment on T. cruzi infection, serology has been the mainstay. A decrease in antibody titer to T. cruzi over time following treatment has been used as a de facto test for treatment response, but no commercial assay has been designed and validated for this use, and available assays only show changes in antibody titer over a period of many years. In Phase I, we identified T. cruzi peptide antigens to which IgG antibody titers declined rapidly in treated patients, providing a sensitive means to measure treatment response within a year. Prototype assays based on these peptides have been developed in both ELISA and lateral flow formats to enable testing in both laboratory and point-of-care settings. In Phase II, the performance of the assays as indicators of treatment response will be evaluated in comparison with conventional serological tests and PCR on well-characterized retrospective serum samples obtained at serial post-treatment time points, and on prospectively acquired samples from patients newly diagnosed and in the course of treatment. Validation of the ELISA and lateral flow assays will lead to introduction of the first commercially available tests of treatment response for Chagas disease.

项目摘要 查加斯病由克氏锥虫感染引起，是非洲最普遍的寄生虫病， 西半球，感染人数为8- 1100万，其中超过7000万人面临风险。感染是通过 但也可以通过输血、器官移植或先天获得。 在短暂的急性期之后，寄生虫作为慢性但通常无症状的感染持续多年， 其可发展为心肌病和导致严重发病率的其它病理状况， mortality.在美国，T.移民人群中的克氏病毒感染导致了 血液筛查检测以防止输血传播。可以预期本地传播 基于昆虫媒介逐渐侵入美国最南端的地区。 查加斯病目前依赖于两种药物，苄硝唑和硝呋莫司。虽然这些药物是高度 如果在急性期使用有效，它们在慢性期的疗效各不相同， 感染的持续时间。此外，由于其已知的毒性，已知这两种药物均具有频繁的不良反应。 影响，随着患者年龄的增长而加剧。苯硝哒唑已被FDA批准仅用于儿童年龄 2-12，而硝呋莫司已被批准用于18岁以下的儿童;成人目前正在接受标签外治疗。一 在公共卫生的支持下，正在进行各种努力，以开发治疗恰加斯病的新药 组织和制药公司。然而，一个主要的限制是缺乏可靠的，标准化的 和验证测试，以衡量南美锥虫病药物的疗效，并确定治疗是否成功， 为了临床管理的目的，消除个体患者的感染。 该项目的目的是开发一种测试方法，以测量对恰加斯病治疗的反应。 患者将满足这些需求。在评估用于衡量 药物治疗对T.克氏感染，血清学一直是主要的。T. cruzi 治疗后一段时间内，已被用作治疗反应的事实测试，但没有商业检测 已经设计并验证了该用途，并且可用的测定仅显示抗体滴度在一个周期内的变化。 多年的时间。在第一阶段，我们确定了T。IgG抗体滴度下降的cruzi肽抗原 在接受治疗的患者中迅速，提供了一种灵敏的方法来测量一年内的治疗反应。原型 基于这些肽的检测方法已开发成ELISA和侧流形式，以进行测试 在实验室和护理点环境中。在II期，检测试剂盒的性能作为治疗指标 将通过与常规血清学试验和PCR对特征明确的 在连续治疗后时间点获得的回顾性血清样本，以及前瞻性获得的 来自新诊断和治疗过程中的患者的样本。ELISA和侧向流的验证 这些检测将导致引入第一个商用的查加斯病治疗反应检测。