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 恰加斯病是由克氏锥虫感染引起的最常见的寄生虫病。 西半球，感染800万至1100万人，7000多万人处于危险之中。感染是传播的 通过昆虫媒介，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，这种寄生虫会作为一种慢性感染持续多年，但通常是无症状的， 可发展为心肌病和其他病理情况，导致严重的发病率和 死亡率。在美国，克鲁兹旋毛虫在移民人群中的流行导致了 血液筛查分析，以防止输血传播。原生的传播是可以预期的 基于昆虫媒介逐渐侵入美国最南端地区的治疗 恰加斯病目前依赖于两种药物--苯硝唑和硝呋莫司。虽然这些药物在很大程度上 如果在急性期使用有效，则在慢性期疗效不同，随着剂量的增加而降低。 感染持续时间。此外，由于已知的毒性，这两种药物都有频繁的不良反应。 影响，这种影响随着患者年龄的增长而增强。FDA已批准苯硝唑仅适用于年龄在 2-12岁，虽然nifurtimox已被批准用于18岁以下的儿童；但成人目前被非标签治疗。一个 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Chagas药物的疗效并确定治疗是否成功 为了临床管理的目的，消除个别病人的感染。 这个项目的目的是开发一种测试，以衡量恰加斯病的治疗反应。 将满足这些需求的患者。已评估哪些方法可用于衡量 药物治疗克氏毛滴虫感染，血清学一直是中流砥柱。克氏毛滴虫抗体效价下降 随着时间的推移，后续治疗已被用作治疗反应的事实测试，但没有商业化的测试。 已经为这种用途设计并验证了，现有的检测只显示抗体滴度在 有很多年的时间。在第一阶段，我们鉴定了抗体效价下降的克氏锥虫多肽抗原。 在接受治疗的患者中迅速增加，提供了一种灵敏的手段来衡量一年内的治疗反应。原型 基于这些多肽的检测已经开发出了ELISA和横向流动两种形式，以使检测成为可能 在实验室和护理点环境中都是如此。在第二阶段，化验作为治疗指标的表现 将通过与传统的血清学检测和聚合酶链式反应进行比较来评估反应。 在连续的治疗后时间点和预期获得的回溯性血清样本 来自新诊断和治疗过程中的患者的样本。酶联免疫吸附试验和侧向流动试验的验证 化验将导致推出第一批商业化的恰加斯病治疗反应测试。