Biomarker-Based Test of Cure for Chagas Disease

项目摘要 查加斯病由寄生虫克氏锥虫感染引起，是最普遍的寄生虫病。 在西半球，有800万至1100万人感染了这种疾病，有7000多万人处于危险之中。感染 是由昆虫传播的，但也可以通过输血，器官移植，或 天生的在短暂的急性期之后，寄生虫作为慢性病持续多年，但通常无症状 感染，可能进展为心肌病和其他病理状况，导致严重发病率 and mortality.在美国，T.移民人群中的克鲁兹感染导致了 实施血液筛查化验，以防止输血传播。本地传输可以 根据昆虫媒介逐渐侵入美国最南端的地区， 查加斯病的治疗目前依赖于两种药物，苄硝唑和硝呋替莫。虽然这些药物 如果在急性期使用非常有效，它们在慢性期的疗效差异很大， 随着感染持续时间的增加。此外，由于它们已知的毒性，已知这两种药物具有频繁的 不良反应，随着患者年龄的增长而加剧。苯硝咪唑已被FDA批准仅用于 2-12岁的儿童，而硝呋替莫司未经FDA批准;这两种药物只能在美国从CDC获得 在批准的适应症之外使用。因此，正在进行各种努力来开发新药， 在公共卫生组织和制药公司的支持下治疗恰加斯病。但 一个主要的局限性是缺乏一个可靠的，标准化的和有效的治疗测试来衡量南美锥虫病的疗效 药物，并确定治疗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测试方法，以满足这些需求。的 已评估的用于测量药物对T. cruzi感染、血清学和PCR 一直是支柱。对一种或另一种T的抗体滴度降低。一段时间后， 以下治疗已在各种研究中用作治愈的因子测试，但所用的内部测定 还没有标准化或验证，并且还没有商业化。PCR提供高阳性预测 价值，但其低阴性预测值排除了它作为一个真正的治愈测试的方法。方法 检测方法的开发将是对一组T. cruzi肽抗原 根据免疫学特征进行选择。检测方法将首先在ELISA中开发，随后在 床旁模式，以满足药物试验和个体患者管理的需求。性能 将对在以下时间获得的可用的良好表征的血清样品集进行治愈试验测定评价： 既往恰加斯病研究的治疗前和治疗后间隔。在第二阶段，将进行更广泛的验证研究 这导致了第一个商业上可用的南美锥虫病治愈测试的引入。

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.