Oral carnitine administration as a novel treatment for chronic-stage Chagas disease

口服肉碱作为慢性阶段恰加斯病的新型治疗方法

• 批准号: 10092938
• 负责人: Laura-Isobel McCall
• 金额: $ 23.25万
• 依托单位: UNIVERSITY OF OKLAHOMA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092938
• 关键词: Acute; Acute Disease; Address; Adverse effects; Americas; Aneurysm; Antiparasitic Agents; Arrhythmia; Benznidazole; Brain natriuretic peptide; Cardiac; Carnitine; Chagas Disease; Chronic; Clinic; Clinical Trials; Combined Modality Therapy; Complement; Data; Development; Disease; Dose; Drug Kinetics; Effectiveness; Energy Metabolism; Esophagus; Esters; Evaluation; Excretory function; FDA approved; Fatty Acids; Guidelines; Heart; Heart Diseases; Heart failure; Human; Immune; Immune response; Individual; Infection; Lead; Levocarnitine; Literature; Mediating; Metabolic Diseases; Myocardial Infarction; Myocardial dysfunction; Names; Nifurtimox; Oral; Parasite Control; Parasites; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Play; Preclinical Drug Development; Public Health; Regimen; Research Priority; Role; Route; Safety; Severity of illness; Symptoms; Testing; Tissues; Toxic effect; Translations; Treatment Protocols; Trypanosoma cruzi; United States; Ventricular; Work; World Health Organization; acylcarnitine; animal mortality; base; bench to bedside; clinical development; coronary fibrosis; dietary supplements; drug development; efficacy study; follow-up; heart damage; heart function; improved; intraperitoneal; member; mortality; mouse model; new combination therapies; novel; preclinical development; prevent; side effect; therapy development; vaccine access

Project Summary/Abstract Chagas disease (CD), caused by infection with T. cruzi parasites, is a major but under-studied cause of heart failure in the Americas. Over seven million people are T. cruzi-positive, including at least 300,000 in the USA. T. cruzi-infected individuals initially progress through an acute disease stage with high parasite burden. Immune control of parasites leads to transition to an asymptomatic disease stage. 30-40% of infected individuals will then progressively develop severe cardiac and/or digestive symptoms (symptomatic chronic CD), with an annual mortality rate of over 12,000/year. No vaccines are available, and current treatment options are limited to two drugs, benznidazole (Bz) and nifurtimox. These antiparasitic agents, although able to effectively kill T. cruzi, have significant side effects and are unable to improve cardiac function in advanced chronic CD. There is therefore an urgent need for new treatments for CD. Combination therapy development has been identified as a major CD research priority by the WHO. We have previously demonstrated that levels of acylcarnitine molecules are altered in severe vs mild CD. We have also generated pilot data demonstrating that L-carnitine (LC) treatment in acute-stage CD prevents animal mortality, and that LC treatment in a chronic-stage CD mouse model reduces indicators of heart dysfunction. Strikingly, these effects occurred without changes in parasite burden, supporting a mechanism by which LC treatment reduces CD-mediated cardiac damage. This would make LC an ideal adjunct to existing antiparasitic regimens that do not improve heart function in late-stage CD. We therefore hypothesize that LC+Bz combination regimens are safe and effective to treat chronic-stage CD, with Bz killing T. cruzi and LC improving heart function. This exploratory/developmental R21 project will focus on rigorously assessing the potential of this combination regimen for chronic CD treatment, as a necessary precursor for further pre-clinical and clinical development of LC +Bz combination regimens. In aim 1, we will assess the efficacy of different LC+Bz combination regimens in terms of parasite clearance and reduction in cardiac damage, when administered in the chronic stage of CD. In aim 2, to meet FDA guidelines for combinations of approved drugs in which one combination member has significant toxicity (Bz) and there is pharmacokinetic interaction potential, we will assess overall safety and tolerability of different LC+Bz combination regimens. These complementary efficacy and safety results will determine which LC+Bz combinations should progress for further evaluation through the pre-clinical drug development pipeline and ultimately to human clinical trials for chronic CD. Importantly, LC is cheap, readily available as a dietary supplement, and FDA-approved to treat metabolic disorders. This proposal therefore has great potential for rapid bench-to-bedside translation and improvement of CD patient outcomes.

项目总结/摘要 恰加斯病（CD），由锥虫感染引起。克氏寄生虫，是一个主要的，但研究不足的原因， 心脏衰竭在美洲超过700万人是T。cruzi阳性，包括至少30万人， USA. t.受克氏病感染的个体最初会经历寄生虫负荷很高的急性疾病阶段。 寄生虫的免疫控制导致过渡到无症状疾病阶段。30 - 40%感染者 然后个体将逐渐发展为严重的心脏和/或消化道症状（症状性慢性 CD），年死亡率超过12，000/年。没有可用的疫苗，目前的治疗方法 选择仅限于两种药物，苯并咪唑（Bz）和硝呋替莫司。这些抗寄生虫剂，虽然能够 有效地杀死T。cruzi，具有显著的副作用，并且不能改善晚期心脏功能， 慢性CD因此，迫切需要新的CD治疗方法。组合疗法 发展已被确定为主要的CD研究的重点由世界卫生组织。我们先前已经 表明酰基肉毒碱分子的水平在严重与轻度CD中改变。我们还产生了 试验数据表明，L-肉毒碱（LC）治疗急性期CD可预防动物死亡， 慢性期CD小鼠模型中的LC治疗减少了心脏功能障碍的指标。引人注目的是，这些 在寄生虫负担没有变化的情况下发生效果，支持LC治疗减少寄生虫负担的机制。 CD介导的心脏损伤。这将使LC成为现有抗寄生虫方案的理想辅助剂， 不能改善晚期CD患者的心脏功能。因此，我们假设LC + Bz联合方案 对慢性CD安全有效，Bz对T. cruzi和LC改善心功能。 这个探索性/开发性的R21项目将集中于严格评估这种组合的潜力 慢性CD治疗方案，作为进一步临床前和临床开发 LC + Bz联合方案。在目标1中，我们将评估不同LC + Bz联合方案的疗效 在CD慢性期给药时，在寄生虫清除和心脏损伤减少方面。 在目标2中，为了满足FDA关于批准药物组合的指南，其中一个组合成员具有 显著毒性（Bz）且存在药代动力学相互作用的可能性，我们将评估总体安全性， 不同LC + Bz组合方案的耐受性。这些互补的疗效和安全性结果将 确定哪些LC + Bz组合应通过临床前药物进行进一步评价 开发管道，并最终用于慢性CD的人体临床试验。重要的是，LC便宜，容易 作为膳食补充剂，FDA批准用于治疗代谢紊乱。因此，这项建议 具有快速从实验室到床边的转换和改善CD患者结局的巨大潜力。