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: 9975286
• 负责人: Laura-Isobel McCall
• 金额: $ 19.38万
• 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 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975286
• 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; Vaccines; 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

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.

项目摘要/摘要 查加斯病(CD)是由克氏毛滴虫感染引起的，是一种主要的但研究不足的原因。 在美洲的心力衰竭。超过700万人克氏锥虫呈阳性，其中至少30万人在 美国。感染克鲁兹毛滴虫的人最初会在高寄生虫负担的情况下经历急性疾病阶段。 对寄生虫的免疫控制导致向无症状疾病阶段的过渡。30%-40%的感染者 然后，个人将逐渐发展为严重的心脏和/或消化症状(有症状的慢性 CD)，年死亡率超过12,000/年。没有疫苗可用，目前的治疗方法 选择仅限于两种药物，苯硝唑(BZ)和硝呋莫司。这些抗寄生虫剂虽然能够 有效杀灭克氏毛滴虫，有明显副作用，晚期无法改善心功能 慢性CD。因此，迫切需要新的CD治疗方法。综合疗法 发展已被世界卫生组织确定为CD研究的主要优先事项。我们之前已经 证明在重度和轻度CD患者中，乙酰肉碱分子水平发生了改变。我们还产生了 初步数据表明，L-肉碱(LC)治疗CD急性期可防止动物死亡，并且 在慢性期CD小鼠模型中，LC治疗减少了心脏功能障碍的指标。令人惊讶的是，这些 在不改变寄生虫负担的情况下发生效果，支持LC治疗减少的机制 镉引起的心脏损伤。这将使LC成为现有抗寄生虫疗法的理想补充 晚期CD患者心功能改善不明显。因此，我们假设LC+BZ联合方案 治疗慢性期CD安全有效，BZ可杀死克氏毛滴虫，LC可改善心功能。 这个试探性/开发性的R21项目将专注于严格评估这一组合的潜力 慢性CD治疗方案，作为进一步开发临床前和临床研究的必要先导 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 在清除寄生虫和减少心脏损害方面，在慢性CD阶段给药。 在目标2中，为了满足FDA关于批准药物的组合的指南，其中一个组合成员 显著毒性(BZ)和存在药代动力学相互作用潜力，我们将评估总体安全性和 不同LC+BZ联合方案的耐受性。这些互补的疗效和安全性结果将 确定哪些LC+BZ组合应该通过临床前药物进行进一步评估 开发流水线，并最终用于慢性CD的人体临床试验。重要的是，LC很便宜，很容易 可作为膳食补充剂，FDA批准用于治疗代谢紊乱。因此，这项提议 在快速从床到床的转换和改善CD患者预后方面具有巨大的潜力。