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 由克鲁齐寄生虫感染引起的chagas病（CD）是一个主要但研究不足的原因 美洲心力衰竭。超过700万人是克鲁兹的阳性，其中包括至少300,000人 美国。 T. Cruzi感染的个体最初通过高寄生虫负担的急性疾病阶段进展。 寄生虫的免疫控制导致过渡到无症状疾病阶段。 30-40％的感染 然后，个人将逐渐发展出严重的心脏和/或消化症状（症状慢性 CD），年死亡率超过12,000。没有疫苗，目前的治疗 期权仅限于两种药物，苯甲酸唑（BZ）和Nifurtimox。这些反寄生虫，尽管能够 有效地杀死克鲁齐（T. cruzi 慢性CD。因此，迫切需要新的CD治疗方法。联合疗法 WHO已将开发确定为主要的CD研究优先级。我们以前有 证明在严重的和轻度CD中会改变酰基炭干分子的水平。我们也生成了 试验数据表明，急性阶段CD中L-肉碱（LC）治疗可防止动物死亡率，并且 在慢性阶段CD小鼠模型中的LC处理可减少心脏功能障碍的指标。令人惊讶的是，这些 效果发生没有变化的寄生虫负担，支持LC治疗减少的机制 CD介导的心脏损伤。这将使LC成为现有反寄生虫方案的理想辅助 在后期CD中不能改善心脏功能。因此，我们假设LC+BZ组合方案 可以安全有效地治疗慢性阶段CD，而BZ杀死Cruzi和LC改善了心脏功能。 这个探索性/发展性R21项目将重点侧重于严格评估这种组合的潜力 慢性CD治疗方案，作为进一步的临床前和临床发展的必要前体 LC +Bz组合方案。在AIM 1中，我们将评估不同LC+BZ组合方案的功效 在CD的慢性阶段给药时，就寄生虫的清除和心脏损伤的减少而言。 在AIM 2中，要符合FDA指南，以制定一个组合成员的批准药物的组合 明显的毒性（BZ），并且具有药代动力学相互作用的潜力，我们将评估总体安全性和 不同LC+Bz组合方案的耐受性。这些互补的功效和安全结果将 确定应通过临床前药物进行进一步评估的LC+Bz组合 开发管道，最终进行慢性CD的人类临床试验。重要的是，LC便宜，很容易 可作为饮食补充剂可用，并批准为治疗代谢疾病。因此，该建议 具有快速的基准翻译和CD患者预后改善的巨大潜力。