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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要恰加斯病 (CD) 由克氏锥虫寄生虫感染引起，是引起该病的一个主要原因，但尚未得到充分研究。美洲的心力衰竭。超过 700 万人呈克氏锥虫阳性，其中至少有 30 万人在美国美国。克氏锥虫感染者最初会经历一个寄生虫负担较高的急性疾病阶段。寄生虫的免疫控制导致过渡到无症状疾病阶段。 30-40%的感染者然后，个体将逐渐出现严重的心脏和/或消化系统症状（有症状的慢性症状） CD），年死亡率超过 12,000 人/年。没有可用的疫苗，目前的治疗方法选择仅限于两种药物：苯并硝唑 (Bz) 和硝呋莫司。这些抗寄生虫药虽然能够有效杀灭克氏锥虫，副作用显着，且无法改善晚期心脏功能慢性CD。因此，迫切需要新的 CD 治疗方法。联合治疗世界卫生组织已将其发展确定为 CD 研究的主要优先事项。我们之前有过研究表明，重度 CD 与轻度 CD 中酰基肉碱分子的水平发生了变化。我们还生成了试验数据表明，左旋肉碱 (LC) 治疗 CD 急性期可预防动物死亡，并且慢性期 CD 小鼠模型中的 LC 治疗可降低心功能障碍指标。引人注目的是，这些在不改变寄生虫负担的情况下发生效应，支持了 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 成为现有抗寄生虫疗法的理想辅助手段。不能改善 CD 晚期的心脏功能。因此，我们假设 LC+Bz 联合方案治疗慢性 CD 是安全有效的，Bz 可以杀死克氏锥虫，而 LC 可以改善心脏功能。这个探索性/开发性 R21 项目将重点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的必要前提 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 慢性阶段施用时，可以清除寄生虫并减少心脏损伤。在目标 2 中，满足 FDA 对已批准药物组合的指南，其中一个组合成员已显着毒性（Bz）并且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。这些互补的功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估开发管道并最终进入慢性 CD 的人体临床试验。重要的是，LC 便宜、容易可作为膳食补充剂，并经 FDA 批准用于治疗代谢紊乱。因此，本提案在快速从实验室到临床转化和改善 CD 患者预后方面具有巨大潜力。