Monitoring Treatment Efficacy in Leprosy

项目摘要 麻风是由麻风分枝杆菌引起的，麻风是一种生长缓慢的细菌，不能在实验室培养。 媒体。这种疾病是可以治愈的，残疾可以通过早期使用多种药物来预防。 治疗(MDT)。实施千年发展目标成功地减少了报告的新病例数量。 1981年为1000万例，2005年为25万例，但此后停滞不前，2019年新增病例20万例，这表明 这种疾病的传播仍然活跃。在病毒的持续传播中需要考虑的一个重要因素 麻风是治疗的有效方法。在临床实践中，治疗效果的主观评估是基于 临床皮损检查在治疗结束后6至12个月，较长时间内 哪些患者可能会发展成永久性残疾。复发在地方性疾病中很常见，但可能仅限于 临床表现在治疗完成后10到15年，这是一个相当大的障碍 后续研究和使新药方案的临床测试极具挑战性。这样就有了 显然需要一种简单的方法，直接从临床上快速准确地评估治疗效果 在化疗期间而不是在治疗结束时采集样本。抗麻风药物的筛选与优化 有可能缩短疗程的药物和药物组合方案也同样复杂 因为麻风杆菌不能在体外培养。 目前测量临床和临床前样本细菌活性的金标准方法包括 将这些样品制备的细菌接种到免疫低下小鼠的足垫中 然后在感染后6至12个月对足垫中的细菌复制进行显微镜评估。 除了耗时外，这种方法还昂贵、具有技术挑战性，并且需要维护 在BSL2或BSL3动物设施中连续几个月大量饲养小鼠。 在这个项目中，我们建议评估一些分子方法，包括最近的一种。 内部开发，用于快速监测对化疗的反应，使用人类 样本(目标1)和麻风杆菌感染的动物模型(目标2)。 该项目的成功可能会通过以下方式在监测麻风患者的治疗反应方面产生变革 使临床医生能够“实时”评估治疗的成功或失败。发展了分子读出技术 进一步有望提供急需的方法来快速评估在动物身上的治疗效果 可用于筛选和优化新药和药物的模型和人体 联合疗法。

Project Summary Leprosy is caused by Mycobacterium leprae, a slow-growing bacterium that cannot be cultured in laboratory media. The disease is curable, and disabilities can be prevented with the early administration of multi-drug therapy (MDT). The implementation of MDT successfully decreased the number of new cases reported from 10 million in 1981 to 250,000 in 2005 but plateaued since then with 200,000 new cases in 2019, suggesting that disease transmission is still active. One important factor to consider in the sustained transmission of leprosy is treatment efficacy. In clinical practice, treatment effectiveness is subjectively assessed based on clinical examination of skin lesions at the end of the 6 to 12-month-long treatment, a long period of time during which patients may develop permanent disabilities. Relapse is common in endemic settings but might only manifest clinically 10 to 15 years after completion of therapy which represents a considerable obstacle to follow-up studies and renders the clinical testing of new drug regimens extremely challenging. There is thus a clear need for easy methods that rapidly and accurately assesses treatment efficacy directly from clinical samples during chemotherapy rather than at the end of treatment. Screening and optimization of anti-leprosy drugs and drug combination regimens with the potential to shorten treatment duration is similarly complicated by the fact that M. leprae cannot be cultured in vitro. The current gold standard method to measure bacterial viability in clinical and pre-clinical samples involves the inoculation of bacteria prepared from these samples into the footpads of immunocompromised mice followed by the microscopic assessment of bacterial replication in the footpads 6 to 12 months post-infection. Besides being time-consuming, this method is expensive, technically challenging, and requires maintaining a high number of mice for several months in BSL2 or BSL3 animal facilities. In this project, we propose to evaluate a number of molecular methods, including one recently developed in-house, to rapidly monitor response to chemotherapeutic treatments using both human samples (Aim 1) and an animal model of M. leprae infection (Aim 2). Success in this project could be transformative in monitoring treatment response in leprosy patients by enabling clinicians to assess in “real-time” treatment success or failure. The molecular read-outs developed are further expected to provide much-needed methods to rapidly evaluate treatment efficacy both in animal models and in humans that may be used in the screening and optimization of new drugs and drug combination regimens.