New Treatments for Chronic Chagas Disease

慢性恰加斯病的新疗法

基本信息

批准号：
10090371
负责人：
ROSA A MALDONADO
金额：
$ 35.4万
依托单位：
UNIVERSITY OF TEXAS EL PASO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-10 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10090371
关键词：
Acute Adjuvant Affect Agonist Americas Animals Antiparasitic Agents Australia Benznidazole CD8-Positive T-Lymphocytes Canada Cardiomyopathies Cell membrane Chagas Disease Chronic Chronic Phase Country Diagnosis Disease Dose Drug usage Effectiveness Emerging Communicable Diseases Enzyme-Linked Immunosorbent Assay Europe Flow Cytometry Goals Histopathology Human Immune response Immuno-Chemotherapy Immunologic Memory Immunotherapeutic agent Immunotherapy In Vitro Infection Japan Keyhole Limpet Hemocyanin Latin America Latino Leishmaniasis Measures Membrane Proteins Modeling Mucins Mus N-myristoyltransferase Nifurtimox Parasitemia Parasites Parasitic Diseases Patients Peptides Pharmaceutical Preparations Pharmacotherapy Phase Preventive vaccine Production Public Health Research Serious Adverse Event Spain Sterility Symptoms T-Cell Activation Technology Testing Therapeutic Trypanosoma cruzi United States Vaccines Validation base bioluminescence imaging cancer therapy chemotherapy cytokine drug candidate drug standard effective therapy enzyme linked immunospot assay experimental study extracellular vesicles flu improved in vivo inhibitor/antagonist mouse model neglected tropical diseases nonhuman primate novel novel therapeutic intervention novel therapeutics preclinical development prophylactic success therapeutic vaccine vaccine candidate

项目摘要

ABSTRACT The overall objective of this proposal is to find a new, more effective treatment for Chagas disease (CD). This neglected tropical disease (NTD) is caused by Trypanosoma cruzi, affecting 6-8 million people worldwide, mainly in Latin America. CD is also an emerging public health concern in the U.S. Currently, there are only two drugs (benznidazole and nifurtimox) available, which are very efficient to treat acute CD, but only partially effective for chronic CD (CCD). There is no prophylactic or therapeutic human vaccine. These facts underscore the urgent need for new therapeutics for CCD, the infection stage with the vast majority of cases. Here, we propose to develop an immunochemotherapeutic platform by combining an effective vaccine with parasite-specific drug(s) to treat CCD. This approach has been particularly successful in the treatment of cancer and leishmaniasis, and it was recently tried in the context of acute CD, but not CCD, with relative success. The PI (Dr. Maldonado) has discovered both the vaccine (MASPpep-KLH) and the drug candidates (T. cruzi N-myristoyltransferase [TcNMT] inhibitors) to be studied in this proposal. We hypothesize that MASPpep-KLH plus an adjuvant, in combination with the novel TcNMT inhibitors (DDD1 and DDD5), will have a synergistic effect, conferring greater efficacy against chronic T. cruzi infection in comparison to single-mode therapies. Our ultimate goal is to generate sterile elimination of the parasite in the murine model of CCD. We propose the following specific aims: Specific Aim 1. To enhance the MASPpep-KLH vaccine platform utilizing an immunostimulatory adjuvant. MASPpep-KLH will be tested in combination with an adjuvant to enhance the efficacy of MASPpep-KLH as therapeutic vaccine in a murine model of CCD. Specific Aim 2. To assess the antiparasitic activity of novel NMT inhibitors DDD1 and DDD5 in the murine model of CCD. We propose to evaluate the antiparasitic effectiveness of the NMT inhibitors in the murine model of CCD. In the case the drugs do not induce 100% cure, they still will be useful in Specific Aim 3, since suboptimal dose will be used to seek for synergistic effect in the immunochemotherapy platform. Specific Aim 3. To determine the therapeutic potential of the immunochemotherapy platform using DDD1 and/or DDD5 NMT inhibitors combined with MASPpep-KLH (+/- adjuvant) for the treatment of CCD. As proof-of-concept of the immunochemotherapeutic platform, we propose to conduct the initial experiments using suboptimal doses of benznidazole, the standard drug for CD, in combination with MASPpep-KLH (+/- adjuvant). We will then measure and optimize the antiparasitic activity of the combined therapy: NMT inhibitors plus MASPpep-KLH (+/-adjuvant) in a murine model of CCD, by evaluating parasitemia, histopathology, and the humoral and cellular immune response profiles. This project is unique in the use of a novel T. cruzi vaccine candidate and anti-parasitic NMT inhibitors. The successful completion of our research will advance new therapeutic strategies against CCD, which will be essential for the control and eradication of this NTD.

抽象的该提案的总体目标是寻找一种新的、更有效的恰加斯病（CD）治疗方法。这被忽视的热带病 (NTD) 由克氏锥虫引起，影响全世界 6-800 万人，主要是在拉丁美洲。 CD 在美国也是一个新兴的公共卫生问题。目前只有两种药物（苯并硝唑和硝呋莫司）可用于治疗急性 CD，但仅部分有效慢性 CD (CCD)。没有预防性或治疗性人类疫苗。这些事实凸显了紧迫性 CCD需要新的治疗方法，绝大多数病例处于感染阶段。在此，我们建议通过将有效的疫苗与寄生虫特异性药物相结合来开发免疫化疗平台来治疗CCD。这种方法在治疗癌症和利什曼病方面特别成功，并且最近在急性 CD（而非 CCD）的背景下进行了尝试，并取得了相对成功。 PI（马尔多纳多博士）发现了疫苗 (MASPpep-KLH) 和候选药物 (T. cruzi N-肉豆蔻酰转移酶 [TcNMT] 抑制剂）在本提案中进行研究。我们假设 MASPpep-KLH 加上佐剂，组合与新型TcNMT抑制剂（DDD1和DDD5）一起使用，将产生协同效应，赋予更大的疗效与单一模式疗法相比，可对抗慢性克氏锥虫感染。我们的最终目标是产生无菌消除 CCD 小鼠模型中的寄生虫。我们提出以下具体目标：具体目标 1。利用免疫刺激佐剂增强 MASPpep-KLH 疫苗平台。 MASPpep-KLH 将与佐剂结合进行测试，以增强 MASPpep-KLH 作为治疗性疫苗的功效在小鼠 CCD 模型中。具体目标 2. 评估新型 NMT 抑制剂的抗寄生虫活性 CCD小鼠模型中的DDD1和DDD5。我们建议评估该药物的抗寄生虫效果 CCD 小鼠模型中的 NMT 抑制剂。即使药物不能 100% 治愈，它们仍然会在具体目标 3 中很有用，因为将使用次优剂量来寻求协同效应免疫化疗平台。具体目标 3. 确定该药物的治疗潜力使用 DDD1 和/或 DDD5 NMT 抑制剂联合 MASPpep-KLH 的免疫化疗平台（+/- 辅助）用于治疗 CCD。作为免疫化疗平台的概念验证，我们建议使用次优剂量的苯并硝唑（CD 的标准药物）进行初步实验。与 MASPpep-KLH（+/- 佐剂）组合。然后我们将测量和优化抗寄生虫活性联合疗法：在 CCD 小鼠模型中使用 NMT 抑制剂加 MASPpep-KLH（+/- 佐剂），通过评估寄生虫血症、组织病理学以及体液和细胞免疫反应概况。该项目的独特之处在于使用新型克氏锥虫候选疫苗和抗寄生虫 NMT 抑制剂。我们的顺利完成研究将推进针对 CCD 的新治疗策略，这对于控制和预防 CCD 至关重要。根除这种 NTD。