New Treatments for Chronic Chagas Disease

慢性恰加斯病的新疗法

• 批准号: 10540754
• 负责人: ROSA A MALDONADO
• 金额: $ 37.75万
• 依托单位: UNIVERSITY OF TEXAS EL PASO
• 依托单位国家: 美国
• 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/10540754
• 关键词: Acute; Adjuvant; Affect; Agonist; Animals; Antiparasitic Agents; Australia; Benznidazole; CD8-Positive T-Lymphocytes; Canada; Cardiomyopathies; Cell membrane; Chagas Disease; Chronic; Chronic Phase; Combined Modality Therapy; 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; Persons; 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; 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; mouse model; neglected tropical diseases; nonhuman primate; novel; novel therapeutic intervention; novel therapeutics; preclinical development; prophylactic; success; therapeutic vaccine; vaccine candidate; vaccine platform

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 该提案的总体目的是找到一种新的，更有效的Chagas病治疗方法（CD）。这 被忽视的热带疾病（NTD）是由克鲁兹锥虫引起的，全球影响了6-8万人，主要影响 在拉丁美洲。 CD目前在美国也是新兴的公共卫生问题，只有两种药物 （苯甲酸和nifurtimox）可用，非常有效地治疗急性CD，但仅部分有效 慢性CD（CCD）。没有预防性或治疗性的人类疫苗。这些事实强调了紧急 CCD需要新的治疗剂，这是绝大多数病例的感染阶段。在这里，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学治疗平台 治疗CCD。这种方法在治疗癌症和利什曼病的治疗方面特别成功，以及 最近在急性CD的背景下尝试了它，但没有取得相对成功。 PI（Maldonado博士） 发现了疫苗（MASPPEP-KLH）和候选药物（T. Cruzi N-Myristoyltrassferase [TCNMT] 抑制剂）将在该提案中进行研究。我们假设MASPPEP-KLH和佐剂组合 使用新型的TCNMT抑制剂（DDD1和DDD5），将具有协同作用，从而赋予更大的疗效 与单模疗法相比，针对慢性T. cruzi感染。我们的最终目标是产生无菌 消除CCD鼠模型中的寄生虫。我们提出以下特定目标：特定目标1。 为了增强使用免疫刺激佐剂的MASPPEP-KLH疫苗平台。 masppep-klh 将与佐剂结合进行测试，以增强MASPPEP-KLH作为治疗疫苗的功效 在CCD的鼠模型中。特定目的2。评估新型NMT抑制剂的抗寄生虫活性 CCD鼠模型中的DDD1和DDD5。我们建议评估抗寄生虫的有效性 CCD鼠模型中的NMT抑制剂。如果药物不能诱导100％治愈，它们仍然会 在特定目标3中有用，因为次优剂量将用于寻求协同作用 免疫化学疗法平台。特定目的3。确定 使用DDD1和/或DDD5 NMT抑制剂与MASPPEP-KLH结合的免疫化学疗法平台 （+/-辅助）用于治疗CCD。作为免疫化学治疗平台的概念证明，我们 建议使用替代剂量的苯甲酸二唑（用于CD的标准药物）进行初始实验 与MASPPEP-KLH（+/-辅助）组合。然后，我们将测量并优化 合并疗法：NMT抑制剂加上MASPPEP-KLH（+/-佐剂）在CCD的鼠模型中，通过评估 寄生虫病，组织病理学以及体液和细胞免疫反应谱。这个项目在 使用新型的克鲁齐疫苗候选和抗寄生虫NMT抑制剂的使用。成功完成我们 研究将推进针对CCD的新治疗策略，这对于控制和控制至关重要 根除此NTD。