New Treatments for Chronic Chagas Disease

摘要 该提案的总体目标是找到一种新的，更有效的治疗恰加斯病（CD）的方法。这 被忽视的热带病（NTD）是由克氏锥虫（Trypanosoma cruzi）引起的，影响全世界600 - 800万人，主要是 在拉美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 （苄硝唑和硝呋莫司），这是非常有效的治疗急性CD，但只有部分有效， 慢性CD（CCD）。没有预防性或治疗性的人类疫苗。这些事实表明， 需要新的治疗CCD，感染阶段的绝大多数情况下。在此，我们建议 通过将有效疫苗与寄生虫特异性药物结合，开发免疫化疗平台 治疗CCD。这种方法在治疗癌症和利什曼病方面特别成功， 它最近在急性CD的情况下进行了尝试，但不是CCD，取得了相对成功。PI（马尔多纳多博士）已 发现了疫苗（MASPpep-KLH）和候选药物（T.克鲁兹N-肉豆蔻酰转移酶[TcNMT] 在这个项目中，我们将研究。我们假设MASPpep-KLH加佐剂，联合使用， 与新的TcNMT抑制剂（DDD 1和DDD 5），将具有协同效应，赋予更大的疗效 抗慢性T.与单一模式疗法相比，我们的最终目标是 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 将与佐剂组合测试以增强MASPpep-KLH作为治疗性疫苗的功效 在CCD小鼠模型中。具体目标2。评估新型NMT抑制剂的抗寄生虫活性 在CCD小鼠模型中的DDD 1和DDD 5。我们建议评估抗寄生虫的有效性， CCD小鼠模型中的NMT抑制剂。如果药物不能100%治愈，它们仍然会 在特定目标3中是有用的，因为次优剂量将用于寻求在特定目标3中的协同效应。 免疫化疗平台。具体目标3。为了确定的治疗潜力， 使用DDD 1和/或DDD 5 NMT抑制剂与MASPpep-KLH组合的免疫化疗平台 （+/-佐剂）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苄硝唑（CD的标准药物）进行初步实验， 与MASPpep-KLH（+/-佐剂）组合。然后，我们将测量和优化的抗寄生虫活性 联合治疗：NMT抑制剂加MASPpep-KLH（+/-佐剂）在CCD鼠模型中，通过评估 寄生虫血症、组织病理学以及体液和细胞免疫应答概况。这个项目是独一无二的， 使用一种新的T. cruzi疫苗候选物和抗寄生虫NMT抑制剂。我们成功完成了 研究将提出新的治疗CCD的战略，这将是必不可少的控制和 根除这种NTD。

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.