New Treatments for Chronic Chagas Disease

摘要 这项提议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)是由克氏锥虫引起的，主要影响全球600-800万人 在拉丁美洲。在美国，CD也是一个新兴的公共卫生问题。目前，只有两种药物 (苯硝唑和硝呋莫司)，这两种药物对急性CD非常有效，但对 慢性CD(CCD)。目前还没有预防性或治疗性的人类疫苗。这些事实强调了当务之急 需要新的治疗方法，感染阶段的患者占绝大多数。在此，我们建议 结合有效疫苗和寄生虫特异性药物开发免疫化疗平台(S) 来治疗ccd。这种方法在癌症和利什曼病的治疗中特别成功， 最近在急性CD的情况下进行了试验，但没有在CD中进行试验，取得了相对成功。少年派(马尔多纳多博士)有 发现了疫苗(MASPpep-KLH)和候选药物(T.ruzi N-肉豆蔻酰基转移酶[TcNMT]) 抑制剂)将在本提案中进行研究。我们假设MASPpep-KLH加一种佐剂 与新型TcNMT抑制剂(DDD1和DDD5)一起，将具有协同效应，赋予更大的疗效 与单一模式治疗相比，抗慢性克雷伯氏毛滴虫感染。我们的最终目标是产生无菌 清除小鼠模型中的寄生虫。我们提出了以下具体目标：具体目标1。 利用免疫刺激佐剂增强MASPpep-KLH疫苗平台。MASPpep-KLH 将与一种佐剂联合进行测试，以增强MASPpep-KLH作为治疗性疫苗的效力 在小鼠的蜂窝状病毒模型中。具体目的2.评价新型NMT抑制剂的抗寄生虫活性 小鼠肝细胞癌模型中的DDD_1和DDD_5。我们建议评估抗寄生虫的有效性。 NMT抑制剂在小鼠肝细胞癌模型中的作用。如果这些药物不能百分之百治愈，它们仍将是 在具体目标3中很有用，因为次优剂量将用于寻求协同效应 免疫化疗平台。具体目标3.确定药物的治疗潜力 DDD1和/或DDD5 NMT抑制剂联合MASPpep-KLH的免疫化疗平台 (+/-佐剂)用于治疗肝细胞癌。作为免疫化疗平台的概念验证，我们 建议使用次佳剂量的苯硝唑进行初步实验，苯硝唑是CD的标准药物 联合MASPpep-KLH(+/-佐剂)。然后我们将测量和优化的抗寄生虫活性 联合治疗：NMT抑制剂联合MASPpep-KLH(+/-佐剂)治疗小鼠CCD模型，通过评估 寄生虫血症，组织病理学，体液和细胞免疫反应图谱。这个项目是独一无二的 一种新的克鲁兹毛滴虫候选疫苗和抗寄生虫NMT抑制剂的使用。圆满完成了我们的 研究将提出针对ccd的新治疗策略，这将是控制和 根除这一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.