Wednesday, May 1, 2024
5/1/2024
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.
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