Animal models of Chagas disease and their translational value to drug development

Abstract

Introduction: American trypanosomiasis, better known as Chagas disease, is a global public health issue. Current treatments targeting the causative parasite, Trypanosoma cruzi, are limited to two old nitroheterocyclic compounds; new, safer drugs are needed. New tools to identify compounds suitable for parasitological cure in humans have emerged through efforts in drug discovery. Areas covered: Animal disease models are an integral part of the drug discovery process. There are numerous experimental models of Chagas disease described and in use; rather than going through each of these and their specific features, the authors focus on developments in recent years, in particular the imaging technologies that have dramatically changed the Chagas R&D landscape, and provide a critical view on their value and limitations for moving compounds forward into further development. Expert opinion:The application of new technological advances to the field of drug development for Chagas disease has led to the implementation of new and robust/standardized in vivo models that contributed to a better understanding of host/parasite interactions.These new models should also build confidence in their translational value for moving compounds forward into clinical development.

Local association of Trypanosoma cruzi chronic infection foci and enteric neuropathic lesions at the tissue micro-domain scale

“…There are also wider reasons to be optimistic about the translational value of these murine DCD models. For example, they perform well in predicting the efficacy of anti-parasitic drugs in clinical trials, in terms of both cure of infection and impact on cardiac tissue pathology [ 52 ].…”

T Cell Specificity: A Great Challenge in Chagas Disease

“…Despite the translational challenges of animal models in Chagas disease (24,25), they are still crucial for increasing the knowledge of the disease and the interaction between the host and the parasite (26)(27)(28)(29). Indeed, mouse models (wild type mice with H2 -mouse MHC-molecules or transgenic ones expressing human MHC) are broadly utilized under different strategies to evaluate the specificity of T cell response against T. cruzi infection (Figure 3).…”

Chagas Disease: Perspectives on the Past and Present and Challenges in Drug Discovery

“…We can mention the lack of biomarkers for the two stages of the disease and for the evaluation of the therapeutic efficacy of the treatments as well as the genetic diversity of T. cruzi strains among others. It is also necessary to review the assays and tools used with in vitro and in vivo models for the translation studies [6,13]. In 1971, benznidazole (BNZ), N-benzyl-2-nitroimidazole acetamide, was released by Roche.…”

“…In recent years, factors that have hindered the development of new drugs have been extensively discussed in the literature. The lack of accurate biomarkers for treatment, failure in diagnoses, diversity of strains of the parasite, problems with the standardization of methodologies such as in vivo animal models, different host cell culture lines and problems in the translation process among other factors are barriers for the development of new drugs [ 6 , 13 , 20 , 21 ].…”