Translational challenges of animal models in Chagas disease drug development: a review

Abstract

Chagas disease, or American trypanosomiasis, caused by Trypanosoma cruzi parasite infection is endemic in Latin America and presents an increasing clinical challenge due to migrating populations. Despite being first identified over a century ago, only two drugs are available for its treatment, and recent outcomes from the first clinical trials in 40 years were lackluster. There is a critical need to develop new drugs to treat Chagas disease. This requires a better understanding of the progression of parasite infection, and standardization of animal models designed for Chagas disease drug discovery. Such measures would improve comparison of generated data and the predictability of test hypotheses and models designed for translation to human disease. Existing animal models address both disease pathology and treatment efficacy. Available models have limited predictive value for the preclinical evaluation of novel therapies and need to more confidently predict the efficacy of new drug candidates in clinical trials. This review highlights the overall lack of standardized methodology and assessment tools, which has hampered the development of efficacious compounds to treat Chagas disease. We provide an overview of animal models for Chagas disease, and propose steps that could be undertaken to reduce variability and improve predictability of drug candidate efficacy. New technological developments and tools may contribute to a much needed boost in the drug discovery process.

Putting Infection Dynamics at the Heart of Chagas Disease

“…Non-human primates, dogs, rabbits, rats and guinea pigs are all useful to study chronic cardiac infection [72], but for practical and ethical reasons mice are by far the most commonly used models. Drawing firm conclusions from the existing literature is complicated by variations in experimental design.…”

“…Identifying whether a patient or experimental animal has been cured of T. cruzi infection is a critical question, whether assessing the effectiveness of the front-line drugs (benznidazole or nifurtimox), or testing new chemotherapeutic agents and immunotherapies [72]. Detection of T. cruzi in humans is usually restricted to blood.…”

“…The increased sampling possibilities available for experimental animal models can potentially generate a greater degree of confidence in predicted cure rates [72]. Quantitative PCR is a powerful tool, but suffers from limitations arising from the focal and dynamic nature of chronic infections.…”

Anti-parasitic effect of novel amidines against Trypanosoma cruzi: phenotypic and in silico absorption, distribution, metabolism, excretion and toxicity analysis

“…Often, in drug development for CD, as well as for other pathologies, there is a lack of direct translation between pre-clinical in vitro and in vivo results and clinical outcomes. Experimental chemotherapy for CD presents serious challenges in part due to experimental difficulties related to reliable demonstration of a sterile cure, particularly during the chronic stage of infection when parasite burden is low and tissue distribution is not fully understood (Chatelain and Konar, 2015;Francisco et al 2015). Our group has studied the in vitro and in vivo activity of AA and analogues and the bulk of the data revealed very promising action of these cations against intracellular pathogens, including T. cruzi (Soeiro et al 2013).…”

Clinical Candidate VT-1161's Antiparasitic Effect In Vitro , Activity in a Murine Model of Chagas Disease, and Structural Characterization in Complex with the Target Enzyme CYP51 from Trypanosoma cruzi

“…Like fungi, T. cruzi is completely dependent on endogenously synthesized sterols (18). However, because T. cruzi is an intracellular parasite and has a complex life cycle involving so-called quiescent (dormant) forms with reduced metabolic activity (15,19), it is reasonable to presume that alternative CYP51 inhibitors with optimized pharmacological properties (e.g., higher bioavailability and cellular permeability, broader tissue distribution, lower toxicity) and, in particular, lower production costs, which would easily allow treatment for longer periods of time, should be seriously considered as potential antichagasic agents.…”