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

Eric Chatelain,¹ Nandini Konar<sup>2

1</sup>Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland; ²Merck & Co, Inc, Whitehouse Station, NJ, USA

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.

Keywords: Trypanosoma cruzi, drug discovery, in vivo models, translation, efficacy prediction