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

Chatelain E, Konar N - Drug Des Devel Ther (2015)

Bottom Line: 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.New technological developments and tools may contribute to a much needed boost in the drug discovery process.

View Article: PubMed Central - PubMed

Affiliation: Drugs for Neglected Diseases initiative (DND i ), Geneva, Switzerland.

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.

No MeSH data available.


Related in: MedlinePlus

Chagas disease progression.Notes:Trypanosoma cruzi infection consists of an acute disease phase characterized by elevated parasite load (green). Immune response brings parasite load down to low/undetectable levels. Chagas disease then progresses to the chronic phase, the severity of which (blue) depends on time since infection and host immune status or genetic background. In all, 30%–40% of Chagas patients in the chronic phase will develop clinical manifestations such as cardiomyopathy or megacolon; the remaining 60%–70% will stay asymptomatic (indeterminate form of the disease). Adapted from Tarleton RL. Trypanosoma cruzi and Chagas disease: cause and effect. In: Tyler KM, Miles MA, editors. American Trypanosomiasis. New York; Springer; 2003:107–116. With kind permission from Springer Science and Business Media.124Abbreviations: m, month; y, year.
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f1-dddt-9-4807: Chagas disease progression.Notes:Trypanosoma cruzi infection consists of an acute disease phase characterized by elevated parasite load (green). Immune response brings parasite load down to low/undetectable levels. Chagas disease then progresses to the chronic phase, the severity of which (blue) depends on time since infection and host immune status or genetic background. In all, 30%–40% of Chagas patients in the chronic phase will develop clinical manifestations such as cardiomyopathy or megacolon; the remaining 60%–70% will stay asymptomatic (indeterminate form of the disease). Adapted from Tarleton RL. Trypanosoma cruzi and Chagas disease: cause and effect. In: Tyler KM, Miles MA, editors. American Trypanosomiasis. New York; Springer; 2003:107–116. With kind permission from Springer Science and Business Media.124Abbreviations: m, month; y, year.

Mentions: The disease is caused by the protozoan parasite Trypanosoma cruzi, transmitted by the triatomine insect vector. Humans can also be infected through ingestion of contaminated food and drink, from mother to child during pregnancy, and through contaminated blood transfusion or organ transplantation. Chagas disease is divided into two distinct clinical phases, namely the acute and chronic phases (Figure 1). Acute T. cruzi infection begins when the parasite actively proliferates in the infected individual. It is generally undiagnosed, because of the non-specific nature of symptoms and because most cases occur in regions with limited access to medical care. In the vast majority of cases, the manifestations resolve spontaneously within 2 months.3 During the acute phase, all nucleated cell types in the host are potential targets for infection. Following activation of the immune response, parasitemia reduces to subpatent levels (below the microscopic threshold), signaling the end of the acute phase. However, the parasite is not completely eliminated, and infection of specific tissues persists indefinitely.3 The acute phase is followed by a chronic disease phase, which can be indeterminate (asymptomatic) and may last decades. Approximately 30% of infected individuals eventually develop chronic symptomatic disease with clinical manifestations,3 the most common and serious being cardiomyopathy and gastrointestinal (GI) involvement. The presentation of chronic symptomatic disease varies widely according to disease duration and the extent and location of cardiac lesions. Digestive forms of the disease result from chronic inflammation and destruction of parasympathetic neurons, leading to progressive enlargement of the esophagus or colon. Chagas disease can also be reactivated if patients in the chronic phase are immunocompromised or in the case of co-infection with HIV. Progressive heart failure and sudden death are the most common causes of death in Chagas patients.3


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

Chatelain E, Konar N - Drug Des Devel Ther (2015)

Chagas disease progression.Notes:Trypanosoma cruzi infection consists of an acute disease phase characterized by elevated parasite load (green). Immune response brings parasite load down to low/undetectable levels. Chagas disease then progresses to the chronic phase, the severity of which (blue) depends on time since infection and host immune status or genetic background. In all, 30%–40% of Chagas patients in the chronic phase will develop clinical manifestations such as cardiomyopathy or megacolon; the remaining 60%–70% will stay asymptomatic (indeterminate form of the disease). Adapted from Tarleton RL. Trypanosoma cruzi and Chagas disease: cause and effect. In: Tyler KM, Miles MA, editors. American Trypanosomiasis. New York; Springer; 2003:107–116. With kind permission from Springer Science and Business Media.124Abbreviations: m, month; y, year.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4548737&req=5

f1-dddt-9-4807: Chagas disease progression.Notes:Trypanosoma cruzi infection consists of an acute disease phase characterized by elevated parasite load (green). Immune response brings parasite load down to low/undetectable levels. Chagas disease then progresses to the chronic phase, the severity of which (blue) depends on time since infection and host immune status or genetic background. In all, 30%–40% of Chagas patients in the chronic phase will develop clinical manifestations such as cardiomyopathy or megacolon; the remaining 60%–70% will stay asymptomatic (indeterminate form of the disease). Adapted from Tarleton RL. Trypanosoma cruzi and Chagas disease: cause and effect. In: Tyler KM, Miles MA, editors. American Trypanosomiasis. New York; Springer; 2003:107–116. With kind permission from Springer Science and Business Media.124Abbreviations: m, month; y, year.
Mentions: The disease is caused by the protozoan parasite Trypanosoma cruzi, transmitted by the triatomine insect vector. Humans can also be infected through ingestion of contaminated food and drink, from mother to child during pregnancy, and through contaminated blood transfusion or organ transplantation. Chagas disease is divided into two distinct clinical phases, namely the acute and chronic phases (Figure 1). Acute T. cruzi infection begins when the parasite actively proliferates in the infected individual. It is generally undiagnosed, because of the non-specific nature of symptoms and because most cases occur in regions with limited access to medical care. In the vast majority of cases, the manifestations resolve spontaneously within 2 months.3 During the acute phase, all nucleated cell types in the host are potential targets for infection. Following activation of the immune response, parasitemia reduces to subpatent levels (below the microscopic threshold), signaling the end of the acute phase. However, the parasite is not completely eliminated, and infection of specific tissues persists indefinitely.3 The acute phase is followed by a chronic disease phase, which can be indeterminate (asymptomatic) and may last decades. Approximately 30% of infected individuals eventually develop chronic symptomatic disease with clinical manifestations,3 the most common and serious being cardiomyopathy and gastrointestinal (GI) involvement. The presentation of chronic symptomatic disease varies widely according to disease duration and the extent and location of cardiac lesions. Digestive forms of the disease result from chronic inflammation and destruction of parasympathetic neurons, leading to progressive enlargement of the esophagus or colon. Chagas disease can also be reactivated if patients in the chronic phase are immunocompromised or in the case of co-infection with HIV. Progressive heart failure and sudden death are the most common causes of death in Chagas patients.3

Bottom Line: 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.New technological developments and tools may contribute to a much needed boost in the drug discovery process.

View Article: PubMed Central - PubMed

Affiliation: Drugs for Neglected Diseases initiative (DND i ), Geneva, Switzerland.

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.

No MeSH data available.


Related in: MedlinePlus