New approaches to circumvent shortcomings of leishmaniasis treatment: design of an in vitro visceral leishmaniasis model based on the organs-on-a-chip technology and testing of strategies to revert antimony resistance

• Grant number: 15/23832-7
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: May 01, 2016
• End date: July 03, 2020
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Silvia Reni Bortolin Uliana
• Grantee: Cristiana de Melo Trinconi Tronco
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated scholarship(s): 16/17665-3 - New approaches to circumvent shortcomings of leishmaniasis treatment: design of an in vitro visceral leishmaniasis model based on the organs-on-a-chip technology, BE.EP.PD

Abstract

Leishmaniasis is caused by more than 20 species of the Leishmania genus resulting in a wide clinical spectrum of diseases distributed worldwide. Visceral leishmaniasis, given its high incidence and mortality, is considered by the World Health Organization as one of the major diseases of our time. Leishmaniasis's chemotherapy relies on a very limited number of drugs, including pentavalent antimonials, amphotericin B, pentamidine and miltefosine. All of these present limitations such as restricted efficacy, necessity of parenteral administration, low tolerability, high cost, as well as treatment failure due to the emergence of resistant parasites. Therefore, the need for developing new strategies for leishmaniasis treatment and new alternatives to the current available drugs is evident. The in vitro and in vivo models for drug activity screening against Leishmania are limited in number and scope, expensive and laborious, not to mention present ethical concerns about animal welfare. Furthermore, these models are mostly based on animal models, which can prove inadequate when translation to humans is attempted. Consequently, novel technologies to predict drug efficacy and toxicity in humans in earlier preclinical stages are necessary. The advent of the organs-on-a-chip technology has made possible the generation of relevant replicas of human models for diseases where drug efficacy, metabolism and interactions can be screened simultaneously. This project aims to design an organs-on-a-chip device capable of simulating human infections by Leishmania chagasi. This device will be tested in the evaluation of efficacy, toxicity and metabolism of anti-leishmanial drug candidates. Aiming at improving the effectiveness of the current available drugs, we will also evaluate whether Leishmania resistance to antimony can be reversed by combined treatment with tamoxifen, a drug with antileishmanial properties and a known inhibitor of the ABC family of transporters.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

ULIANA, SILVIA R. B.; TRINCONI, CRISTIANA T.; COELHO, ADRIANO C.. Chemotherapy of leishmaniasis: present challenges. Parasitology, v. 145, n. 4, SI, p. 464-480, APR 2018. (15/09080-2, 12/14629-5, 15/23832-7)

ULIANA, SILVIA R. B.; TRINCONI, CRISTIANA T.; COELHO, ADRIANO C.. Chemotherapy of leishmaniasis: present challenges. Parasitology, v. 145, n. 4, p. 17-pg., 2018-04-01. (15/23832-7, 15/09080-2, 12/14629-5)