To develop in vitro and in vivo predictive models for the evaluation of new drugs and new pharmaceutical formulations for the treatment of cutaneous leishmaniasis. To reduce the number of animals used in experiments in line with EU wide 3Rs policy and search for alternatives.
(1) New in vitro cellular and tissue models of infection, using mouse and human stem cells and skin, established for evaluation of new drugs
(2) New methodology based on microdialysis to evaluate the penetration kinetics and distribution (pharmacokinetics) of drugs in infected skin
(3) Identification of 1 novel drug for cutaneous leishmaniasis and
(4) Development of a topical formulation of the drug
Background: Although there has been significant progress in the discovery and development of new drugs and treatments for visceral leishmaniasis (VL), there has been limited for cutaneous leishmaniasis (CL). The different sensitivity of Leishmania species that cause CL, the dermal site of development of the infection, and the lack of predictive rodent models, demand a re-evaluation of the methodologies for drug discovery and development for this disease.
Methodology: The project will be based on taking 2-3 hit and lead compounds with anti-leishmanial activity through the R & D process, and investigate, through comparative studies with older models – (a) improved reproducible in vitro activities through homogenous stem cell macrophage populations (b) the use of flow culture methods, in comparison with static culture, differences in drug sensitivities, (c) the ability to maintain infection and test drugs on both ex vivo skin and skin tissue cultures, with qPCR and colorimetric assays to determine parasite and host cell viabilities, (d) use of skin strip and microdialysis methodologies, linked to LC-MS MS, the kinetics of drug penetration and distribution in mouse skin, developing a methodology which can also be used to assess the effectiveness of specific topical formulations.