Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY AND ABSTRACT Targeting the Genus Leishmania with Small Molecules Leishmaniasis is a neglected disease caused by protozoan parasites from the genus Leishmania sp. It is transmitted by the sandfly vector and manifests in different clinical forms including skin ulcers, mucosa destruction, damage to visceral organs such as the liver and spleen, and bone marrow damage. The clinical outcome is determined primarily by the species of the parasite and the immune system of the host. There are 98 countries affected by leishmaniasis with more than 2 million people currently infected and 350 million people at risk. The spread of leishmaniasis is of particular concern to US citizens in southern states such as Texas and Oklahoma, where cases have recently been reported, as well as to US military troops stationed abroad in geopolitically unstable regions where the disease tends to thrive. Chemotherapy options for leishmaniasis are limited. Antimonials have been the first line drug for decades in most endemic countries, despite antimony’s notorious adverse effects, hospitalization requirements and increasing cases of antimony-resistant parasites. Amphotericin B, the main alternative treatment, also causes significant harmful side effects. Liposomal formulations are better tolerated, but are prohibitively expensive for most affected populations. Miltefosine, an anti-cancer drug, was recently repurposed to treat leishmaniasis and is the only oral treatment available and approved for use in the US. Miltefosine also has toxicity limitations, teratogenicity and lack of efficacy against certain Leishmania species. The development of new chemotherapies to treat the different clinical forms of leishmaniasis is in urgent demand, and is clearly an unmet medical need. To address this unmet medical need, Scott Schaus and Lauren Brown from Boston University (BU) will lead a collaborative project with Jair Lage Siqueira-Neto at the UC San Diego Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Camila Indiani de Oliveira at FIOCRUZ and Mark Grinstaff at BU to characterize the activity of antileishmanial small molecules and develop them as systemic and topical therapeutics. Preliminary work by the team has led to the identification of a chemotype with nanomolar in vitro efficacy against both visceral- and cutaneous-causative species of the parasite, a suitable pharmacokinetic profile for in vivo studies, and demonstrated in vivo efficacy in a cutaneous leishmaniasis infection model. This grant outlines a proposal to further develop the chemotype and address specific challenges in antileishmanial drug discovery, including drug target identification, options for dosing and administration, and most importantly the applicability of the chemotype to treat multiple manifestations of the disease, including those that are most relevant and endemic to the American continents. Our end goal is to develop at least one pre- clinical candidate for the treatment of either visceral or cutaneous leishmaniasis.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
