As a group, neglected tropical diseases disproportionately impact impoverished and underserved communities, and particularly women and children. Morbidity associated with these diseases makes up a significant component of their burden, and has far-reaching and long-lasting consequences for those infected, affecting their ability to marry, gain an education, and earn a living. Two such diseases, caused by parasitic nematodes, are lymphatic filariasis and onchocerciasis. Individuals with lymphatic filariasis can suffer lymphedema and debilitating elephantiasis; those with onchocerciasis may experience severe skin disease and blindness. Current control methods for these diseases call for annual or bi-annual mass administration of the antihelminthics ivermectin and/or albendazole. This treatment kills the larval stages responsible for transmission and temporarily sterilizes the female adult parasites, though does not cause death of the long-lived adult stages. As a result, mass drug administration must be maintained for five to seven years in the case of lymphatic filariasis and fourteen to seventeen years in the case of onchocerciasis in order to break the transmission cycle and achieve elimination. Development of a macrofilaricide capable of killing these adult forms is needed, but technical challenges in drug discovery for these parasites have limited progress. A particular example is that the adult forms of the relevant parasite species are not readily cultivated: the difficulty in obtaining these parasites, coupled with their relatively large size, has limited the throughput of compound screening activities, and as a result, restricted the chemical space that has been explored. A broader issue is that the underlying biology related to survival of adult worms is incompletely understood, and the available tools in the native worm species are very limited. As a result, the mechanism-of-action for hits stemming from whole-organism phenotypic screens is difficult to elucidate and target-based drug discovery efforts have been limited. While use of C. elegans purely as a surrogate screening organism for discovery of antihelminthics has been explored in the past with limited success, leveraging the suite of sophisticated genetic and cellular tools and techniques developed for this organism over the past 50 years could significantly open up the biology of parasitic nematodes, as well as new, orthologous approaches for drug discovery sorely needed to accelerate discovery of macrofilaricidal agents.
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