RNA encoded nanobody-based immunotherapeutics targeting essential, host-interactive schistosome ectoenzymes

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Schistosomes are parasitic flatworms that cause a chronic, debilitating disease afflicting >200 million people in >70 countries. Since there are limited anti-schistosome drugs available and since these is no vaccine to prevent infection, we aim here to generate and test nanobody-based immunotherapeutics targeting essential surface-exposed parasite proteins as a novel intervention to control schistosomiasis. Nanobodies (camelid single- domain antibodies or VHHs) are small, versatile binding agents that can be multimerized for enhanced activities and delivered effectively by formulated mRNA. We have identified and characterized three S. mansoni tegumental ectoenzymes (SmNPP5, SmT-AChE, SmCA) that represent novel molecular targets for intervention to treat schistosomiasis. Each of the three enzymes is exposed at the host parasite interface and each is essential for the parasite to infect its vertebrate host. We aim to generate nanobodies that inhibit the function of these three target enzymes (each enzyme has been purified in functional form in CHO-S cells). The small size, stability to heat and pH extremes, low immunogenicity, and facility to express as multimers with enhanced activities, makes VHHs preferred therapeutic agents. We exploit advances in RNA therapeutics as our strategy to efficiently and economically deliver sustained levels of serum VHH-based therapeutics. Our overall goal is to generate a simple, practical, and potent anti-schistosome therapeutic that curtails disease at all stages of infection. In sum, we have identified new, well characterized, accessible and rational targets for anti-schistosome intervention, and we incorporate an innovative, novel, cutting-edge approach to control schistosomiasis. We have assembled a strong team and have on-hand all reagents and tools necessary to ensure the success of this project. Our data will act as a proof of principle supporting an approach that, in the longer term, could form the basis of a new therapeutic for human schistosomiasis, as well as for other debilitating helminth diseases.