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

血吸虫是一种寄生的扁虫，会引起一种慢性的、令人衰弱的疾病。 分布在70个国家的2亿人。由于抗血吸虫药物有限 由于这些都不是预防感染的疫苗，我们在这里的目标是产生和 测试针对基本表面暴露寄生虫的纳米体基免疫疗法 蛋白质作为一种控制血吸虫病的新干预措施。纳米小体(骆驼单核- 结构域抗体或VHH)是可以多聚化的小的、多功能的结合剂 用于增强活动并通过配方的信使核糖核酸有效传递。我们已经确定了 并鉴定了三种曼氏链球菌外膜外酶(SmNPP5、SMT-AChE、 SMCA)代表了干预治疗血吸虫病的新分子靶点。 这三种酶中的每一种都暴露在寄主寄生虫的界面上，每一种都是必不可少的。 使寄生虫感染其脊椎动物宿主。我们的目标是产生纳米体来抑制 这三种靶酶的功能(每种酶都以功能形式进行了纯化 在Cho-S细胞中)。体积小，对高温和极端pH稳定，免疫原性低， 并且便于表达为具有增强活性的多聚体，使VHH成为首选 治疗剂。我们利用RNA疗法的进展作为我们的战略，高效地 并经济地提供基于VHH的血清疗法的持续水平。我们的整体 目标是产生一种简单、实用和有效的抗血吸虫疗法 在感染的所有阶段都能减少疾病。总而言之，我们发现了新的、很好的 有特点的、可获得的和合理的抗血吸虫干预目标，以及 我们结合了创新、新颖、尖端的方法来控制 血吸虫病。我们已经组建了一支强大的团队，手头有所有的试剂和 确保该项目成功所需的工具。我们的数据将作为证据 支持一种方法的原则，从长远来看，这种方法可以形成新的 治疗人类血吸虫病以及其他使人衰弱的蠕虫疾病。

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.