SBIR Phase II: A Platform for Anthelmintic Drug Discovery using Genome-modified C. elegans

这个小企业创新研究（SBIR）第二阶段项目的更广泛的影响/商业潜力是开发一个平台，用于发现新的驱虫（抗寄生虫）药物。目前市场上所有的驱虫剂都出现了耐药性。目前的药物开发只是向现有的药物靶点引入新的分子。结果，这些新药的耐药性迅速上升，使它们在上市后不久就失效了。如果没有足够的有效驱虫药来源，牲畜产量、作物损失和人力资本将开始受到影响。这种社会负担正在全球范围内造成总计数千亿美元的经济损失。通过专注于一种控制感染生命形式进入的新型药物靶点，该提案旨在产生一类新的驱虫药来对抗这一日益严重的问题。将这种潜在的新型驱虫药商业化的制药公司将获得每年15亿美元或更多的市场潜力。SBIR二期项目建议开发一个利用基因工程线虫（秀丽隐杆线虫）发现新的驱虫药物的平台。所使用的方法将插入一段寄生虫基因来取代一段本地基因。由此产生的嵌合体基因将秀丽隐杆线虫转化为一种更好地模仿寄生虫状态的形式。在嵌合体表达的线虫上发现有活性的药物，然后通过对寄生虫感染模型的有效性测试，将其提炼成先导物。该提案的嵌合体平台适应了多种寄生虫基因。由此产生的多样化平台有望为发现和最终引入一类具有广谱活性的新型抗寄生虫药物提供快速途径。

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase II project is the development of a platform for the discovery of new anthelmintic (anti-parasite) drugs. Drug resistance is occurring with all anthelmintics currently on the market. Current drug development only introduces new molecules to the existing drug targets. As a result, drug resistance quickly jumps to these new drugs, which makes them ineffective shortly after market introduction. Without an adequate source of effective anthelmintics, livestock yields, crop damage, and human capital are starting to suffer. The social burden is creating economic losses totaling hundreds of billions of dollars worldwide. By focusing on a novel drug target that controls entry into infective life forms, this proposal aims to generate a new class of anthelmintics to combat this growing problem. The drug companies that commercialize this potential new class of anthelmintics will access a market potential of $1.5 B per year or more.The SBIR Phase II project proposes to develop a platform for the discovery of new anthelmintic drugs using genetically engineered nematods (C. elegans). The approach used will insert a segment of a parasite gene in replacement of a segment of a native gene. The resulting chimera gene converts the C. elegans nematode into a form that better mimics the parasite state. Drug hits found active on the chimera-expressing nematode are then refined into leads by testing for efficacy against parasite infection model. The proposal's chimera platform is adapted to a diverse set of parasite genes. The resulting diverse platform is expected to provide a rapid path to discovery and eventual introduction of a novel class of anti-parasite drugs with broad-spectrum activity.