Self-eliminating strategy to control gene drive

控制基因驱动的自我消除策略

• 批准号: 10401434
• 负责人: Zach N. Adelman
• 金额: $ 74.11万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-25 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10401434
• 关键词: Aedes; Alleles; Animal Model; Arboviruses; Arthropods; Behavior; Biological Models; Biology; CRISPR gene drive; CRISPR/Cas technology; Chikungunya virus; Communities; Culicidae; DNA; DNA Repair; Data; Dengue; Development; Direct Repeats; Disease Vectors; Drosophila genus; Drosophila melanogaster; Ecosystem; Effectiveness; Environment; Eukaryota; Excision; Funding; Future; Genes; Genetic Models; Health; Human; Infrastructure; International; Intervention; Length; Longevity; Malaria; Measures; Modeling; Mosquito Control; Natural Resistance; Nature; Population; Population Sizes; Process; Resistance; Series; Site; System; Tail; Target Populations; Technology; Testing; Time; Transgenes; Transgenic Organisms; Yellow Fever; base; combat; density; ds-DNA; expectation; fly; gene drive system; genetic element; hazard; innovation; malaria transmission; novel; nuclease; pathogen; repaired; resistance gene; restoration; safety testing; simulation; targeted nucleases; trait; vector; vector mosquito

The ability to deliver pathogen-resistance genes into mosquito populations has long been sought as a potential alternative for disrupting dengue or malaria transmission where funds and infrastructure are the limiting factors in effective mosquito control. The recent development of effective gene drive transgenes based on CRISPR/Cas9 has largely solved the technical challenges of achieving super-Mendelian introgression, however there exists no means to control or recall such genetic elements once released making safety testing in the relevant environments problematic. Drosophila melanogaster is an extremely trackable genetic model organism, while Aedes aegypti is the main vector of dengue, yellow fever and chikungunya viruses, as well as a model system for studies of other mosquitoes. In this project, we will employ both D. melanogaster and A. aegypti to evaluate a transgene self-elimination strategy whereby a transgene can be pre-programmed to first drive itself into a population and then remove itself from the population without any intervention from the experimenter. We will characterize some of the limiting parameters of the self-elimination system, such as direct repeat length (Aim 1) and number and type of nuclease targeting sites (Aim 2). Finally, we will test this self-elimination strategy in the context of an active gene drive in both flies and mosquitoes (Aim 3). Our innovative approach takes advantage of naturally occurring processes that are conserved throughout eukaryota to completely eliminate all transgenic sequences following potential field releases. Thus, we anticipate that this project will dramatically alter the National and International conversations concerning gene drive technology as a whole, and will raise expectations for what is possible in any future trial to generate pathogen-resistant mosquitoes.

将病原体抗性基因传递到蚊子种群中的能力长期以来一直是 作为阻断登革热或疟疾传播的潜在替代方案， 基础设施是有效控制蚊子的限制因素。的最新发展 基于CRISPR/Cas9的有效基因驱动转基因在很大程度上解决了技术难题， 实现超孟德尔基因渗入的挑战，但是没有办法 控制或召回这些基因元件，一旦释放，在相关的安全测试 环境问题。黑腹果蝇是一种非常容易追踪的遗传模型 埃及伊蚊是登革热、黄热病和基孔肯雅热的主要传播媒介 病毒，以及用于研究其他蚊子的模型系统。在这个项目中，我们将 使用D。melanogaster和A.埃及评估转基因自我消除策略 由此转基因可以被预编程以首先将其自身驱动到群体中，然后 在没有实验者任何干预的情况下从种群中消失。我们将 描述自消除系统的一些限制参数，例如直接 重复长度（Aim 1）和核酸酶靶向位点的数量和类型（Aim 2）。最后我们将 在两种果蝇的主动基因驱动背景下测试这种自我消除策略， 蚊子（目标3）。我们的创新方法利用自然发生的过程 这些基因在真核生物中是保守的， 释放了潜在的磁场因此，我们预计，该项目将大大改变 关于基因驱动技术的国家和国际对话，并将 提高了对未来任何试验中可能产生的病原体抗性的期望， 蚊子