Impact of gene-drive systems for population modification on malaria vector mosquitoes

基因驱动系统对疟疾媒介蚊子种群改造的影响

• 批准号: 10658710
• 负责人: George Dimopoulos
• 金额: $ 109.21万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-09 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658710
• 关键词: Accounting; Address; Africa; Africa South of the Sahara; Alleles; Anopheles gambiae; Area; Automobile Driving; Biology; CRISPR/Cas technology; Cessation of life; Cities; Clustered Regularly Interspaced Short Palindromic Repeats; Communities; Complement; Country; Culicidae; DNA; Deceleration; Development; Disease; Ecology; Engineering; Environment; Event; Future; Gene Dosage; Generations; Genes; Genetic; Genetic Engineering; Genetic Load; Genetic Recombination; Genetic Structures; Genome; Goals; Guide RNA; Immigration; Infection; Insecta; Knowledge; Laboratories; Maintenance; Malaria; Measurable; Measures; Modeling; Modification; Molecular; Molecular Genetics; Morbidity - disease rate; Parasite resistance; Parasites; Partner in relationship; Performance; Persons; Population; Predisposition; Prevalence; Property; Refractory; Research; Resistance; Science; Site; Source; Southern Asia; Structure; System; Technology; Testing; Therapeutic; Time; Transgenes; Transgenic Organisms; Vaccines; Work; World Health Organization; cost effective; design; disorder control; drug discovery; endonuclease; gene drive system; genetic approach; genetic element; indexing; innovation; malaria transmission; mortality; novel; novel therapeutics; population migration; prevent; programs; prophylactic; repaired; reproductive fitness; reproductive success; resilience; success; tool; transmission blocking; transmission process; vector; vector control; vector mosquito

Project Summary While significant progress has been made in reducing the malaria burden since the turn of the century, the last few years have seen a deceleration of this success and the World Health Organization (WHO) in its 2020 World Malaria Reportestimates ~229 million cases (morbidity) and 409,000 deaths (mortality) in 2019. Approximately 95% of the global malaria deaths occurred in only 31 countries with seven in sub-Saharan Africa accounting for ~51% of all the deaths. Furthermore, the WHO predicts no further significant decreases without greater use of the existing technologies and the necessary development of new tools. The challenges of the continued demand for new drugs and the slow roll-out of an efficacious vaccine makes urgent the need for new, cost-effective and efficacious disease-control tools that are safe for people and the environment. This need justifies efforts to develop genetic approaches for controlling malaria parasite transmission. Long-term, sustainable genetic control will require the deployment of strategies designed to be resilient to the immigration of susceptible mosquitoes and parasite-infected people. Genetically-engineered mosquito strains for population modification have the appropriate performance features for this purpose. Wild mosquitoes immigrating into a region populated by engineered, parasite-resistant mosquitoes will acquire beneficial genes by mating with the local insects, and persons with malaria moving into the same region will not be able to infect the resident vectors, and therefore are not a source for infection of other people. We have exploited the molecular mechanisms of CRISPR/Cas biology to develop autonomous gene-drive systems for site-specific, transgene copy number amplification in the mosquito germline. These drive systems carry a cargo of anti-parasite effector genes that prevent transmission of the parasites by the mosquitoes carrying them. The working hypothesis is that these systems will be able to impact transmission dynamics even if they confer a genetic load that impacts reproductive fitness. We shall investigate the impact of gene-drive system insertions on the recipient mosquitoes to determine effects on reproductive success and drive and effector gene efficacy and stability. Towards these ends, our Specific Aims are: 1) evaluate the impact of autonomous gene-drive systems on the reproductive success of Anopheles gambiae ss. and An. coluzzii and 2) evaluate the multigenerational stability of autonomous gene-drive systems in Anopheles gambiae ss. and An. coluzzii in laboratory cage trials. The successful completion of these Specific Aims will inform plans and modelling for the future use of this technology in malaria control.

项目摘要 虽然自进入世纪以来在减少疟疾负担方面取得了重大进展，但上个世纪 几年来，这一成功的速度有所减缓，世界卫生组织（世卫组织）在其2020年世界 疟疾报告显示，2019年约有2.29亿例（发病率）和409，000例死亡（死亡率）。 全球约95%的疟疾死亡发生在31个国家，其中7个在撒哈拉以南非洲。 占所有死亡人数的51%此外，世卫组织预测，如果没有 更多地利用现有技术和必要地开发新工具。的挑战 对新药的持续需求和有效疫苗的缓慢推出使得迫切需要新的， 对人类和环境安全的具有成本效益和有效的疾病控制工具。这种需要 证明努力开发控制疟疾寄生虫传播的遗传方法是合理的。长期来看， 可持续的遗传控制将需要部署旨在适应移民的战略， 易感蚊子和寄生虫感染者的数量。用于种群的基因工程蚊子品系 修改具有用于此目的的适当性能特征。野生蚊子迁徙到 一个由工程改造的抗寄生虫蚊子居住的地区将通过与蚊子交配获得有益的基因。 当地昆虫和疟疾患者进入同一地区将无法感染居民 病媒，因此不是感染其他人的来源。我们已经利用了 CRISPR/Cas生物学的机制，以开发用于位点特异性转基因的自主基因驱动系统 蚊子生殖系中的拷贝数扩增。这些驱动系统携带了大量的抗寄生虫药物 防止携带寄生虫的蚊子传播寄生虫的效应基因。工作 一种假设是，这些系统将能够影响传播动态，即使它们赋予遗传负荷 会影响生殖健康我们将研究基因驱动系统插入对 受体蚊子，以确定对繁殖成功的影响以及驱动和效应基因功效， 稳定为了实现这些目标，我们的具体目标是：1）评估自主基因驱动系统的影响 冈比亚按蚊繁殖成功率的研究和一个. coluzzii和2）评估多代 冈比亚按蚊自主基因驱动系统稳定性和一个. coluzzii在实验室笼试验。 这些具体目标的成功完成将为未来使用这些目标的计划和建模提供信息。 疟疾控制技术。