Development of next-generation gene drive technologies for Anopheles population engineering

开发用于按蚊种群工程的下一代基因驱动技术

• 批准号: 10624305
• 负责人: ETHAN BIER
• 金额: $ 46.26万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10624305
• 关键词: Address; Affect; Alleles; Animals; Anopheles Genus; Antimalarials; Biology; Bypass; Child; Chromosomes; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Culicidae; DNA Double Strand Break; DNA cassette; Deposition; Development; Disease; Disease Outbreaks; Drosophila genus; Drosophila melanogaster; Effectiveness; Embryo; Embryonic Development; Endonuclease I; Endowment; Engineering; Failure; Female; Future; Gene Conversion; Generations; Genes; Genetic Engineering; Genome; Goals; Guide RNA; Health; Immune; Impairment; Inherited; Insect Vectors; Insecta; Laboratories; Location; Malaria; Methods; Modification; Morbidity - disease rate; Mosquito-borne infectious disease; Mutation; Parasites; Pathway interactions; Persons; Pesticides; Population; Process; Production; Property; Public Health; Recycling; Research; Resistance; Technology; Testing; Translations; Work; burden of illness; design; disease transmission; egg; fighting; fitness; gene drive system; genetic technology; human pathogen; improved; insertion/deletion mutation; novel; offspring; pathogen; prevent; repaired; resistance allele; response; tool; trait; transmission process; vector; vector mosquito

PROJECT SUMMARY Malaria is currently the most impactful mosquito-borne disease worldwide, sickening 228 million people and killing over 405,000 in 2018, 2/3 of which are young children — the most vulnerable demographic. Several mosquito species of the Anopheles genus can act as vectors of the parasite causing malaria, and in recent years their increasing resistance to pesticides is hampering current control methods and blunting our response to eventual disease outbreaks. Globalization is further allowing both vectors and pathogens to move freely and in certain situations to permanently establish themselves in new locations. CRISPR-based gene drive technologies for mosquito population engineering are being developed as they represent a new promising addition to our arsenal for fighting this disease. These technologies are up-and-coming, yet few issues have come up during their development. Briefly, a gene drive system based on CRISPR is composed of a Cas9 and a gRNA gene inserted in the mosquito genome at the location where the gRNA targets it. The arrangement of this genetic cassette endowed it with self-replicating properties that allow it to propagate to the same location on a wild-type chromosome. This property can be harnessed to spread within a population a beneficial trait that would help reducing disease transmission (population modification), or a deleterious trait to help reduce the mosquito population (suppression). While this process is extremely accurate, it can result in the failure of self-propagating, and the generation of small mutations at the targeted locus preventing further conversion by the gene drive. These “resistance alleles” generated during the drive process have been identified as a major hindrance to field applications of these tools. In addition, due to the deposition of active Cas9 and gRNA in the developing embryo, the mosquito biology allows an extensive production of such resistance alleles when a gene drive is inherited from a female. The long-term goal of this project is to develop powerful gene drive tools that can be used for the fast and reliable engineering of wild Anopheles populations. In order for these tools to be ready to have an impact on the malaria morbidity worldwide, the two issues described above need to be overcome. To tackle these two problems, in the three Aims of the proposed research, we will develop and optimize three parallel technologies in the fruit fly Drosophila melanogaster and subsequently apply them to the major malaria vector Anopheles stephensi.

项目摘要 疟疾目前是全球最有影响力的蚊子疾病，令人作呕的2.28亿人和 2018年杀死405,000多名，其中2/3是年幼的孩子，这是最脆弱的人群。一些 蚊子属的蚊子物种可以充当寄生虫的向量，从而引起疟疾，并且在最近 多年来，他们对农药的抵抗力增加正在阻碍当前的控制方法并削弱我们的反应 最终疾病暴发。全球化进一步使媒介和病原体都可以自由移动和 在某些情况下，可以永久建立在新地点。 基于CRISPR的基因驱动技术用于蚊子人口工程技术正在开发 代表了我们的武器库与这种疾病作斗争的新诺言。这些技术是 有前途的，但在他们的发展过程中很少出现问题。简而言之，基于基因驱动系统 CRISPR由CAS9和GRNA基因组成，该基因插入了蚊子基因组中的位置 GRNA针对它。这种遗传盒的布置赋予了它的自我复制特性，允许 它可以在野生型染色体上传播到同一位置。可以利用此属性传播 在人群中，有助于减少疾病传播（人口修改）或 有害特征可帮助减少蚊子种群（抑制）。 尽管此过程非常准确，但它可能导致自我传播的失败，并产生 靶向基因座的小突变阻止了基因驱动的进一步转化。这些“抵抗力 在驱动过程中产生的等位基因”已被确定为对现场应用的主要障碍 这些工具。另外，由于活性cas9和GRNA在发育中的胚胎中的沉积，蚊子 当基因驱动从女性继承时，生物学允许广泛产生这种抗性等位基因。 该项目的长期目标是开发可用于快速和快速和 可靠的野性蚊帐的工程。 为了使这些工具准备好对全球疟疾发病率产生影响，这两个问题 上面描述的需要克服。解决这两个问题，在提议的三个目标中 研究，我们将在果蝇果蝇中开发并优化三种并行技术 随后将它们应用于主要的疟疾载体atopheles stephensi。

项目成果

A nickase Cas9 gene-drive system promotes super-Mendelian inheritance in Drosophila.

• DOI: 10.1016/j.celrep.2022.110843
• 发表时间: 2022-05-24
• 期刊: CELL REPORTS
• 影响因子: 8.8
• 作者: Del Amo, Victor Lopez;Juste, Sara Sanz;Gantz, Valentino M.
• 通讯作者: Gantz, Valentino M.

Ethical Considerations for Gene Drive: Challenges of Balancing Inclusion, Power and Perspectives.

• DOI: 10.3389/fbioe.2022.826727
• 发表时间: 2022
• 期刊: Frontiers in bioengineering and biotechnology
• 影响因子: 5.7
• 作者: Kormos A;Lanzaro GC;Bier E;Santos V;Nazaré L;Pinto J;Aguiar Dos Santos A;James AA
• 通讯作者: James AA

Application of the Relationship-Based Model to Engagement for Field Trials of Genetically Engineered Malaria Vectors.

• DOI: 10.4269/ajtmh.20-0868
• 发表时间: 2020-12-21
• 期刊: The American journal of tropical medicine and hygiene
• 作者: Kormos A;Lanzaro GC;Bier E;Dimopoulos G;Marshall JM;Pinto J;Aguiar Dos Santos A;Bacar A;Sousa Pontes Sacramento Rompão H;James AA
• 通讯作者: James AA