基因驱动技术在蚊媒疾病防控中的研究进展与挑战

doi:10.12300/j.issn.1674-5817.2025.138

实验动物与比较医学 ›› 2025, Vol. 45 ›› Issue (6): 773-783.DOI: 10.12300/j.issn.1674-5817.2025.138

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基因驱动技术在蚊媒疾病防控中的研究进展与挑战

贠佳琦¹^,², 马芹¹^,², 王官栋¹, 孙佩璐¹, 王义冠¹, 王四宝¹()()

^1.中国科学院分子植物科学卓越创新中心, 上海 200032
^2.华东理工大学生物工程学院, 上海 200237

收稿日期:2025-09-05 修回日期:2025-10-14 出版日期:2025-12-25 发布日期:2025-12-19
作者简介:贠佳琦（1997—），女，博士研究生，研究方向：医学媒介昆虫与微生物互作。E-mail： yunjiaqi@cemps.ac.cn；
马芹（1998—），女，博士研究生，研究方向：医学媒介昆虫与微生物互作。E-mail： maqin23@cemps.ac.cn
王四宝，（1972—），男，博士，研究员，研究方向：医学媒介昆虫与微生物互作。E-mail： sbwang@cemps.ac.cn。ORCID： 0000-0002-5880-0815
基金资助:
国家自然科学基金项目“按蚊长链非编码RNA SW1调控生殖与免疫权衡的分子机制”(32230015);“昆虫发育的分子遗传与微生物互作调控”(32021001)

Research Advances and Challenges of Gene Drive Technology in Mosquito-Borne Disease Control

YUN Jiaqi¹^,², MA Qin¹^,², WANG Guandong¹, SUN Peilu¹, WANG Yiguan¹, WANG Sibao¹()()

^1.Chinese Academy of Sciences Center for Excellence in Molecular Plant Science, Shanghai 200032, China
^2.East China University of Science and Technology, School of Biotechnology, Shanghai 200237, China

Received:2025-09-05 Revised:2025-10-14 Published:2025-12-25 Online:2025-12-19
Contact: WANG Sibao (ORCID:0000-0002-5880-0815), E-mail: sbwang@cemps.ac.cn

摘要/Abstract

摘要：

蚊媒疾病（如疟疾、登革热、寨卡病毒病、基孔肯雅热等）对全球公共卫生造成了重大威胁，然而基于化学农药的传统防控手段面临着媒介蚊虫耐药性增强、污染环境等严峻挑战。遗传控制策略因具有物种特异性及环境友好等优势，成为蚊媒控制中极具潜力的替代方案。基因驱动（gene drive）技术利用成簇规律间隔短回文重复序列（clustered regularly interspaced short palindromic repeats，CRISPR）/CRISPR相关蛋白核酸酶9（CRISPR-associated nuclease 9，Cas9）等基因编辑工具，使特定基因以超孟德尔遗传的方式在目标蚊种群中高效传播，为蚊媒疾病防控提供了革命性策略。本文系统综述了基因驱动技术在该领域的关键进展、核心挑战及应对策略。研究进展：（1）在疟疾媒介按蚊中，靶向性别决定基因或雌性生殖基因的种群抑制型驱动可致雌性不育或性别失衡，实现种群抑制；靶向按蚊中与疟原虫感染相关的宿主基因或递送抗疟疾效应分子的种群替代型基因驱动策略，可有效阻断病原体传播。（2）在蚊媒病毒媒介伊蚊中，靶向雌蚊飞行必需基因实现种群抑制，并探索抗病毒效应系统与驱动元件的偶联；优化的分割型基因驱动策略展现出高切割与重组效率，模型预测可实现抗病性状的安全可控扩散。（3）在淋巴丝虫病媒介库蚊中，将同源驱动元件分别整合至两个参与眼睛色素合成通路的基因中，可以通过眼色观察到明显的基因驱动效率。核心挑战：技术层面存在同源重组修复效率低、非同源末端连接修复导致抗性等位基因产生、CRISPR/Cas9脱靶效应及物种适配性差异；生态与安全层面涉及驱动元件意外扩散导致的基因池污染、生态平衡潜在影响及长期不可逆性风险。应对策略与展望：采用多重向导RNA（guide RNA，gRNA）靶向策略以提升驱动稳定性和对抗潜在抗性；开发可逆性设计，如合成抗性、逆转驱动及免疫性逆转驱动作为“基因刹车”；建立长期生态监测系统与数学模型进行风险评估；探索“环境响应型驱动”以增强可控性。未来研究亟须持续优化驱动效率与特异性，深化生态风险评估，加强跨国合作，并推动伦理共识与监管框架构建，以期在安全可控前提下，使基因驱动技术成为应对蚊媒疾病这一全球健康挑战的可持续性防控策略。

关键词: 基因驱动, 蚊媒疾病, 种群抑制/种群替代, CRISPR/Cas9

Abstract:

Mosquito-borne diseases (such as malaria, dengue fever, Zika virus disease, and Chikungunya) pose major threats to global public health, while traditional control methods based on chemical pesticides face severe challenges including enhanced drug resistance in vector mosquitoes and environmental pollution. Genetic control strategies have become high-potential alternative solutions for mosquito control due to their species specificity and environmental friendliness. Gene drive technology uses gene editing tools such as clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated nuclease 9 (Cas9) to enable specific genes to efficiently spread in target mosquito populations through "super-Mendelian inheritance", offering a revolutionary strategy for the prevention and control of mosquito-borne diseases. This review systematically summarizes key advances, core challenges, and response strategies of gene drive technology in this field. Research advances: (1) In Anopheles malaria vectors, population suppression drives targeting sex determination genes or female reproductive genes can cause female sterility or skewed sex ratios to achieve population suppression. Population replacement gene drive strategies targeting host genes associated with Plasmodium infection or delivering anti-Plasmodium effector molecules in Anopheles can effectively block pathogen transmission. (2) In Aedes mosquito vectors of arboviruses, targeting female flight-essential genes achieves population suppression, and coupling of antiviral effector systems with drive elements is explored. Optimized split gene drive strategies demonstrate high cutting and recombination efficiency, and models predict safe and controllable spread of disease-resistance traits. (3) In Culex mosquitoes transmitting lymphatic filariasis, homology drive elements are integrated into two genes involved in the eye pigment synthesis pathway, allowing clear visualization of gene drive efficiency through eye color. Core Challenges: technological challenges include low homologous recombination repair efficiency, non-homologous end joining repair causing resistance allele generation, CRISPR/Cas9 off-target effects, and species adaptation differences. Ecological and safety challenges involve gene pool pollution caused by accidental spread of drive elements, potential ecological balance impacts, and long-term irreversible risks. Response strategies and prospects: employing multiplex guide RNA (gRNA) targeting strategies to enhance drive stability and combat potential resistance. Developing reversible designs such as synthetic resistance, reversal drives, and immunizing reversal drives as "genetic brakes". Establishing long-term ecological monitoring systems and mathematical modeling for risk assessment. Exploring "environmentally responsive drives" to enhance controllability. Future research should continuously optimize drive efficiency and specificity, deepen ecological risk evaluation, strengthen international cooperation, and promote ethical consensus and regulatory framework construction, with the aim of making gene drive technology a sustainable prevention and control strategy to address the global health challenge of mosquito-borne diseases under the premise of safety and controllability.

Key words: Gene drive, Mosquito-borne diseases, Population suppression/population replacement, CRISPR/Cas9

中图分类号:

Q95-33

贠佳琦,马芹,王官栋,等. 基因驱动技术在蚊媒疾病防控中的研究进展与挑战[J]. 实验动物与比较医学, 2025, 45(6): 773-783. DOI: 10.12300/j.issn.1674-5817.2025.138.

YUN Jiaqi,MA Qin,WANG Guandong,et al. Research Advances and Challenges of Gene Drive Technology in Mosquito-Borne Disease Control[J]. Laboratory Animal and Comparative Medicine, 2025, 45(6): 773-783. DOI: 10.12300/j.issn.1674-5817.2025.138.

图/表 3

图1 基于不同驱动元件的基因驱动类型注：A，减数分裂介导的基因驱动，X染色体粉碎导致强烈的性别比例扭曲，后代趋于雄性；B，基于归巢核酸内切酶的基因驱动，归巢核酸内切酶能够识别并切割特定DNA序列，触发同源重组修复机制；C，基于转座子和转座酶系统的基因驱动，转座酶催化转座子的插入和移动，将目标基因随机插入宿主基因组中；D，基于CRISPR/Cas9系统的基因驱动，将驱动基因定点插入目标基因位点，并利用Cas9蛋白持续切割野生型等位基因。

Figure 1 Gene drive types based on different driver elementsNote： A， Meiosis-mediated gene drive， X chromosome shattering leads to a strong sex ratio distortion， with offspring tending to be male； B， Gene drive based on meganuclease， meganuclease recognizes and cuts specific DNA sequence， triggering the homologous recombination repair mechanism； C， Gene drive based on transposon and transposase systems， transposases catalyze the insertion and movement of transposons， randomly inserting target genes into the host genome； D， Gene drive based on the CRISPR/Cas9 system， the drive gene is precisely inserted into the target gene locus， and the Cas9 protein continuously cuts the wild-type allele.

图2 基于功能划分的基因驱动类型注：A，种群抑制型基因驱动，通过设计具有“自私遗传”特性的基因元件，在蚊媒种群中快速扩散致死性或生殖干扰性基因，最终实现种群数量抑制；B，种群替代型基因驱动，通过基因编辑赋予蚊媒抗病特性，在不显著改变种群数量的前提下阻断病原体传播链。

Figure 2 Gene drive types based on functional classificationNote： A， Population suppression gene drive， by designing genetic elements with "selfish inheritance" characteristics， rapidly spreads lethal or reproduction-interfering genes in the mosquito population， ultimately achieving population suppression； B， Population replacement gene drive： through gene editing， endows mosquitoes with disease-resistance characteristics， blocking the transmission chain of pathogens without significantly altering the population size.

表1 基因驱动技术在防控蚊媒疾病中的主要进展

Table 1 Main advances of gene drive technology in mosquito-borne disease control

蚊虫品种 Mosquito species	靶标 Target	基因驱动类型 Gene drive type	参考文献 Reference
冈比亚按蚊 Anopheles gambiae	ribosomal gene	减数分裂介导的基因驱动	Galizi R, et al. (2014)^[22]
	doublesex	CRISPR/Cas9介导的基因驱动 CRISPR/Cas9介导的基因驱动 CRISPR/Cas9介导的基因驱动 CRISPR/Cas9介导的基因驱动 CRISPR/Cas9介导的基因驱动	Kyrou K, et al. (2018)^[18]
	female-sterility gene		Hammond A, et al. (2016)^[19]
	fibrinogen-related protein 1		Dong Y, et al. (2018)^[20]
	cardinal		Carballar-lejarazu R, et al. (2020)^[21]
	single chain variable fragment		Carballar-lejarazu R, et al. (2023)^[26]
斯氏按蚊 Anopheles stephensi	doublesex	CRISPR/Cas9介导的基因驱动 CRISPR/Cas9介导的基因驱动	Xu X, et al. (2025)^[23]
斯氏按蚊 Anopheles stephensi	kynurenine hydroxylase	CRISPR/Cas9介导的基因驱动 CRISPR/Cas9介导的基因驱动	Gantz V M, et al. (2015)^[27]
科卢兹按蚊 Anopheles coluzzii	Saglin	CRISPR/Cas9介导的基因驱动	Green E I, et al. (2023)^[25]
致倦库蚊 Culex quinquefasciatus	cardinal, white, kynurenine 3-monooxygenase	CRISPR/Cas9介导的基因驱动CRISPR/Cas9介导的基因驱动	Feng X C, et al. (2021)^[36]
埃及伊蚊 Aedes aegypti	AeAct-4, myo-fem	CRISPR/Cas9介导的基因驱动CRISPR/Cas9介导的基因驱动	O'Leary S, et al. (2020)^[29]
	white	CRISPR/Cas9介导的基因驱动CRISPR/Cas9介导的基因驱动	Li M, et al. (2020)^[34]
	inverted repeat RNA	归巢核酸内切酶介导的基因驱动	Franz A W, et al. (2006)^[30] Williams A E, et al. (2020)^[31]
	single chain variable fragment	转座子介导的基因驱动	Buchman A, et al. (2020)^[32]

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基因驱动技术在蚊媒疾病防控中的研究进展与挑战

Research Advances and Challenges of Gene Drive Technology in Mosquito-Borne Disease Control

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