Abstract
While efforts to control malaria with available tools have stagnated, and arbovirus outbreaks persist around the globe, the advent of clustered regularly interspaced short palindromic repeat (CRISPR)-based gene editing has provided exciting new opportunities for genetics-based strategies to control these diseases. In one such strategy, called “population replacement”, mosquitoes, and other disease vectors are engineered with effector genes that render them unable to transmit pathogens. These effector genes can be linked to “gene drive” systems that can bias inheritance in their favor, providing novel opportunities to replace disease-susceptible vector populations with disease-refractory ones over the course of several generations. While promising for the control of vector-borne diseases on a wide scale, this sets up an evolutionary tug-of-war between the introduced effector genes and the pathogen. Here, we review the disease-refractory genes designed to date to target Plasmodium falciparum malaria transmitted by Anopheles gambiae, and arboviruses transmitted by Aedes aegypti, including dengue serotypes 2 and 3, chikungunya, and Zika viruses. We discuss resistance concerns for these effector genes, and genetic approaches to prevent parasite and viral escape variants. One general approach is to increase the evolutionary hurdle required for the pathogen to evolve resistance by attacking it at multiple sites in its genome and/or multiple stages of development. Another is to reduce the size of the pathogen population by other means, such as with vector control and antimalarial drugs. We discuss lessons learned from the evolution of resistance to antimalarial and antiviral drugs and implications for the management of resistance after its emergence. Finally, we discuss the target product profile for population replacement strategies for vector-borne disease control. This differs between early phase field trials and wide-scale disease control. In the latter case, the demands on effector gene efficacy are great; however, with new possibilities ushered in by CRISPR-based gene editing, and when combined with surveillance, monitoring, and rapid management of pathogen resistance, the odds are increasingly favoring effector genes in the upcoming evolutionary tug-of-war.
Highlights
While a dramatic reduction in malaria-related deaths was seen in the early part of this century, progress has halted since 2015 (Bhatt et al, 2015; Feachem et al, 2019), and models predict that elimination is not possible in the majority of diseaseendemic countries with currently available tools (Walker et al, 2016)
We review the disease-refractory effectors designed to date to target the malaria parasite Plasmodium falciparum transmitted by Anopheles gambiae, and arboviruses transmitted by Ae. aegypti, including dengue virus (DENV) serotypes 1–4, CHIKV, and ZIKV
We conclude with a discussion of the target product profile (TPP) for gene drive systems intended for vector-borne disease control, with emphasis on the time span that the effector genes should be prevalent and functional in the vector population
Summary
While efforts to control malaria with available tools have stagnated, and arbovirus outbreaks persist around the globe, the advent of clustered regularly interspaced short palindromic repeat (CRISPR)-based gene editing has provided exciting new opportunities for geneticsbased strategies to control these diseases. In one such strategy, called “population replacement”, mosquitoes, and other disease vectors are engineered with effector genes that render them unable to transmit pathogens.
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