Gene drive blocks malaria transmission in mosquitoes

Employing a strategy known as ‘population modification’, which involves using a CRISPR-Cas9 gene drive system to introduce genes preventing parasite transmission into mosquito chromosomes, University of California (UC) researchers have made a major advance in the use of genetic technologies to control the transmission of malaria parasites. Their work has been published in the journal Nature Communications.

Adriana Adolfi, a postdoctoral researcher at the University of California, Irvine (UCI), collaborated with colleagues at UCI, UC Berkeley and UC San Diego who had been working on CRISPR-based gene drive systems for making mosquito vectors resistant to transmitting malaria parasites by increasing gene drive effectiveness in female mosquito progeny. The team’s original gene drive, developed in 2015 for the Indo-Pakistani malaria vector mosquito Anopheles stephensi, was the first demonstration of a CRISPR-based gene drive in mosquitoes.

In that first study, published in the journal Proceedings of the National Academy of Sciences, the gene drive was transmitted to about 99% of progeny when the parent in which the gene drive was inserted was a male, but only 60–70% of offspring when the parent in which the gene drive was inserted was a female. A significant number of drive-resistant chromosomes are generated in females; this, in principle, could allow those females to continue to transmit parasites.

Adolfi and collaborators solved the failure to drive efficiently through females by equipping the gene drive with a functional copy of the target gene into which the drive is inserted. Normal function of this target gene is required in this mosquito species for female survival and fertility after she feeds on blood, and its functionality is usually disrupted when the drive system is inserted into the gene. The resulting female mosquitoes showed strong and consistent drive in a population cage study and negligible production of drive-resistant chromosomes.

This strategy of inserting a gene drive into a gene essential for viability or fertility, and at the same time including a functional gene that rescues the loss of viability or fertility, provides a general solution to drive resistance through females. The new system also efficiently eliminates genetic errors made in the drive process.

“This work mitigates a big issue with the first gene drive systems, which is the accumulation of drive-resistant mosquitoes that could still transmit malaria parasites,” said UCI Professor Anthony James, a co-primary investigator on the study.

“The second-generation gene drive system described in this paper can be applied to any of the several thousand genes that are essential for insects to survive or reproduce,” added UC San Diego Distinguished Professor Ethan Bier, a co-author on the study. “While it was developed in fruit flies, this system is readily transportable to a broad selection of insect species that serve as vectors for devastating disorders such as Chagas disease, sleeping disease, leishmaniasis and arboviral diseases.”

The new gene drive system — in combination with genes for blocking parasite transmission — can now be used to design field-ready strains of mosquitoes, the researchers say. Thorough testing is, however, required to demonstrate safety and efficacy before advancing to field testing.

Image caption: UCI vector biologist Anthony James. Image credit: Steve Zylius/UCI.

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