UC researchers are pioneering a more effective way to block malaria...

Using a strategy known as “population modification,” which involves using a CRISPR-Cas9 gene propulsion system to introduce genes that prevent parasite transmission into mosquito chromosomes, University of California researchers have made a great leap forward in the use of genetic technologies for the Control of the transmission of made malaria parasites.

Postdoctoral fellow Adriana Adolfi of the University of California at Irvine, working with colleagues from UCI, UC Berkeley and UC San Diego, pursued the group’s pioneering efforts to develop CRISPR-based gene drive systems to make mosquito vectors resistant to the transmission of malaria parasites Genetic drive in female mosquito offspring.

“This work alleviates a major problem with the early gene propulsion systems, namely the buildup of propulsion-resistant mosquitoes that can still transmit malaria parasites,” said UCI vector biologist Anthony James, Donald Bren Professor of Microbiology and Molecular Genetics and Molecular Biology & Biochemistry, who co -Primary Investigator was involved in the study.

“The second generation gene propulsion system described in this article can be applied to any of the several thousand genes that are essential for insects to survive or reproduce,” said Ethan Bier, co-author of the study at UC San Diego Scientific Director at Tata Institute of Genetics and Society. “While this system was developed in fruit flies, it can be easily transported to a wide variety of insect species that act as vectors for devastating diseases such as Chagas disease, sleeping sickness, leishmaniasis, and arbovirus diseases.”

Study results appear in Communication with nature. They describe a highly efficient version of the second generation of the team’s original gene drive developed for the Indo-Pakistani malaria vector mosquito Anopheles stephensi. The work from 2015, published in Procedure of the National Academy of Sciences, war the first demonstration of a CRISPR-based gene drive in mosquitoes.

In this first study, the gene drive was transmitted to about 99 percent of the offspring if the parent the gene drive was inserted into was a male, but only 60 to 70 percent of the offspring if the parent who the gene drive was inserted into was a male. was female. A significant number of drive-resistant chromosomes are created in women; This could, in principle, allow these women to continue transmitting parasites.

Adolfi, lead author of the new study, and coworkers solved the failure to drive efficiently by women by equipping the gene engine with a functional copy of the target gene into which the engine was inserted. The normal function of this target gene in this species of mosquito is necessary for the survival and fertility of the woman after it has fed on blood, and its functionality is usually disrupted when the drive system is introduced into the gene.

The resulting female mosquitoes showed strong and persistent drive and negligible production of drive-resistant chromosomes in a population cage study. This strategy of inserting a gene drive into a gene essential to viability or fertility while including a functional gene that rescues the loss of viability or fertility offers a general solution to promoting resistance in women. As with a catalytic converter that removes combustion pollution from automobiles, the new system also eliminates genetic errors that occur in propulsion.

This gene propulsion system can now be used in combination with genes to block parasite transmission to develop field-ready mosquito strains. Thorough testing is required to demonstrate safety and effectiveness before proceeding with field testing.

Nijole Jasinskiene, Hsu-Feng Lee, Arunachalam Ramaiah, JJ Emerson and Kristy Hwang from the UCI; Valentino Gantz, Gerard Terradas, and Emily Bulger from UC San Diego; Jared Bennett and John Marshall of UC Berkeley also participated in the study, which resulted from collaborations between the UCI Malaria Initiative and the UC San Diego Tata Institute of Genetics and Society.

Research support was provided by the Tata Institute of Genetics and Society, the UCI Malaria Initiative, the National Institutes of Health (AI29746, DP5OD023098, and GM123303), and the DARPA Safe Genes program (HR0011-17-2-0047).