New CRISPR-based system could help eliminate malaria-carrying mosquitoes

Malaria remains a significant global health threat, causing numerous fatalities each year, particularly among children under five. Recently, the Centers for Disease Control and Prevention reported five cases of mosquito-borne malaria in the United States, marking the first instances of local transmission in the country in twenty years.

However, scientists are making progress in developing safe technologies to combat the transmission of malaria. One promising approach involves genetically modifying mosquitoes that carry the malaria parasite. Researchers at the University of California San Diego, led by Professor Omar Akbari, have devised a new method to suppress populations of Anopheles gambiae mosquitoes, which are the primary malaria carriers in Africa and contribute to economic hardship in affected regions.

Their innovative system, named Ifegenia (short for “inherited female elimination by genetically encoded nucleases to interrupt alleles”), specifically targets and eliminates female A. gambiae mosquitoes, as they are responsible for transmitting the disease through biting.

The study, published in the journal Science Advances on July 5, was conducted by first-author Andrea Smidler, a postdoctoral scholar at UC San Diego School of Biological Sciences, along with former master’s students James Pai and Reema Apte, who served as co-first authors. Collaborating with scientists from UC Berkeley and the California Institute of Technology, the team employed CRISPR technology to disrupt a gene called femaleless (fle) that controls sexual development in A. gambiae mosquitoes.

Ifegenia achieves this by genetically incorporating the key components of CRISPR into African mosquitoes. These components include a Cas9 nuclease, which acts as molecular “scissors” for making precise gene edits, and a guide RNA that directs the Cas9 system to the target gene. In Akbari’s lab, the researchers modified two mosquito families to separately express Cas9 and the fle-targeting guide RNA.

This breakthrough represents a significant step forward in the ongoing battle against malaria. By selectively targeting and reducing the female A. gambiae mosquito population, the transmission of malaria can be significantly curtailed, potentially leading to a decrease in the disease’s impact on human populations.

Larva of Anopheles gambiae mosquitoes were injected with CRISPR-based genetic editing tools in a new population suppression system. Credit: Akbari Lab, UC San Diego

Smidler described the results as extraordinary, stating, “When we crossed the mosquitoes together, all the female mosquitoes died.” However, the genetic modification had no impact on the reproductive abilities of male A. gambiae mosquitoes. They remained fully capable of reproducing and spreading the Ifegenia system.

As a result, the spread of the malaria parasite was eventually halted because the female mosquitoes, responsible for transmitting the disease, were eliminated, leading to a reproductive dead end for the population. The authors of the study highlight that Ifegenia overcomes certain challenges faced by other genetic control methods, such as gene drives, by keeping the Cas9 and guide RNA components separate until the population is ready to be suppressed.

The researchers state in their paper, “We show that Ifegenia males remain reproductively viable and can carry both fle mutations and CRISPR machinery to induce fle mutations in subsequent generations, resulting in sustained population suppression. Through modeling, we demonstrate that iterative releases of non-biting Ifegenia males can serve as an effective, controllable, safe, and confinable system for population suppression and elimination.”

Conventional methods of combating the spread of malaria, such as bed nets and insecticides, have proven to be increasingly ineffective. Insecticide use continues to be widespread, primarily aimed at curbing malaria, but it poses health and ecological risks in African and Asian regions.

Smidler, who obtained a Ph.D. in biological sciences of public health from Harvard University before joining UC San Diego, applies her expertise in genetic technology development to address the spread of malaria and its associated economic burdens. The effectiveness of Ifegenia as a suppression system surprised her and her colleagues.

Professor Akbari, from the Department of Cell and Developmental Biology at UC San Diego, expressed optimism about the potential of this technology, stating, “This technology has the potential to be the safe, controllable, and scalable solution the world urgently needs to eliminate malaria once and for all.” He emphasized the need to focus on seeking social acceptance, regulatory authorizations, and funding opportunities to test and implement the Ifegenia system for suppressing wild populations of malaria-transmitting mosquitoes. The researchers are determined to make a significant impact in the world and will continue their efforts until that goal is achieved.

Source: University of California – San Diego

The researchers also suggest that the technology behind Ifegenia could be adapted for other disease-spreading species, such as mosquitoes that transmit dengue, chikungunya, and yellow fever viruses.

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