Editing population genetics for vector control. Atti Accademia Nazionale Italiana di Entomologia

Mosquitoes species of the genus Aedes and Anopheles are responsible for transmitting severe and life threatening diseases including a number of viral encephalitis, Dengue yellow fever, Malaria and more recently Zika. A few Anopheles species are responsible for causing 200 million cases of malaria every year and the death of half a million children under the age of five in less developed regions of Africa. During the last twenty years a worldwide concerted effort based on the use of bed nets, insecticides and drug treatment has halved malaria morbidity and mortality. The implementation of these control measures necessitates about 10 billion per year mostly in the form of donations thus questioning the long-term sustainability of this approach and its suitability for eradicating the disease in the next 30-40 years. The vectorial capacity of a mosquito species to transmit malaria depends on genetically determined traits such as feeding behavior, longevity, density and ability to support parasite development. Editing of the corresponding genes is anticipated to impair mosquito ability to transmit malaria. The recent development of CRISPR/CAS9 based gene drive technology has unlocked the possibility to selectively edit a mosquito population. Genetic modifications designed to either impair female fertility or interfere with mosquito ability to transmit the malaria parasite have been spread from few laboratory individual to large caged mosquito populations. These laboratory experiments have also supported mathematical modelling predicting how gene technology has the potential to eradicate malaria transmission in a span of few years from vast regions of Africa. Technical challenges in the development of a gene drive technology suitable for release include the development nucleaseresistant functional gene variant that would block the spreading of the drive as well as off target activity of the CAS9 nuclease that may generate undesirable mutations at other loci. We present here a number of solutions to overcome these problems.