Forging the path to rational design of synthetic homing endonuclease gene drive systems in Aedes aegypti

The alarming escalation of disease caused by Aedes aegypti, the primary vector of dengue, Zika, and chikungunya viruses, presents a pressing challenge for Low-and-Middle-Income Countries (LMICs) and is strongly predicted to worsen with climate change affecting mosquito distribution. Despite the promise of the homing endonuclease gene (HEG) drive system as a powerful, low-cost genetic biocontrol method for this mosquito vector, a limited understanding of the underlying mechanism of the system has hindered rational design for systematic improvement of its efficiency. Therefore, my research project aims to bridge these gaps and optimise the HEG drive efficiency in Ae. aegypti to a level fit for field application. The project's key goals include the following: 1. Identifying homing-susceptible cell stages and associated regulatory elements 2. Developing tools for the strict regulation and multiplexing of sgRNAs/crRNAs 3. Optimising HEG drive efficiency in Ae. aegypti The achievement of these objectives will have significant implications for public health by enabling more effective control of mosquito-borne diseases. The tools will be developed in parallel and successful development will not only advance the field of Ae. aegypti genetic biocontrol, but also act as a model for the rational design of HEG systems in various other pest species.