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Genome Editing and Gene Therapies: Complex and Expensive Drugs
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
Hammond et al. (2016) employed CRISPR and TALEN nucleases to target successfully and selectively coding sequence of three genes that confer a recessive female sterility phenotype upon disruption in the malaria mosquito vector Anopheles gambiae. This targeting of female reproduction is an example of adapting genome editing to gene drive technologies. A gene drive may be engineered to reduce the potential of an insect vector population to transmit disease or to impair its reproduction potential and provides a means to transform natural populations without permanent human intervention (Hammond and Galizi, 2017). Kyrou et al. (2018) proposed to employ CRSPR/Cas for the eradication of the malaria vector Anopheles gambiae by deactivating the gene doublesex (AgdsxF) of Anopheles females via CRSPR/Cas-mediated targeting of the intron 4-exon 5 boundary. Under laboratory conditions the mutated gene spread rapidly resulting in reduced egg production and a total collapse of population within 7 to 11 generations.
Agricultural production: assessment of the potential use of Cas9-mediated gene drive systems for agricultural pest control
Published in Journal of Responsible Innovation, 2018
Maxwell J. Scott, Fred Gould, Marcé Lorenzen, Nathaniel Grubbs, Owain Edwards, David O’Brochta
Since infestations in poorer countries are frequently the result of a few beetles invading locally stored grain, and migration of mated females pose a significant problem, skewing sex ratios could be a better option. How could this be accomplished? While there is still much to learn about sex determination in T. castaneum, several critical genes have already been identified. The T. castaneum doublesex (Tcdsx) gene produces sex-specific transcription factors critical for proper production of gametes (Shukla and Palli 2012a). The production of these specific transcription factors produced by Tcdsx transcripts is controlled by the proteins encoded by the T. castaneum transformer (Tctra) and Transformer-2 (Tctra-2) genes. Like Tcdsx, Tctra functions in a sex-specific way, but unlike Tcdsx, only the female version of Tctra RNA produces an active protein (Shukla and Palli 2012b). Interestingly, the female-specific TcTRA protein is necessary to maintain its own production (Shukla and Palli 2012a). TcTRA-2 is necessary for the sex-specific versions of both Tcdsx and Tctra (Shukla and Palli 2013). Because of their important roles in regulating sex determination and reproduction, each of these genes could be targeted to control pest populations. However, the most useful gene is likely to be Tctra. Reduced expression of this gene has little effect on males, but females are masculinized, and no female progeny are produced (Shukla and Palli 2012b). Skewing sex ratios could serve a number of purposes. SIT is more effective when only males are used (Rendon et al. 2004). Using males that can only produce male progeny would also be effective at reducing pest populations. If this male-only mutation is coupled with gene drive, then a self-maintaining population control can easily be established. Penetrance of this approach in target populations is dependent on random mating, so its success may be impacted by the high levels of pre- and post-zygotic reproductive incompatibilities present in Tribolium species, which can lead to insipient speciation events (Wade, Chang, and McNaughton 1995; Demuth and Wade 2007a, 2007b).