Broad Dengue Neutralization in Mosquitoes Expressing an Engineered Antibody

Buchman, Anna; Gamez, Stephanie; Li, Ming; Antoshechkin, Igor; Lee, Shin-Hang; Wang, Shin-Wei; Chen, Chunhong; Klein, Melissa J.; Duchemin, Jean-Bernard; Crowe, James E.; Paradkar, Prasad N.; Akbari, Omar S.

doi:10.1101/645481

Cited by 14 publications

(14 citation statements)

References 74 publications

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“…Given the recent progress toward developing HGDs in pest species such as mosquitoes Hammond et al 2016Hammond et al , 2018Kyrou et al 2018;Li et al 2019), there is significant enthusiasm regarding their potential use to control wild populations. For example, given the enormous burden mosquitoes pose on humans, the release of HGDs linked with effector genes inhibiting mosquito pathogen transmission (Isaacs et al 2011;Jupatanakul et al 2017;Buchman et al 2019a;) may lead to replacement of disease-susceptible mosquitoes with disease-resistant counterparts resulting in reduced pathogen transmission (i.e., population modification drive). Alternatively, HGDs targeting genes affecting the fitness of female mosquitoes could also spread, resulting in gradual population declines and potentially even elimination (i.e., population suppression drive) (Windbichler et al 2008(Windbichler et al , 2011Kyrou et al 2018).…”

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confidence: 99%

Assessment of a Split Homing Based Gene Drive for Efficient Knockout of Multiple Genes

Kandul¹,

Liu²,

Buchman³

et al. 2020

G3 Genes|Genomes|Genetics

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103

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Homing based gene drives (HGD) possess the potential to spread linked cargo genes into natural populations and are poised to revolutionize population control of animals. Given that host encoded genes have been identified that are important for pathogen transmission, targeting these genes using guide RNAs as cargo genes linked to drives may provide a robust method to prevent disease transmission. However, effectiveness of the inclusion of additional guide RNAs that target separate genes has not been thoroughly explored. To test this approach, we generated a split-HGD in Drosophila melanogaster that encoded a drive linked effector consisting of a second gRNA engineered to target a separate host-encoded gene, which we term a gRNA-mediated effector (GME). This design enabled us to assess homing and knockout efficiencies of two target genes simultaneously, and also explore the timing and tissue specificity of Cas9 expression on cleavage/homing rates. We demonstrate that inclusion of a GME can result in high efficiency of disruption of both genes during super-Mendelian propagation of split-HGD. Furthermore, both genes were knocked out one generation earlier than expected indicating the robust somatic expression of Cas9 driven by Drosophila germline-limited promoters. We also assess the efficiency of ‘shadow drive’ generated by maternally deposited Cas9 protein and accumulation of drive-induced resistance alleles along multiple generations, and discuss design principles of HGD that could mitigate the accumulation of resistance alleles while incorporating a GME.

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mentioning

confidence: 99%

Assessment of a Split Homing Based Gene Drive for Efficient Knockout of Multiple Genes

Kandul¹,

Liu²,

Buchman³

et al. 2020

G3 Genes|Genomes|Genetics

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103

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“…Essentially, females with a Medea drive deposit a toxin into all their eggs that must be counteracted by an antidote that is expressed early in development, or the offspring dies. In successive generations, this system results in a disadvantage for wild-type alleles and, therefore, if the Medea system is linked to an effector to make the population disease resistant, for example in mosquitoes (Buchman et al, 2019a(Buchman et al, preprint, 2019bMarshall et al, 2019), or an effector targeting a conditional essential gene, or another conditional lethal effector such as one that confers temperature or small-molecule sensitivity to kill the population, it is predicted to favorably bias inheritance of the effector and therefore modify the population. The drive could also behave as a non-localized drive when released over a certain threshold, which is dependent on the fitness cost of the gene drive and its associated genetic elements as well as the rate of toxin resistance or natural genetic resistance in the population.…”

Section: Medea Drivesmentioning

confidence: 99%

Progress towards engineering gene drives for population control

Raban

Marshall

Akbari

2020

Journal of Experimental Biology

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Vector-borne diseases, such as dengue, Zika and malaria, are a major cause of morbidity and mortality worldwide. These diseases have proven difficult to control and currently available management tools are insufficient to eliminate them in many regions. Gene drives have the potential to revolutionize vector-borne disease control. This suite of technologies has advanced rapidly in recent years as a result of the availability of new, more efficient gene editing technologies. Gene drives can favorably bias the inheritance of a linked diseaserefractory gene, which could possibly be exploited (i) to generate a vector population incapable of transmitting disease or (ii) to disrupt an essential gene for viability or fertility, which could eventually eliminate a population. Importantly, gene drives vary in characteristics such as their transmission efficiency, confinability and reversibility, and their potential to develop resistance to the drive mechanism. Here, we discuss recent advancements in the gene drive field, and contrast the benefits and limitations of a variety of technologies, as well as approaches to overcome these limitations. We also discuss the current state of each gene drive technology and the technical considerations that need to be addressed on the pathway to field implementation. While there are still many obstacles to overcome, recent progress has brought us closer than ever before to geneticbased vector modification as a tool to support vector-borne disease elimination efforts worldwide.

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“…Meanwhile, some mosquito researchers hope to try something more subtle than completely wiping out insect populations as a means of preventing disease. In a May preprint 7 , Omar Akbari and his colleagues at UCSD engineered Aedes aegypti mosquitoes to express an antibody that protected the insects against all four major strains of dengue. They are now attaching that antibody to a drive to see whether it will spread.…”

Section: What Else Are Gene Drives Good For?mentioning

confidence: 99%

Self-destructing mosquitoes and sterilized rodents: the promise of gene drives

Scudellari¹

2019

Nature

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had been trying for eight years to hijack the mosquito genome. They wanted to bypass natural selection and plug in a gene that would mushroom through the population faster than a mutation handed down by the usual process of inheritance. In the back of their minds was a way to prevent malaria by spreading a gene to knock out mosquito populations so that they cannot transmit the disease. Crisanti remembers failing over and over. But finally, in 2011, the two geneticists at Imperial College London got back the DNA results they' d been hoping for: a gene they had inserted into the mosquito genome had radiated through the population, reaching more than 85% of the insects' descendants 1. It was the first engineered 'gene drive': a genetic modification designed to spread through a population at higher-than-normal rates of inheritance. Gene drives have rapidly become a routine technology in some laboratories; scientists can now whip up a drive in months. The technique relies on the gene-editing tool CRISPR and some bits of RNA to alter or silence a specific gene, or insert a new one. In the next generation, the whole drive copies itself onto its partner chromosome so that the genome no longer has the natural version of the chosen gene, and instead has two copies of the gene drive. In this way, the change is passed on to up to 100% of offspring, rather than around 50% (see 'How gene drives work'). Since 2014, scientists have engineered CRISPR-based gene-drive systems in mosquitoes, fruit flies and fungi, and are currently developing them in mice. But that's just the beginning of the story. Questions about whether a gene drive is possible have been supplanted by other unknowns: how well they will work, how to test them and who should regulate the technology. Gene drives have been proposed as a way to reduce or eliminate insect-borne diseases, control invasive species and even reverse insecticide resistance in pests. No engineered gene drive has yet been released into the wild, but the technology could in principle be ready as soon as three years from now, says Crisanti. He collaborates with Target Malaria, a non-profit international research consortium seeking to use gene-drive mosquitoes for malaria control in Africa. On 1 July, the group released a test batch of mosquitoes-genetically engineered but not yet equipped with gene drives-in a village in Burkina Faso. Gene drives are unlike any ecological fix ever tested before, says Gene-drive technology could alter the genome of an entire species. Researchers need to answer these key questions before deploying it in the wild.

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Broad Dengue Neutralization in Mosquitoes Expressing an Engineered Antibody

Cited by 14 publications

References 74 publications

Assessment of a Split Homing Based Gene Drive for Efficient Knockout of Multiple Genes

Assessment of a Split Homing Based Gene Drive for Efficient Knockout of Multiple Genes

Progress towards engineering gene drives for population control

Self-destructing mosquitoes and sterilized rodents: the promise of gene drives

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