Gene Drive Strategies for Population Replacement

Marshall, John M.; Akbari, Omar S.

doi:10.1016/b978-0-12-800246-9.00009-0

Cited by 49 publications

(47 citation statements)

References 82 publications

(106 reference statements)

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“…The possibility of eventually combining population suppression and population modification approaches should be considered. Yet other approaches to synthetic gene drive systems do not use the homing reaction, such as those mimicking MEDEA elements or based on underdominance (Marshall and Akbari 2016), and these will have their own design criteria for maximizing the duration of protection.…”

Section: Discussionmentioning

confidence: 99%

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Requirements for Driving Antipathogen Effector Genes into Populations of Disease Vectors by Homing

et al. 2017

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There is a need for new interventions against the ongoing burden of vector-borne diseases such as malaria and dengue. One suggestion has been to develop genes encoding effector molecules that block parasite development within the vector, and then use the nuclease-based homing reaction as a form of gene drive to spread those genes through target populations. If the effector gene reduces the fitness of the mosquito and does not contribute to the drive, then loss-of-function mutations in the effector will eventually replace functional copies, but protection may nonetheless persist sufficiently long to provide a public health benefit. Here, we present a quantitative model allowing one to predict the duration of protection as a function of the probabilities of different molecular processes during the homing reaction, various fitness effects, and the efficacy of the effector in blocking transmission. Factors that increase the duration of protection include reducing the frequency of pre-existing resistant alleles, the probability of nonrecombinational DNA repair, the probability of homing-associated loss of the effector, the fitness costs of the nuclease and effector, and the completeness of parasite blocking. For target species that extend over an area much larger than the typical dispersal distance, the duration of protection is expected to be highest at the release site, and decrease away from there, eventually falling to zero, as effector-less drive constructs replace effector-containing ones. We also model an alternative strategy of using the nuclease to target an essential gene, and then linking the effector to a sequence that restores the essential function and is resistant to the nuclease. Depending upon parameter values, this approach can prolong the duration of protection. Our models highlight the key design criteria needed to achieve a desired level of public health benefit.

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Section: Discussionmentioning

confidence: 99%

“…Many different approaches have been proposed for making synthetic gene drive constructs able to spread effector genes through a vector population (Marshall and Akbari 2016). One such approach uses genes encoding enzymes (nucleases) that recognize and cleave a specific DNA sequence (Burt 2003).…”

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confidence: 99%

Requirements for Driving Antipathogen Effector Genes into Populations of Disease Vectors by Homing

et al. 2017

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“…Interventions currently under study include Sterile Insect-technique, which relies on irradiation of mosquitoes to make them sterile [48], genetic modification of mosquitoes to introduce sterility or other disadvantageous traits [49], and use of gene drive systems to spread novel traits (e.g. lethality or refractoriness to pathogen transmission) in mosquito populations [19,50]. While the technology has never been integrated into a malaria control programme, laboratory studies, mathematical models and preliminary field trials indicate its potential [51] Spatial repellents Spatial repellents prevent host-seeking mosquitoes from entering certain areas, thus limiting contact between humans and mosquitoes [27].…”

Section: Intervention Descriptionmentioning

confidence: 99%

Opinions of key stakeholders on alternative interventions for malaria control and elimination in Tanzania

Finda

Christofides

Lezaun

et al. 2020

Malar J

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Background: Malaria control in Tanzania currently relies primarily on long-lasting insecticidal nets and indoor residual spraying, alongside effective case management and behaviour change communication. This study explored opinions of key stakeholders on the national progress towards malaria elimination, the potential of currently available vector control interventions in helping achieve elimination by 2030, and the need for alternative interventions that could be used to supplement malaria elimination efforts in Tanzania. Methods: In this exploratory qualitative study, Focus group discussions were held with policy-makers, regulators, research scientists and community members. Malaria control interventions discussed were: (a) improved housing, (b) larval source management, (c) mass drug administration (MDA) with ivermectin to reduce vector densities, (d) release of modified mosquitoes, including genetically modified or irradiated mosquitoes, (e) targeted spraying of mosquito swarms, and (f) spatial repellents. Results: Larval source management and spatial repellents were widely supported across all stakeholder groups, while insecticide-spraying of mosquito swarms was the least preferred. Support for MDA with ivermectin was high among policy makers, regulators and research scientists, but encountered opposition among community members, who instead expressed strong support for programmes to improve housing for poor people in high transmission areas. Policy makers, however, challenged the idea of government-supported housing improvement due to its perceived high costs. Techniques of mosquito modification, specifically those involving gene drives, were viewed positively by community members, policy makers and regulators, but encountered a high degree of scepticism among scientists. Overall, policy-makers, regulators and community members trusted scientists to provide appropriate advice for decision-making. Conclusion: Stakeholder opinions regarding alternative malaria interventions were divergent except for larval source management and spatial repellents, for which there was universal support. MDA with ivermectin, housing improvement and modified mosquitoes were also widely supported, though each faced concerns from at least one stakeholder group. While policy-makers, regulators and community members all noted their reliance on scientists to make informed decisions, their reasoning on the benefits and disadvantages of specific interventions included factors beyond technical efficiency. This study suggests the need to encourage and strengthen dialogue between research scientists, policy makers, regulators and communities regarding new interventions.

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“…One innovative technology, first articulated by Austin Burt in 2003 (19), utilizes homing-based gene-drive technologies to expedite the elimination and eradication of vector-borne diseases (20)(21)(22)(23)(24)(25). Conceptually, these drives function by exploiting the organism's innate DNA repair machinery to copy or "home" themselves into a target genomic location prior to meiosis in the germline.…”

Section: Introductionmentioning

confidence: 99%

Development of a Confinable Gene-Drive System in the Human Disease Vector,Aedes aegypti

Li¹,

Yang²,

Kandul³

et al. 2019

Preprint

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Aedes aegypti, the principal mosquito vector for many arboviruses that causes yellow fever, dengue, Zika, and chikungunya, increasingly infects millions of people every year. With an escalating burden of infections and the relative failure of traditional control methods, the development of innovative control measures has become of paramount importance. The use of gene drives has recently sparked significant enthusiasm for the genetic control of mosquito populations, however no such system has been developed in Ae. aegypti. To fill this void and demonstrate efficacy in Ae. aegypti, here we develop several CRISPR-based split-gene drives for use in this vector. With cleavage rates up to 100% and transmission rates as high as 94%, 2 mathematical models predict that these systems could spread anti-pathogen effector genes into wild Ae. aegypti populations in a safe, confinable and reversible manner appropriate for field trials and effective for controlling disease. These findings could expedite the development of effectorlinked gene drives that could safely control wild populations of Ae. aegypti to combat local pathogen transmission. Significance StatementAe. aegypti is a globally distributed arbovirus vector spreading deadly pathogens to millions of people annually. Current control methods are inadequate and therefore new technologies need to be innovated and implemented. With the aim of providing new tools for controlling this pest, here we engineered and tested several split gene drives in this species. These drives functioned at very high efficiency and may provide a tool to fill the void in controlling this vector. Taken together, our results provide compelling path forward for the feasibility of future effector-linked split-drive technologies that can contribute to the safe, sustained control and potentially the elimination of pathogens transmitted by this species.

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Gene Drive Strategies for Population Replacement

Cited by 49 publications

References 82 publications

Requirements for Driving Antipathogen Effector Genes into Populations of Disease Vectors by Homing

Requirements for Driving Antipathogen Effector Genes into Populations of Disease Vectors by Homing

Opinions of key stakeholders on alternative interventions for malaria control and elimination in Tanzania

Development of a Confinable Gene-Drive System in the Human Disease Vector,Aedes aegypti

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