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      Taking stock: Is gene drive research delivering on its principles?

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          Abstract

          Gene drive technology has been recognized for its potential to provide durable and cost-effective solutions for previously intractable problems in public health, conservation, and agriculture. In recognition of the rapid advances in this field, in 2016 the U.S. National Academies of Sciences, Engineering, and Medicine issued a report making several recommendations aimed at researchers, funders, and policymakers for the safe and responsible research and development of gene drive technology. Subsequently, in 2017 sixteen global organizations self-identifying as sponsors and supporters of gene drive research became public signatories committed to the ‘Principles for Gene Drive Research’ which were inspired by the report’s recommendations.

          Herein we reflect on the progress of gene drive research in relation to the ethical principles laid out and committed to by the signatories to the Principles. Our analysis indicates high levels of alignment with the Principles in the field of gene drive research. The manuscript also discusses the Gene Drive Research Forum, which had its genesis in the publication of the Principles. Discussions between participants at the latest meeting of the Forum point to the work that lies ahead for gene drive research in line with the Principles. Going forward the gene drive research community can productively focus on: i) safety and efficacy criteria for open release, ii) risk assessment frameworks and methods, iii) more downstream technical, regulatory and policy considerations for field evaluations and implementation, iv) continued transparency and developing mechanisms of accountability, and v) strengthening capacity in locales of potential release and expected drive spread.

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          Most cited references32

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          A CRISPR-Cas9 Gene Drive System Targeting Female Reproduction in the Malaria Mosquito vector Anopheles gambiae

          Gene-drive systems that enable super-Mendelian inheritance of a transgene have the potential to modify insect populations over a timeframe of a few years [AU please provide a real estimate, this seems vague]. We describe CRISPR-Cas9 endonuclease constructs that function as gene-drive systems in Anopheles gambiae, the main vector for malaria [AU:OK?]. We identified three genes (AGAP005958, AGAP011377 and AGAP007280) that confer a recessive female sterility phenotype upon disruption, and inserted into each locus CRISPR-Cas9 gene-drive constructs designed to target and edit each gene [AU:OK?]. For each locus targeted we observed strong gene drive at the molecular level, with transmission rates to progeny of 91 to 99.6%. Population modelling and cage experiments indicate that a CRISPR-Cas9 construct targeting one of these loci, AGAP007280, meets the minimum requirement for a gene drive targeting female reproduction in an insect population. These findings could expedite the development of gene drives to control suppress mosquito populations to levels that do not support malaria transmission.
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            Highly efficient Cas9-mediated gene drive for population modification of the malaria vector mosquito Anopheles stephensi.

            Genetic engineering technologies can be used both to create transgenic mosquitoes carrying antipathogen effector genes targeting human malaria parasites and to generate gene-drive systems capable of introgressing the genes throughout wild vector populations. We developed a highly effective autonomous Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-associated protein 9 (Cas9)-mediated gene-drive system in the Asian malaria vector Anopheles stephensi, adapted from the mutagenic chain reaction (MCR). This specific system results in progeny of males and females derived from transgenic males exhibiting a high frequency of germ-line gene conversion consistent with homology-directed repair (HDR). This system copies an ∼ 17-kb construct from its site of insertion to its homologous chromosome in a faithful, site-specific manner. Dual anti-Plasmodium falciparum effector genes, a marker gene, and the autonomous gene-drive components are introgressed into ∼ 99.5% of the progeny following outcrosses of transgenic lines to wild-type mosquitoes. The effector genes remain transcriptionally inducible upon blood feeding. In contrast to the efficient conversion in individuals expressing Cas9 only in the germ line, males and females derived from transgenic females, which are expected to have drive component molecules in the egg, produce progeny with a high frequency of mutations in the targeted genome sequence, resulting in near-Mendelian inheritance ratios of the transgene. Such mutant alleles result presumably from nonhomologous end-joining (NHEJ) events before the segregation of somatic and germ-line lineages early in development. These data support the design of this system to be active strictly within the germ line. Strains based on this technology could sustain control and elimination as part of the malaria eradication agenda.
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              Pathway to Deployment of Gene Drive Mosquitoes as a Potential Biocontrol Tool for Elimination of Malaria in Sub-Saharan Africa: Recommendations of a Scientific Working Group †

              Abstract. Gene drive technology offers the promise for a high-impact, cost-effective, and durable method to control malaria transmission that would make a significant contribution to elimination. Gene drive systems, such as those based on clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated protein, have the potential to spread beneficial traits through interbreeding populations of malaria mosquitoes. However, the characteristics of this technology have raised concerns that necessitate careful consideration of the product development pathway. A multidisciplinary working group considered the implications of low-threshold gene drive systems on the development pathway described in the World Health Organization Guidance Framework for testing genetically modified (GM) mosquitoes, focusing on reduction of malaria transmission by Anopheles gambiae s.l. mosquitoes in Africa as a case study. The group developed recommendations for the safe and ethical testing of gene drive mosquitoes, drawing on prior experience with other vector control tools, GM organisms, and biocontrol agents. These recommendations are organized according to a testing plan that seeks to maximize safety by incrementally increasing the degree of human and environmental exposure to the investigational product. As with biocontrol agents, emphasis is placed on safety evaluation at the end of physically confined laboratory testing as a major decision point for whether to enter field testing. Progression through the testing pathway is based on fulfillment of safety and efficacy criteria, and is subject to regulatory and ethical approvals, as well as social acceptance. The working group identified several resources that were considered important to support responsible field testing of gene drive mosquitoes.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal AnalysisRole: InvestigationRole: MethodologyRole: Project AdministrationRole: Writing – Original Draft PreparationRole: Writing – Review & Editing
                Role: ConceptualizationRole: Writing – Review & Editing
                Role: Writing – Review & Editing
                Role: Writing – Review & Editing
                Role: Writing – Review & Editing
                Role: Writing – Review & Editing
                Role: ConceptualizationRole: Writing – Review & Editing
                Journal
                Gates Open Res
                Gates Open Res
                Gates Open Research
                F1000 Research Limited (London, UK )
                2572-4754
                22 February 2024
                2024
                : 8
                : 14
                Affiliations
                [1 ]Institute on Ethics & Policy for Innovation, McMaster University, Hamilton, ON, L8S 4L8, Canada
                [2 ]Philosophy, McMaster University, Hamilton, ON, L8S 4L8, Canada
                [3 ]Emerging ag inc., Dugald, Manitoba, R0E 0K0, Canada
                [4 ]GeneConvene Global Collaborative, Foundation for the National Institutes of Health, Bethesda, Maryland, 20852, USA
                [5 ]Global Health Ethics & Governance Unit, Research for Health, World Health Organization, Geneva, Switzerland
                [6 ]Medicine, McMaster University, Hamilton, ON, L8S 4L8, Canada
                [1 ]University of Missouri, Columbia, Missouri, USA
                [1 ]California Institute of Technology, Pasadena, California, USA
                [1 ]University of East Anglia, Norwich, England, UK
                [1 ]Keele University, Keele, England, UK
                [1 ]The University of Melbourne, Melbourne, Victoria, Australia
                Author notes

                No competing interests were disclosed.

                Competing interests: No competing interests were disclosed.

                Competing interests: Patent applications on gene drive technology

                Competing interests: No competing interests were disclosed.

                Competing interests: No competing interests were disclosed.

                Competing interests: No competing interests were disclosed.

                Author information
                https://orcid.org/0000-0003-3375-7643
                https://orcid.org/0000-0003-2786-8689
                Article
                10.12688/gatesopenres.15323.1
                11259591
                39035848
                a4451850-e6ba-4665-8cfb-9935d5163d34
                Copyright: © 2024 Roberts AJ et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 9 February 2024
                Funding
                Funded by: World Health Organization
                This work was supported by the Bill & Melinda Gates Foundation INV-003448 (AJR, KH, CIE), INV-008525 (SLJ, MS), INV-056999 (IC). KL is employed by the World Health Organization.
                The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Open Letter
                Articles

                gene drive,ethics,governance,capacity building,biotechnology,synthetic biology,crispr

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