Considerations for first field trials of low-threshold gene drive for malaria vector control.

Sustainable reductions in African malaria transmission require innovative tools for mosquito control. One proposal involves the use of low-threshold gene drive in Anopheles vector species, where a 'causal pathway' would be initiated by (i) the release of a gene drive system in target mosquito vector species, leading to (ii) its transmission to subsequent generations, (iii) its increase in frequency and spread in target mosquito populations, (iv) its simultaneous propagation of a linked genetic trait aimed at reducing vectorial capacity for Plasmodium, and (v) reduced vectorial capacity for parasites in target mosquito populations as the gene drive system reaches fixation in target mosquito populations, causing (vi) decreased malaria incidence and prevalence. Here the scope, objectives, trial design elements, and approaches to monitoring for initial field releases of such gene dive systems are considered, informed by the successful implementation of field trials of biological control agents, as well as other vector control tools, including insecticides, Wolbachia, larvicides, and attractive-toxic sugar bait systems.

Bioinformatic and literature assessment of toxicity and allergenicity of a CRISPR-Cas9 engineered gene drive to control Anopheles gambiae the mosquito vector of human malaria.

Background: Population suppression gene drive is currently being evaluated, including via environmental risk assessment (ERA), for malaria vector control. One such gene drive involves the dsxF transgene encoding (i) hCas9 endonuclease, (ii) T1 guide RNA (gRNA) targeting the doublesex locus, and (iii) DsRed fluorescent marker protein, in genetically-modified mosquitoes (GMMs). Problem formulation, the first stage of ERA, for environmental releases of dsxF previously identified nine potential harms to the environment or health that could occur, should expressed products of the transgene cause allergenicity or toxicity.

Gene drive in species complexes: defining target organisms.

Engineered gene drives, which bias their own inheritance to increase in frequency in target populations, are being developed to control mosquito malaria vectors. Such mosquitoes can belong to complexes of both vector and nonvector species that can produce fertile interspecific hybrids, making vertical gene drive transfer (VGDT) to sibling species biologically plausible. While VGDT to other vectors could positively impact human health protection goals, VGDT to nonvectors might challenge biodiversity ones.

Comprehensive characterization of a transgene insertion in a highly repetitive, centromeric region of mosquitoes.

The availability of the genomic sequence of the malaria mosquito has in recent years sparked the development of transgenic technologies with the potential to be used as novel vector control tools. These technologies rely on genome editing that confer traits able to affect vectorial capacity. This can be achieved by either reducing the mosquito population or by making mosquitoes refractory to the parasite infection.

Recommendations for environmental risk assessment of gene drive applications for malaria vector control.

Building on an exercise that identified potential harms from simulated investigational releases of a population suppression gene drive for malaria vector control, a series of online workshops identified nine recommendations to advance future environmental risk assessment of gene drive applications.

A systematic review assessing the potential for release of vector species from competition following insecticide-based population suppression of Anopheles species in Africa.

Background: While insecticide-based vector control can effectively target vector species in areas of high malaria endemicity, such as Anopheles gambiae in Africa, residual disease transmission can occur. Understanding the potential role of competitive displacement between vector species could inform both current insecticide-based vector control programmes and the development of future complementary interventions.

Methods: A systematic review was conducted to identify published studies of insecticide-based vector control of Anopheles species in Africa that reported indices for absolute densities of vector species.

Systematic identification of plausible pathways to potential harm via problem formulation for investigational releases of a population suppression gene drive to control the human malaria vector Anopheles gambiae in West Africa.

Background: Population suppression gene drive has been proposed as a strategy for malaria vector control. A CRISPR-Cas9-based transgene homing at the doublesex locus (dsxF) has recently been shown to increase rapidly in frequency in, and suppress, caged laboratory populations of the malaria mosquito vector Anopheles gambiae. Here, problem formulation, an initial step in environmental risk assessment (ERA), was performed for simulated field releases of the dsxF transgene in West Africa.

Neurodegeneration caused by the translation of nonsense: does macromolecular misfolding impair the synchrony of gene expression?

Here, it is proposed that the principal event underlying neurodegeneration occurs when cytotoxic, truncated proteins are expressed from normally-untranslated nonsense RNA and pseudogene transcripts. The proximal event occurs when a small fraction of the total pool of gene expression machinery within the cell is disrupted by rare events of macromolecular misfolding during gene expression. Macromolecular misfolding, such as beta-sheet formation of protein leading to intracellular aggregation, has been implicated in a number of neurodegerative diseases.