414: Durability of Cas9 Gene Drives in Anopheles: A 2‑Year Cage Study

Carballar-Lejarazúa R et al., PNAS (2026) - This episode summarizes a 2-year, 35-generation multireplicate cage trial evaluating three autonomous Cas9/gRNA gene-drive strains (AcTP13, AcTP43 in Anopheles coluzzii; AgTP13 in Anopheles gambiae). The study tracked drive inheritance, cassette integrity, resistance allele emergence, off-target activity, and sustained antiparasite efficacy against Plasmodium falciparum. Key terms: gene drive, Anopheles, Cas9/gRNA, parasite suppression, long-term stability.

Study Highlights:
Over 2 years (35 generations) triplicate cage trials of three Cas9/gRNA gene-drive strains monitored drive dynamics, cassette integrity, resistance, off-target effects, and parasite suppression. All A. coluzzii replicates achieved rapid fixation and remained stable; two AgTP13 replicates fixed while one accumulated a functional cleavage-resistant allele that reduced drive frequency. Effector transgene sequences and mRNA expression were largely preserved, though one AcTP43 replicate lost a TP10 monomer copy. Parasite challenge assays at low and medium-low gametocytemias showed significant reductions in oocyst and sporozoite prevalence and intensity.

Conclusion:
Multimetric longitudinal data show that Cas9/gRNA-based population-modifying drives can remain genetically stable and retain antiparasite activity over a 2-year period in laboratory Anopheles populations, with replicate-level resistance emergence underscoring the need for replicated risk assessment and monitoring.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Long-term stability and performance of Cas9/guide RNA-based gene drives in anopheline mosquitoes

First author:
Carballar-Lejarazúa R

Journal:
PNAS (2026)

DOI:
10.1073/pnas.2605739123

Reference:
Carballar-Lejarazúa R, Winokura L, Pham TB, Tushar T, Tao M, Dimopoulos G, James AA, et al. Long-term stability and performance of Cas9/guide RNA-based gene drives in anopheline mosquitoes. PNAS. 2026;123(28):e2605739123. doi:10.1073/pnas.2605739123

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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Episode link: https://basebybase.com/episodes/414-gene-drive-stability-anopheles

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-07-17.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript sections describing gene-drive mechanism, target-product profile criteria, long-term cage trials, molecular/cassette integrity, resistance emergence, off-target analysis, and parasite-suppression outcomes, with attention to quantitative results and limitations.
- transcript topics: Gene-drive mechanism and inheritance (Cas9/gRNA, HDR); Target Product Profile (TPP) criteria for gene-drive systems; Long-term cage trial design (AcTP13, AcTP43 in Anopheles coluzzii; AgTP13 in Anopheles gambiae); Cargo design and tracking markers (CFP, mCherry) and antiparasite effectors (M1C3, M2A10, MultiEff, TP10, EPIP); Resistance emergence at the target site (AgTP13) and 3 bp insertion; Payload stability and tandem repeats (...