GFP-on mouse model for interrogation of in vivo gene editing

Carla Dib, Jack A. Queenan, Leah Swartzrock, Hana Willner, Morgane Denis, Nouraiz Ahmed, Fareha Moulana Zada, Beltran Borges, Carsten T. Charlesworth, Tony Lum, Bradley P. Yates, Caleb Y. Kwon, Augustino V. Scorzo, Scott C. Davis, Jessie R. Davis, Ran He, Jun Xie, Guangping Gao, Tippi C. MacKenzie, David R. Liu (), Gregory A. Newby () and Agnieszka D. Czechowicz ()
Additional contact information
Carla Dib: Stanford University School of Medicine
Jack A. Queenan: Broad Institute of MIT and Harvard
Leah Swartzrock: Stanford University School of Medicine
Hana Willner: Stanford University School of Medicine
Morgane Denis: Stanford University School of Medicine
Nouraiz Ahmed: Broad Institute of MIT and Harvard
Fareha Moulana Zada: University of California San Francisco
Beltran Borges: University of California San Francisco
Carsten T. Charlesworth: Stanford University
Tony Lum: University of California San Francisco
Bradley P. Yates: Johns Hopkins University School of Medicine
Caleb Y. Kwon: Thayer School of Engineering
Augustino V. Scorzo: Thayer School of Engineering
Scott C. Davis: Thayer School of Engineering
Jessie R. Davis: Broad Institute of MIT and Harvard
Ran He: University of Massachusetts Chan Medical School
Jun Xie: University of Massachusetts Chan Medical School
Guangping Gao: University of Massachusetts Chan Medical School
Tippi C. MacKenzie: University of California San Francisco
David R. Liu: Broad Institute of MIT and Harvard
Gregory A. Newby: Broad Institute of MIT and Harvard
Agnieszka D. Czechowicz: Stanford University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Gene editing technologies have revolutionized therapies for numerous genetic diseases. However, in vivo gene editing hinges on identifying efficient delivery vehicles for editing in targeted cell types, a significant hurdle in fully realizing its therapeutic potential. A model system to rapidly evaluate systemic gene editing would advance the field. Here, we develop the GFP-on reporter mouse, which harbors a nonsense mutation in a genomic EGFP sequence correctable by adenine base editor (ABE) among other genome editors. The GFP-on system was validated using single and dual adeno-associated virus (AAV9) encoding ABE8e and sgRNA. Intravenous administration of AAV9-ABE8e-sgRNA into adult GFP-on mice results in EGFP expression consistent with the tropism of AAV9. Intrahepatic delivery of AAV9-ABE8e-sgRNA into GFP-on fetal mice restores EGFP expression in AAV9-targeted organs lasting at least six months post-treatment. The GFP-on model provides an ideal platform for high-throughput evaluation of emerging gene editing tools and delivery modalities.

Date: 2025
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DOI: 10.1038/s41467-025-61449-y

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