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September 10, 2025Nature Communications4 citationsOpen Access

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

CDCarla DibCalifornia Institute for Regenerative Medicine JQJack A. QueenanBroad Institute LSLeah SwartzrockCalifornia Institute for Regenerative Medicine

Key Points

Intravenous AAV9 administration into GFP-on mice resulted in significant and consistent EGFP expression over six months.
The GFP-on model successfully restored EGFP expression in targeted organs after intrahepatic delivery of AAV9-ABE8e-sgRNA.
Using dual adeno-associated viruses showcased improved efficacy of the adenine base editor in delivering gene editing.
This model facilitates high-throughput testing of new gene editing technologies and delivery methods, enhancing research possibilities.

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.

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