Molecular therapy : the journal of the American Society of Gene TherapyFeb 16, 2023

Mouse model using glowing marker to improve gene editing tested with lipid nanoparticles delivering precise DNA editors

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 31, 2026

Abstract

The ALC-0315 lipid nanoparticle formulation achieved 83.5% restoration of luciferase activity in the liver of treated mice.

A luminescent ABE mouse model was created to assess genome editing efficacy.
The model carries the R387X mutation, which disables luciferase activity but can be restored by A-to-G correction.
Intravenous injection of lipid nanoparticles encapsulating ABE mRNA and guide RNA was used for delivery.
Whole-body imaging revealed consistent luminescence restoration lasting up to 4 months.
The ALC-0315 and MC3 lipid nanoparticle formulations demonstrated significantly different restoration levels of luciferase activity.

Simplified

The rapid development of CRISPR genome editing technology has provided the potential to treat genetic diseases effectively and precisely. However, efficient and safe delivery of genome editors to affected tissues remains a challenge. Here, we developed luminescent ABE (LumA), a luciferase reporter mouse model containing the R387X mutation (c.A1159T) in the luciferase gene located in the Rosa26 locus of the mouse genome. This mutation eliminates luciferase activity but can be restored upon A-to-G correction by SpCas9 adenine base editors (ABEs). The LumA mouse model was validated through intravenous injection of two FDA-approved lipid nanoparticle (LNP) formulations consisting of either MC3 or ALC-0315 ionizable cationic lipids, encapsulated with ABE mRNA and LucR387X-specific guide RNA (gRNA). Whole-body bioluminescence live imaging showed consistent restoration of luminescence lasting up to 4 months in treated mice. Compared with mice carrying the wild-type luciferase gene, the ALC-0315 and MC3 LNP groups showed 83.5% ± 17.5% and 8.4% ± 4.3% restoration of luciferase activity in the liver, respectively, as measured by tissue luciferase assays. These results demonstrated successful development of a luciferase reporter mouse model that can be used to evaluate the efficacy and safety of different genome editors, LNP formulations, and tissue-specific delivery systems for optimizing genome editing therapeutics.

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Mouse model using glowing marker to improve gene editing tested with lipid nanoparticles delivering precise DNA editors

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