Molecular therapy : the journal of the American Society of Gene TherapyMar 24, 2019

Non-viral delivery of gene-editing instructions allows efficient editing of multiple therapeutic genes in living organisms

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 29, 2026

Abstract

mRNA formulated into lipid nanoparticles enabled >90% knockout of gene expression in mice at doses 10-fold lower than previously reported.

Engineered zinc finger nucleases delivered via lipid nanoparticles can induce significant gene editing in the liver.
Targeting the TTR or PCSK9 gene resulted in effective gene expression knockout.
Co-delivery of ZFN mRNA with AAV containing therapeutic transgenes achieved high levels of targeted integration.
Repeat administration of ZFN mRNA-LNP after an AAV dose led to increased genome editing and transgene expression.
LNP-mediated delivery could represent a novel approach for treating various diseases.

Simplified

It has previously been shown that engineered zinc finger nucleases (ZFNs) can be packaged into adeno-associated viruses (AAVs) and delivered intravenously into mice, non-human primates, and most recently, humans to induce highly efficient therapeutic genome editing in the liver. Lipid nanoparticles (LNPs) are synthetic delivery vehicles that enable repeat administration and are not limited by the presence of preexisting neutralizing antibodies in patients. Here, we show that mRNA encoding ZFNs formulated into LNP can enable >90% knockout of gene expression in mice by targeting the TTR or PCSK9 gene, at mRNA doses 10-fold lower than has ever been reported. Additionally, co-delivering mRNA-LNP containing ZFNs targeted to intron 1 of the ALB locus with AAV packaged with a promoterless human IDS or FIX therapeutic transgene can result in high levels of targeted integration and subsequent therapeutically relevant levels of protein expression in mice. Finally, we show repeat administration of ZFN mRNA-LNP after a single AAV donor dose results in significantly increased levels of genome editing and transgene expression compared to a single dose. These results demonstrate LNP-mediated ZFN mRNA delivery can drive highly efficient levels of in vivo genome editing and can potentially offer a new treatment modality for a variety of diseases.

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Non-viral delivery of gene-editing instructions allows efficient editing of multiple therapeutic genes in living organisms

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