An engineered U7 small nuclear RNA scaffold greatly increases ADAR-mediated programmable RNA base editing

Susan M. Byrne, Stephen M. Burleigh, Robert Fragoza, Yue Jiang, Yiannis Savva, Ricky Pabon, Evan Kania, Joseph Rainaldi, Andrew Portell, Prashant Mali and Adrian W. Briggs ()
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Susan M. Byrne: Shape Therapeutics
Stephen M. Burleigh: Shape Therapeutics
Robert Fragoza: Shape Therapeutics
Yue Jiang: Shape Therapeutics
Yiannis Savva: Shape Therapeutics
Ricky Pabon: Shape Therapeutics
Evan Kania: Shape Therapeutics
Joseph Rainaldi: University of California San Diego
Andrew Portell: University of California San Diego
Prashant Mali: University of California San Diego
Adrian W. Briggs: Shape Therapeutics

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Custom RNA base editing exploiting the human Adenosine Deaminase Acting on RNA (ADAR) enzyme may enable therapeutic gene editing without DNA damage or use of foreign proteins. ADAR’s adenosine-to-inosine (effectively A-to-G) deamination activity can be targeted to transcripts using an antisense guide RNA (gRNA), but efficacy is challenged by limits of in vivo delivery. Embedding gRNAs into a U7 small nuclear RNA (snRNA) framework greatly enhances RNA editing with endogenous ADAR, and a 750-plex single-cell mutagenesis screen further improved the framework. An optimized scaffold with a stronger synthetic U7 promoter enables 76% RNA editing in vitro from a single DNA construct per cell, and 75% editing in a Hurler syndrome mouse brain after one systemic AAV injection, surpassing circular gRNA approaches. The technology also improves published DMD exon-skipping designs 25-fold in differentiated myoblasts. Our engineered U7 framework represents a universal scaffold for ADAR-based RNA editing and other antisense RNA therapies.

Date: 2025
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DOI: 10.1038/s41467-025-60155-z

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