SPLICER: a highly efficient base editing toolbox that enables in vivo therapeutic exon skipping

Angelo Miskalis, Shraddha Shirguppe, Jackson Winter, Gianna Elias, Devyani Swami, Ananthan Nambiar, Michelle Stilger, Wendy S. Woods, Nicholas Gosstola, Michael Gapinske, Alejandra Zeballos, Hayden Moore, Sergei Maslov, Thomas Gaj and Pablo Perez-Pinera ()
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Angelo Miskalis: University of Illinois Urbana-Champaign
Shraddha Shirguppe: University of Illinois Urbana-Champaign
Jackson Winter: University of Illinois Urbana-Champaign
Gianna Elias: University of Illinois Urbana-Champaign
Devyani Swami: University of Illinois Urbana-Champaign
Ananthan Nambiar: University of Illinois Urbana-Champaign
Michelle Stilger: University of Illinois Urbana-Champaign
Wendy S. Woods: University of Illinois Urbana-Champaign
Nicholas Gosstola: University of Illinois Urbana-Champaign
Michael Gapinske: University of Illinois Urbana-Champaign
Alejandra Zeballos: University of Illinois Urbana-Champaign
Hayden Moore: University of Illinois Urbana-Champaign
Sergei Maslov: University of Illinois Urbana-Champaign
Thomas Gaj: University of Illinois Urbana-Champaign
Pablo Perez-Pinera: University of Illinois Urbana-Champaign

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Exon skipping technologies enable exclusion of targeted exons from mature mRNA transcripts, which have broad applications in medicine and biotechnology. Existing techniques including antisense oligonucleotides, targetable nucleases, and base editors, while effective for specific applications, remain hindered by transient effects, genotoxicity, and inconsistent exon skipping. To overcome these limitations, here we develop SPLICER, a toolbox of next-generation base editors containing near-PAMless Cas9 nickase variants fused to adenosine or cytosine deaminases for the simultaneous editing of splice acceptor (SA) and splice donor (SD) sequences. Synchronized SA and SD editing improves exon skipping, reduces aberrant splicing, and enables skipping of exons refractory to single splice site editing. To demonstrate the therapeutic potential of SPLICER, we target APP exon 17, which encodes amino acids that are cleaved to form Aβ plaques in Alzheimer’s disease. SPLICER reduces the formation of Aβ42 peptides in vitro and enables efficient exon skipping in a mouse model of Alzheimer’s disease. Overall, SPLICER is a widely applicable and efficient exon skipping toolbox.

Date: 2024
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DOI: 10.1038/s41467-024-54529-y

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