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Review
. 2021 Nov 3;29(11):3107-3124.
doi: 10.1016/j.ymthe.2021.09.002. Epub 2021 Sep 10.

In vivo somatic cell base editing and prime editing

Gregory A Newby  1 , David R Liu  2
Affiliations
Review

In vivo somatic cell base editing and prime editing

Gregory A Newby et al. Mol Ther. .

Abstract

Recent advances in genome editing technologies have magnified the prospect of single-dose cures for many genetic diseases. For most genetic disorders, precise DNA correction is anticipated to best treat patients. To install desired DNA changes with high precision, our laboratory developed base editors (BEs), which can correct the four most common single-base substitutions, and prime editors, which can install any substitution, insertion, and/or deletion over a stretch of dozens of base pairs. Compared to nuclease-dependent editing approaches that involve double-strand DNA breaks (DSBs) and often result in a large percentage of uncontrolled editing outcomes, such as mixtures of insertions and deletions (indels), larger deletions, and chromosomal rearrangements, base editors and prime editors often offer greater efficiency with fewer byproducts in slowly dividing or non-dividing cells, such as those that make up most of the cells in adult animals. Both viral and non-viral in vivo delivery methods have now been used to deliver base editors and prime editors in animal models, establishing that base editors and prime editors can serve as effective agents for in vivo therapeutic genome editing in animals. This review summarizes examples of in vivo somatic cell (post-natal) base editing and prime editing and prospects for future development.

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Conflict of interest statement

Declaration of interests The authors have filed patent applications on genome editing technologies through the Broad Institute of MIT and Harvard. D.R.L. is a consultant and cofounder of Beam Therapeutics, Prime Medicine, Pairwise Plants, Editas Medicine, and Chroma Medicine, companies that use genome editing or genome engineering, including base editing, prime editing, and epigenetic modification.

Figures

None
Graphical abstract
Figure 1
Figure 1
Genome editing mechanisms of base editors, prime editors, and nucleases (A) Nuclease-mediated editing. (B) Cytidine base editing. (C) Adenine base editing. (D) Prime editing. PAM, protospacer-adjacent motif; UGI, uracil glycosylase inhibitor domain; Cas9n, Cas9 nickase; sgRNA, single guide RNA; pegRNA, prime editor guide RNA; HITI, homology-independent targeted integration; HDR, homology-directed repair.
Figure 2
Figure 2
In vivo delivery options and demonstrations (A) Key delivery options and their typical advantages. (B) Published reports of in vivo base editor and prime editor delivery to tissues. Images created using BioRender.com. CNS, central nervous system; HSC, hematopoietic stem cell.
Figure 3
Figure 3
Timeline of base editor and prime editor development and applications CBE, cytidine base editor; ABE, adenine base editor; AAV, adeno-associated virus; LNP, lipid nanoparticle; NHP, non-human primate.,
See this image and copyright information in PMC

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