The most well-developed genome editing system that does not require the creation of a DSB in the genome is base editing.[1-5] In base editing, single nucleotide changes are made by deamination of either adenine (adenine base editors [ABEs]) and cytosine (cytosine base editors [CBEs]). The natural repair mechanisms that exist to convert deaminated adenine and cytosine back to adenine and cytosine are inhibited as part of the base editing system. In ABEs the adenine is thus converted to a guanine, whereas with CBEs the cytosine is con verted to a thymidine.

Since the first reports of the development of the CBE and ABE systems in cancer cell lines, both have been applied therapeutically as well. These applications include making new stop codons in genes to create null versions of the gene. Because base editors do not generate a DSB, they can be applied to make multiplex edits without a high risk of causing translocations such as can occur when using multiplexing nuclease-based editing.21 In addition to making new stop codons, base editors have also now been applied ex vivo to genetically convert the mutation that causes sickle cell disease to a hemoglobin (Hb) variant called Hb Makaser (HbM). In contrast to HbS in which a valine is at position 6 of the HBB protein, in HbM an alanine is at position 6, a harmless change.[4,5] Finally, base editing has been applied in vivo in a mouse model of a Hutchinson-Gilford progeria (a genetic premature aging disease in humans) and been demonstrated to increase the longevity and improve the symptoms.[6]

The limit of base editing is that only single nucleotide changes can be made, although simultaneous single nucleotide changes can be made at multiple sites, and that the ABE and CBEs still do not allow every possible single nucleotide substitution to be made. Although the avoidance of a DSB has been described as a possible way to reduce genotoxicity compared with nuclease-based genome editing, the full scope of off-target effects of base editors on both genomic DNA and RNA are still being investigated.

References

--------------

[1] Komor AC, et al. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature. 2016;533(7603):420–424.

 [2] Gaudelli NM, et al. Programmable base editing of AT to GC in genomic DNA without DNA cleavage. Nature. 2017;551(7681):464–471.

[3] Webber BR, et al. Highly efficient multiplex human T cell engineering without double-strand breaks using Cas9 base editors. Nat Commun. 2019;10(1):5222.

[4] Chu SH, et al. Rationally Designed Base Editors for Precise Editing of the Sickle Cell Disease Mutation. CRISPR J. 2021;4(2):169–177.

[5] Newby GA, et al. Base editing of haematopoietic stem cells rescues sickle cell disease in mice. Nature. 2021;595(7866):295–302.

[6] Koblan LW, et al. In vivo base editing rescues Hutchinson-Gilford progeria syndrome in mice. Nature. 2021;589(7843):608–614.

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