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. 2023 Jun 22;14:3714. doi: 10.1038/s41467-023-39352-1

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© The Author(s) 2023

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 2 — a–c Transient expression of base editor and gRNA in human iPSCs and iPSC-CMs. Experimental outline in (a), editing efficiency of P633L in (b) and R634Q in (c). “CP” labels the circular permuted base editor CP-1041. Purple line indicates average repair efficiency in iPSC-CMs. d Generation of stable base editor expression in R634Q iPSCs with a repair efficiency of 34.26 ± 2.36% as determined by amplicon-seq. N = 3 independent differentiations. e Expression of spliced and unspliced isoforms of TTN and IMMT in parental, R634Q and edited R634Q iPSC-CMs differentiated for 15 and 32 days. Significant changes compared to R634Q indicated when present and analyzed by unpaired, two-tailed t tests. *P < 0.05, **P < 0.01, ****P < 0.0001. f Experimental outline of AAVMYO-mediated base editing in mice. g Percentage of editing of P635L HOM mice injected with AAVMYO carrying different gRNA-base editor combinations or PBS as empty control. For NRCH-gRNA1, AAV9 was also used as vector. Significance was assessed using unpaired, two-tailed t tests ***P < 0.001, **P < 0.01, *P < 0.05. Sequence shows location of the on-target edit in blue and the two bystander edits in red. Numbers depict the position of the nucleotides within the targeting gRNA (gRNA2 was used as reference) with the PAM sequence in position 21–23. h Allele frequency of repaired DNA in the muscle tissues heart, diaphragm and quadriceps femoris (quadriceps f.), as well as the liver, plotted for ten mice with the highest editing events in (g). i Percentage of editing of Rbm20 mRNA in mice treated with AAVMYO-SpRY for 6 or 12 weeks. Editing was assessed by amplicon-seq of cDNA isolated from the whole heart. Most base editors contain the deaminase variant Abemax except when indicated by “8e”, which are base editors with the Abe8e version. Percentage “repaired” in (b, c, g–i) is defined by NGS reads from amplicon-seq with only the wild-type sequence. The number of biological replicates i.e., independent differentiations in (b, c, e) or mice in (g, i) is indicated in brackets above the bars. Error bars depict the SEM in all panels.