Fig. 4: In vivo comparison of PE_Y18^∆RnH and PEmax delivered via AAV or mRNA-LNP.

a Experimental setup and editing rates at the targeted Adrb1 locus in cortices. Intein-split PEmax^∆RnH and PE_Y18^∆RnH were packaged into AAV-PHP.eB capsids and injected intracerebroventricular into P1 mice. For PE_Y18^∆RnH, four animals were individually treated for each timepoint. For PEmax, time points 5, 10, 15, 20, and 30 days were assessed by four (n = 4) individually treated animals, whereas three (n = 3) animals were treated for 25 and 35 days respectively; **P = 0.0012, ****P < 0.0001, ****P < 0.0001, ****P < 0.0001, **P = 0.0071, ****P < 0.0001 and ***P = 0.0003 (left to right). b Editing rates at the targeted Dnmt1 locus, assessed in different tissues at days 7 and 21 after temporal vein injection of the intein-split PE_Y18^∆RnH and PEmax^∆RnH packaged in AAV9. For PEmax^∆RnH nine animals (n = 9) were individually treated for the time point 7d and five animals (n = 5) for 21d respectively. For PE_Y18^∆RnH ten animals (n = 10) were treated for time point 7d and five (n = 5) for 21d respectively; *P = 0.0199, not significant (ns) P = 0.1939, ns P > 0.9999, ****P < 0.0001, ns P > 0.9999 and ns P > 0.9999 (left to right). c Four weeks before single administration of mRNA-LNPs (2 mg/kg PEmax or PE_Y18 mRNA) via the tail vein, male mice were injected with an scAAV9 expressing the epegRNA that targets the Dnmt1 locus. Editing rates after LNP administration were assessed in the tail, liver tissue, and isolated hepatocytes. Organs were analyzed from nine individually treated animals (n = 9) for PEmax and PE_Y18; not significant (ns) P = 0.999, ns P = 0.2932 and ns P = 0.1306 (left to right). Data are displayed as means±s.d. of the indicated and were analyzed using a two-way ANOVA using Tukey’s multiple comparisons.