Efficient HSC editing at the HBG1 promoter in Townes;SpCas9-EGPF animals.HBB^A/A and HBB^S/S animals were IV injected as adults (A,C,E) or neonates (B,D,F) with vehicle or scAAV-3xHBG1.gRNA and analyzed 12 weeks after injection. Approximately 4 × 10¹² vg per animal was used for adults and ∼2 × 10¹¹ vg per animal was used for neonates. HBG1 promoter modification in HSCs of adult injected (panel A) or neonatally injected (panel B) animals. HBG1 promoter modification in BM Ery progenitors from adult injected (panel C) or neonatally injected (panel D) animals. HBG1 promoter modification in whole blood from adult injected (panel E) or neonatally injected (panel F) animals and analyzed 12 weeks after injection. One-way ANOVA with Brown-Forsythe and Welch correction. ∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001. Data compiled from 4 (panels A,C,E) or 3 (panels B,D,F) independent experiments. Females, square; males, triangles. A/A, healthy HBB^A/A; BM Ery, BM erythroid; S/S, sickle homozygote HBB^S/S.