St. Jude Children’s Research Hospital developed CHANGE‑seq‑BE, an unbiased and resource‑efficient genome‑wide method to map off‑target activity of base editors. The team published the method in Nature Biotechnology and demonstrated its clinical utility by supporting an emergency FDA application for a base-editor therapy for CD40L‑deficient X‑linked Hyper‑IgM syndrome; CHANGE‑seq‑BE confirmed 95.4% on‑target specificity and no significant off‑target activity in that case. The authors argue the approach fills a gap between comprehensive off‑target mapping and resource constraints in translational labs, enabling rapid, high‑confidence safety data to inform regulatory interactions. Adoption in clinical pipelines could speed IND/IDE review for base‑editor programs by providing standardized safety evidence. The method’s uptake will depend on cross‑lab reproducibility and regulatory acceptance as a validated off‑target assessment for base editors in human therapeutics.