CHANGE-seq-BE: Transforming Pathology Practice with Enhanced Genome Safety Measures

CHANGE-seq-BE is an unbiased, high‑sensitivity, resource‑efficient genome‑wide off‑target mapping assay for base editors that improves regulatory‑relevant safety assessment. It detects additional off‑target sites while using roughly 5% of the sequencing reads required by conventional approaches.

The assay reveals sites missed by targeted screens by combining broader genomic coverage with lower sequencing depth and reduced resource needs. As a result, CHANGE‑seq‑BE integrates readily into preclinical safety screening pipelines.

The St. Jude news release reported that CHANGE‑seq‑BE recovered nearly all sites nominated by other methods and identified additional exclusive sites while using about 5% of the sequencing reads. That throughput advantage expands laboratory capacity and lowers per‑sample sequencing expense.

In one regulatory case described by St. Jude, the assay informed a submission for a CD40L‑directed therapy and supported a finding of high on‑target specificity with minimal off‑target activity. Rapid, precise profiling yielded safety data that helped accelerate review and shaped the submission strategy.

Other approaches either sacrifice sensitivity to cut cost or require prohibitively deep whole‑genome sequencing to remain unbiased. CHANGE‑seq‑BE balances comprehensive, unbiased mapping with resource efficiency, enabling broad discovery without prohibitive sequencing budgets.

Laboratories should consider integrating the assay early in the validation cascade when unbiased, whole‑genome off‑target data are required. Near‑term adoption is likely in clinical research programs; external validation and interlaboratory reproducibility studies are the logical next steps.

Key Takeaways:

• CHANGE‑seq‑BE delivers unbiased, high‑sensitivity off‑target mapping while using approximately 5% of the sequencing reads—enabling broader safety characterization with lower sequencing burden.
• Molecular pathologists, laboratory directors, and translational researchers planning preclinical safety studies and regulatory submissions should update validation checklists to include unbiased whole‑genome off‑target screening.
• Adoption will shift candidate triage toward editors with higher demonstrated specificity, speeding selection for clinical development and reducing downstream safety risk.