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On-target and off-target activities of CRISPR therapeutics across scales.

Created on 18 Aug 2026

Authors

Merna Magdy, Justin R Gibson, Abishek Dhungana, Ashley Herring-Nicholas, Renee N Cottle, Eric A Josephs

Published in

Trends in biotechnology. Aug 17, 2026. Epub Aug 17, 2026.

Abstract

Recent FDA-approved gene-editing therapies illustrate not only the transformative potential of biotechnologies using CRISPR (clustered regularly interspaced short palindromic repeats)-derived ribonucleoproteins in treating a broad range of diseases but also the spectrum of possible molecular variations CRISPR therapeutics can adopt. These include exagamglogene autotemcel, an ex vivo therapy for hemoglobinopathies using CRISPR nuclease Cas9, and kayjayguran abengcemeran, an in vivo therapy using a protospacer adjacent motif-altered base-editing Cas9 variant for an ultra-rare metabolic disorder. Together, these therapies underscore how far CRISPR has advanced beyond its original use as a tool in biological/biomedical research. In this opinion article, we argue that as CRISPR biotechnologies advance beyond the relative simplicity of in vitro applications, our understanding must also evolve to address the challenges of optimizing 'on-target' and 'off-target' mutational activities across the diverse contexts in which they occur.

PMID:
42608275
Bibliographic data and abstract were imported from PubMed on 18 Aug 2026.

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