Specificity of CRISPR-Cas9 Editing in Exagamglogene Autotemcel

This correspondence evaluates the offtarget editing risk of exagamglogene autotemcel (exa cel), a CRISPR Cas9 based therapy for sickle cell disease and β thalassemia. Using computational homology searches, GUIDE seq, and high coverage hybrid capture sequencing, the authors assessed 335 candidate off-target sites in CD34+ cells from six patients. No off-target editing was detected. A variant-aware search incorporating 22 million human genetic variants confirmed that even sites with >10% global allele frequency showed no editing. Risk assessment found no candidate sites within coding exons or genes linked to myeloid cancer. The study supports the high specificity of exa-cel editing and outlines limitations and future monitoring strategies.

This correspondence evaluates the offtarget editing risk of exagamglogene autotemcel (exa cel), a CRISPR Cas9 based therapy for sickle cell disease and β thalassemia. Using computational homology searches, GUIDE seq, and high coverage hybrid capture sequencing, the authors assessed 335 candidate off-target sites in CD34+ cells from six patients. No off-target editing was detected. A variant-aware search incorporating 22 million human genetic variants confirmed that even sites with >10% global allele frequency showed no editing. Risk assessment found no candidate sites within coding exons or genes linked to myeloid cancer. The study supports the high specificity of exa-cel editing and outlines limitations and future monitoring strategies.