Editorial: Safety and efficacy of CRISPR/Cas-based genome editing tools: applications and considerations in cell and gene therapy

The practical application of these concepts is exemplified by the original research article by Bray and 32 colleagues (Bray et al. 2018). The protein tyrosine phosphatase PTPN22 is a critical negative 33 regulator of T-cell receptor (TCR) signaling, and its variants have been linked to numerous 34 autoimmune diseases. By exploiting CRISPR/Cas9 to generate the first human PTPN22-knockout T-35 cell lines, the authors were able to isolate the functional effects of this gene. Their findings 36 demonstrate that the loss of PTPN22 enhances the expression of the activation marker CD69 and the 37 production of IL-2, particularly in response to weak-antigen stimulation. This research not only 38 clarifies the mechanism of a key regulator in autoimmune pathogenesis but also suggests potential 39 strategies for engineering T cells with lower activation thresholds for immunotherapy. 40While T-cell therapies remain the gold standard, the field is expanding toward other immune subsets. 41The perspective by Lund et al. (Lund et al. 2025) shifts the focus from knock-out to knock-in genome 42 editing strategies. Their work provides robust protocols for modeling the genetic heterogeneity of B-43 cell malignancies like diffuse large B-cell lymphoma (DLBCL). By enabling the introduction of 44 specific oncogenic mutations into primary B cells, this methodology facilitates more accurate 45 preclinical disease models and identifies potential targets for therapeutic intervention. This work 46 provides a roadmap for using CRISPR to unlock the biology of hematological malignancies or 47 generate preclinical models for regulatory-grade data. 48 Finally, as these therapies move toward the clinic, the safety address of the topic becomes the primary 49 gatekeeper. Fazeli et al. (Fazeli et al. 2025) argue that safety assessment must be an integral design 50 principle rather than a final checklist. Focusing on Natural Killer (NK) cells (the emerging candidates 51 for allogeneic therapy) the authors emphasize that technical enhancements, such as the expression of 52 IL-15 to increase persistence, carry inherent risks of unintended genomic instability. They provide a 53 comprehensive roadmap of safety platforms, ranging from in silico prediction to advanced in vivo 54 humanized mouse models and organ-on-chip systems, ensuring that the next generation of edited cells 55 can be rigorously investigated for clinical use. 56