Gene-Edited Pancreatic Cell Therapy for Diabetes Mellitus: Current Advances, Clinical Evidence, Challenges, and Future Perspectives

Abstract

Diabetes mellitus remains one of the most prevalent chronic metabolic disorders worldwide, affecting hundreds of millions of people and placing a substantial burden on healthcare systems. Although exogenous insulin therapy has significantly improved patient survival, it does not fully replicate the physiological regulation of endogenous insulin secretion and therefore cannot completely prevent long-term complications. Recent advances in regenerative medicine, stem cell biology, and gene-editing technologies have introduced innovative therapeutic strategies aimed at restoring endogenous insulin production through the transplantation of genetically modified pancreatic β-cells. Gene-editing platforms, particularly Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-associated protein 9 (CRISPR-Cas9), together with induced Pluripotent Stem Cells (iPSCs) and embryonic stem cell-derived pancreatic islets, have demonstrated considerable potential for replacing dysfunctional β-cells and improving long-term glycemic control. Several preclinical investigations and early-phase clinical trials have reported encouraging outcomes, including sustained insulin production, improved glucose homeostasis, reduced dependence on exogenous insulin, and acceptable safety profiles. In addition, advances in immune-evasive gene editing, biomaterial encapsulation technologies, and precision genome engineering are addressing major challenges associated with immune rejection, graft survival, and long-term cellular function. Nevertheless, important scientific and clinical barriers remain, including optimization of gene-editing efficiency, prevention of off-target genomic alterations, large-scale manufacturing, regulatory approval, ethical considerations, and 

long-term safety evaluation. This review summarizes current progress in gene-edited pancreatic cell therapy for diabetes mellitus by examining recent advances in stem cell engineering, genome editing, clinical evidence, translational challenges, and future therapeutic directions. Collectively, the available evidence suggests that gene-edited pancreatic cell therapy has the potential to transform diabetes management by moving beyond lifelong insulin replacement toward durable restoration of endogenous insulin secretion, thereby improving metabolic control, reducing diabetes-related complications, and enhancing patients' quality of life.