Gene editing strategies to address current challenges in stem cell-derived β cell therapy for type 1 Diabetes

Abstract

Type 1 diabetes (T1D) results from the autoimmune destruction of pancreatic beta cells, leading to lifelong insulin dependence and significant health complications. Human pluripotent stem cell-derived beta cells (hPSC-beta cells) have emerged as a promising therapeutic alternative for restoring endogenous insulin production; however, limitations such as functional immaturity, immune rejection, and biosafety concerns such as tumorigenic risk continue to hinder clinical application. Recent advances in gene editing technologies, particularly clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9), offer precise tools to enhance or correct hPSC-beta cell performance by improving glucose-stimulated insulin secretion (GSIS), reducing immune rejection, and reducing biosafety concerns. This review explores gene editing strategies developed to overcome the key barriers in hPSC-beta cell-based therapy for T1D. We highlight how genetic modifications enhance or correct beta cell function, promote immune evasion, and reduce biosafety concerns through precise and clinically relevant engineering. Finally, we discuss the current landscape of clinical trials and future directions for translating gene-edited hPSC-beta cells into curative treatments for T1D.