Abstract

Monogenic diabetes mellitus comprised a heterogeneous group of disorders caused by single-gene mutations 
affecting pancreatic β-cell function or insulin action, accounting for approximately 1--2% of all diabetes cases yet 
frequently misdiagnosed as type 1 or type 2 diabetes. The advent of CRISPR-Cas9 gene editing technology had 
introduced unprecedented opportunities for definitive genetic correction of these conditions. This narrative review 
critically examined the therapeutic potential and translational challenges of CRISPR-Cas9 applications in 
monogenic diabetes. A comprehensive literature search was conducted using PubMed, Embase, and Web of Science 
databases (2015--2025) with terms including "CRISPR," "gene editing," "monogenic diabetes," "MODY," and 
"neonatal diabetes." Principal findings reveal that CRISPR-Cas9 has demonstrated remarkable efficacy in correcting 
pathogenic mutations in patient-derived induced pluripotent stem cells and animal models of monogenic diabetes, 
with successful restoration of glucose-stimulated insulin secretion and normoglycemia. However, substantial 
barriers persisted including off-target mutagenesis, delivery vehicle limitations, immunogenicity concerns, and 
regulatory complexities that collectively impeded clinical translation. Emerging base editing and prime editing 
technologies offered enhanced precision with reduced double-strand breaks, potentially mitigating safety concerns. 
The evidence supported cautious optimism that CRISPR-based therapeutics may eventually provide curative 
interventions for monogenic diabetes, contingent upon resolution of safety, delivery, and ethical challenges through 
rigorous preclinical validation and carefully designed clinical trials.