Gene Therapy in Crohn’s Disease: Current Preclinical Challenges and Future Translational Avenues

Crohn's disease (CD) remains a highly complex disorder, and the progress of preclinical gene therapy for CD has been constrained by several significant challenges. These include the identification of optimal therapeutic gene targets, the difficulty of targeting therapy-resistant cells within a chronic inflammatory microenvironment, particularly in the enteric nervous system (ENS), and the lack of robust animal models that faithfully recapitulate human pathology, as classical models largely rely on toxin-induced colitis. This review synthesizes major preclinical studies on gene therapy for CD and related inflammatory bowel diseases (IBD). We critically assess the rationale and biodistribution data for different vector platforms, considering vector type, promoter, and route of administration, in the ileum and colon of both rodent and non-human primate models. Special attention is given to strategies targeting the ENS. Finally, we explore the putative therapeutic aims of these approaches, including direct attenuation of intestinal inflammation and prevention of postoperative recurrence of CD via local intraoperative gene delivery. Although most data derive from chemical colitis models, this review establishes a foundational framework to inform translational research in gene therapy for CD and other IBDs.