Advancing Gene Therapy for Pancreatitis: From Genetic Insights to Clinical Translation

Pancreatitis is a complex inflammatory disease with substantial genetic determinants. It progresses from acute to chronic forms and poses substantial clinical challenges due to a lack of disease-modifying therapies. Conventional treatments are largely palliative, highlighting the urgent need for mechanism-based interventions. Gene therapy represents a transformative strategy, directly targeting the root genetic causes. This review comprehensively outlines the current landscape and future directions of gene therapy for pancreatitis. We first delineate the genetic underpinnings of the disease, categorizing susceptibility genes into 4 key pathways involving lipid metabolism, trypsin regulation, ductal secretion, and endoplasmic reticulum stress. We then detail the core therapeutic strategies-gene augmentation, suppression, and editing-highlighting both clinically validated drugs (targeting lipid metabolism) and novel preclinical approaches for pancreatitis. Furthermore, to achieve pancreas-targeted delivery, we thoroughly describe the delivery vectors, including viral and nonviral systems, as well as the administration routes. However, translating these therapies faces considerable hurdles, such as physiological and pathological barriers to pancreatic targeting, the challenge of determining intervention timing, the lack of optimal animal models recapitulating human pancreatitis, and host immune responses. We discuss potential solutions to these hurdles, including innovative vector design, improved models, and immunotherapy. Ultimately, gene therapy holds the promise to fundamentally transform the pancreatitis treatment paradigm, offering a path from palliative care to definitive, precision medicine.