Gene-based therapies could transform future pancreatitis treatment

Background

Pancreatitis is a complex inflammatory disease driven by both genetic and environmental factors. It poses substantial clinical challenges due to a lack of disease-modifying therapies. Existing treatments are largely limited to symptomatic supportive care, which falls short of addressing the root causes. Gene therapy, as a novel strategy targeting the genetic etiology of the disease, holds promise for shifting the therapeutic paradigm from "symptom relief" toward "a precision curative approach".

Research Progress
The susceptibility genes for pancreatitis are primarily categorized into lipid metabolism pathways, trypsin regulation pathways, ductal secretion pathways and ER stress pathways, which jointly fuel pancreatitis onset and progression, making them critical targets for the development of gene-based therapeutic strategies for pancreatitis.

There are three mainstream gene therapy strategies (gene augmentation, gene inhibition, and gene editing), offering precise intervention approaches for different pathogenic mutation types. Recently, breakthroughs have been achieved in targeting lipid metabolism pathways. Several gene medicines, including Alipogene tiparvovec, Volanesorsen, Olezarsen, and ARO-APOC3, have been approved for clinical use, effectively reducing hyperlipidemia levels and the risk of acute pancreatitis. Furthermore, regarding the regulation of the trypsin pathway, AAV‑mediated SPINK1 gene augmentation has been validated in animal models to durably suppress the pathological progression of both acute and chronic pancreatitis.

Achieving targeted delivery to the pancreas represents a critical step in gene therapy. This review comprehensively summarizes viral and non‑viral vectors suitable for pancreatic application and extensively discusses the advantages and limitations of diverse administration routes. Among these, retrograde pancreatic duct injection demonstrates unique potential, as it can be integrated with clinically established endoscopic techniques, conferring favorable translational prospects.

Future Prospects
Gene therapy provides a novel direction for the curative treatment of pancreatitis. Although important progress has been made in related research, its clinical translation still faces core challenges, including insufficient efficiency of pancreas-targeted delivery, difficulty in defining the timing of treatment, limited translational relevance of preclinical models, and the impact of host immune responses. As these key challenges are gradually addressed, gene therapy for pancreatitis is expected to evolve from palliative care to definitive cure, providing more precise and effective therapeutic regimens for patients and improving their prognosis and quality of life.