Cystic Fibrosis of the Pancreas: In Vitro Duct Models for CFTR-Targeted Translational Research

Area of Science:

• Cell biology
• Gastroenterology
• Medical biochemistry

Background:

• Cystic fibrosis (CF) arises from loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, primarily impacting the pancreas.
• CFTR dysfunction leads to impaired bicarbonate secretion in pancreatic ducts, causing exocrine insufficiency, pancreatitis, and CF-related diabetes.

Purpose of the Study:

• To review pancreatic pathophysiology in CF and current management strategies.
• To examine in vitro pancreatic duct models for evaluating CFTR-targeted therapeutics.
• To highlight the importance of bicarbonate transport as a key endpoint for CFTR modulator development.

Main Methods:

• Review of existing literature on CF pancreatic pathophysiology and therapeutic approaches.
• Analysis of various in vitro models: native tissue, primary cultures, organoids, co-cultures, and microfluidic devices.
• Emphasis on bicarbonate-relevant endpoints like pH and HCO3- flux measurements.

Main Results:

• Selective impairment of CFTR-dependent bicarbonate transport is linked to severe pancreatic manifestations in CF.
• Diverse in vitro models offer complementary advantages for studying CFTR function and drug screening.
• Bicarbonate transport and pH regulation are critical readouts for assessing therapeutic efficacy.

Conclusions:

• Developing effective CFTR modulators requires models that accurately reflect pancreatic duct physiology, particularly bicarbonate secretion.
• Prioritizing bicarbonate-relevant endpoints in preclinical models will improve the translation of therapeutic discoveries to clinical outcomes.
• Next-generation CFTR modulators and adjunctive therapies are needed to preserve both exocrine and endocrine pancreatic function in CF patients.