Development of a Potent Engineered Microbial Lipase for the Treatment of Exocrine Pancreatic Insufficiency

Background and Aims: Exocrine pancreatic insufficiency (EPI) is a chronic condition associated with inadequate digestive enzyme secretion from the pancreas, causing impaired digestion, malabsorption, and malnutrition. EPI affects 10%-20% of the general population, and the standard of care includes pancreatic enzyme replacement therapy (PERT) that is exclusively derived from porcine pancreatic extracts. However, PERT is associated with several limitations, including suboptimal efficacy, which results in increased pill burden and high treatment costs. This work aimed to identify and engineer a potent microbial lipase that can function in the gastrointestinal tract without needing enteric coating and capable of hydrolyzing a wide range of dietary fats for the development of an alternative PERT. Methods: State-of-the-art protein engineering and biochemical characterization techniques were applied to optimize and characterize a therapeutically relevant lipase. The lipase was evaluated in a pancreatic duct ligation minipig model, as well as in a clinical trial involving healthy subjects and EPI patients. Conclusion: These results provide a foundation for the clinical development of a novel engineered recombinant lipase for treating EPI and warrant further evaluation in clinical trials.