Celiac Disease Enzyme Therapies Face Substrate Heterogeneity, Gastric Harshness, and Activation Challenges.

Celiac disease (CD) is an autoimmune disorder triggered by dietary gluten, leading to small intestinal damage and malabsorption. The current standard of care, a strict gluten-free diet, is challenging to maintain and often insufficient for complete mucosal healing. Gluten-derived toxic peptides, particularly those modified by calcium-dependent transglutaminase 2 (TG2), are central to CD pathogenesis, making their proteolytic degradation a promising therapeutic target. Despite over two decades of research, an effective enzymatic therapy remains an unmet medical need.

This critical review analyzed historical shortcomings in the development of enzyme-based drugs for celiac disease. Researchers systematically identified key hurdles that have prevented regulatory approval, examining factors related to enzyme efficacy, stability, and in vivo performance. They then synthesized essential criteria for an optimal therapeutic enzyme, providing a strategic roadmap for future research efforts in this challenging field. The analysis was based on existing literature and drug development history.

The review identified four primary hurdles hindering enzyme therapy development for celiac disease: substrate heterogeneity of gluten epitopes, the harsh gastric environment impacting enzyme stability, unreliable activation mechanisms for enzyme zymogens, and a lack of standardized evaluation protocols. This analysis underscores that while the fundamental enzymatic strategy retains significant potential, these specific challenges must be addressed to develop a viable therapy.

An optimal therapeutic enzyme must combine high catalytic efficiency against diverse gluten epitopes, robust stability under acidic conditions, and predictable in vivo activation.