Celiac Disease Enzyme Therapy: Why Is There Still No Approved Drug?

For over two decades, the development of an effective enzymatic therapy for celiac disease has remained an unresolved challenge. Although the identification of gluten-derived toxic peptides as the disease trigger has made them promising targets for proteolytic degradation, not a single enzyme-based drug has gained regulatory approval. This work critically analyzes historical shortcomings in drug development, identifying key hurdles: substrate heterogeneity, the harsh gastric environment, unreliable activation mechanisms for zymogens, and a lack of standardized evaluation protocols. We then systematize the essential criteria for an optimal therapeutic enzyme, which must combine high catalytic efficiency against diverse gluten epitopes, stability under acidic conditions, and predictable in vivo activation. We conclude that the fundamental enzymatic strategy retains significant potential and provide a roadmap for future research aimed at developing a viable therapy for this unmet medical need.