Immunogenic gluten peptides that resist gastrointestinal breakdown are the main triggers for celiac disease. Gluten degrading enzymes represent a promising treatment option for managing celiac disease, but need to meet certain conditions within the gut to render gluten harmless before it reaches the duodenum.

A team of researchers recently set out to review oral, gluten-degrading enzymes meant for use by celiacs on a gluten-free diet, discussing their origin and activities, their clinical evaluation and challenges for therapeutic application.

The research team included Guoxian Wei, Eva J Helmerhorst, Ghassan Darwish, Gabriel Blumenkranz, and Detlef Schuppan. They are variously affiliated with the Department of Molecular and Cell Biology, Henry M. Goldman School of Dental Medicine, Boston, MA, USA; the Institute for Translational Immunology and Research Center for Immunotherapy (FZI), Johannes Gutenberg University (JGU) Medical Center in Mainz, Germany; and the Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

Most people with celiac disease are exposed to trace amounts of gluten on a regular basis. Whether due to high sensitivity or repeated exposure, many celiac patients continue to suffer both symptoms and damage despite following a gluten-free diet.

In addition to simplified testing for ongoing gluten-exposure, there’s a pressing need for safe treatments that can help address the realities of gluten-exposure by those on a gluten-free diet. Gluten-degrading enzymes are one especially promising option.

To be effective, such enzymes would need to be safe for people, active under gastro-duodenal conditions, and rapidly neutralizing T cell activating gluten peptides.

Gluten peptides normally resist digestion, but a number of enzymes, including bacterial, fungal and plant derived glutenases, especially food-grade subtilisins (Sub-A), prolyl endopeptidases (PEP), AN-PEP enzymes, barley seed derived glutamine-specific cysteine endoprotease (EP-B2) and synthetic glutenases (Kuma030) are all potential game changers for oral enzyme therapy for people with celiac disease.

Researchers have had some success with various combinations of enzymes, molecular modeling and chemical modifications, such as PEGylation, enteric coatings or enzyme carriers. The goal is to develop a product that can quickly and completely break down immunogenic gluten peptides that are bound up in foods. The digestion of gluten peptides must happen fully within the stomach and proximal small intestine before these peptides reach the mucosal immune system of the small intestine.

Without exception, these enzymes must function in the glutamine- and proline-rich environments of antigenic gluten peptides. Such enzymes also need to remain stable in stomach acid, and in the near neutral pH in the duodenum.

According to the researchers:  “Bacterial, fungal and plant derived glutenases, especially (food-grade) subtilisins (Sub-A), prolyl endopeptidases (PEP), barley seed derived glutamine-specific cysteine endoprotease (EP-B2) and synthetic glutenases (Kuma030) are considered promising candidates for an (adjunctive) oral enzyme therapy. ”

The team’s recent review acknowledges the potential for oral enzymes in improving celiac disease treatment, and focuses on the origins and actions, clinical evaluations and therapeutic challenges faced by enzymes intended to treat celiac disease.