From left to right, Francisco José López Cano, Arturo Rodríguez-Banqueri, F. Xavier Gomis-Rüth and Marina Girbal González.
Photo Credit: Courtesy of University of Barcelona
Scientific Frontline: Extended "At a Glance" Summary: Celiacase and Celiac Disease Therapeutics
The Core Concept: Celiacase is a molecularly engineered enzyme designed to break down toxic gluten immunogenic peptides (GIPs) in the stomach before they can reach the small intestine and trigger an autoimmune response.
Key Distinction/Mechanism: Unlike existing glutenases that require a neutral pH and high doses to function in the duodenum, celiacase operates highly effectively at very low concentrations in the acidic environment of the stomach (pH 2). It works synergistically with pepsin and completely deactivates upon reaching the intestine, preventing unintended interference with other proteins in the body.
Major Frameworks/Components:
- Pathophysiology of Celiac Disease: Prolamins (such as wheat gluten) break down during digestion into toxic peptides, most notably the highly immunogenic α-gliadin '33-mer' fragment.
- Autoimmune Trigger Mechanism: The binding of GIPs to the human leukocyte antigen (HLA) receptor in the small intestine, which initiates a damaging inflammatory response.
- Molecular Engineering: The derivation, structural design, and optimization of the celiacase molecule based on the naturally occurring nephrosin enzyme.
- In Vivo Validation: Efficacy demonstrated in a specialized mouse model, exhibiting reductions in intestinal atrophy, inflammation, antibody responses, and dysbiosis, alongside the restoration of normal immunoregulatory markers and microbial metabolic pathways.
Branch of Science: Biochemistry, Molecular Biology, Immunology, Pharmacology, Gastroenterology.
Future Application: Development as an adjunctive therapeutic pharmaceutical to support individuals on a strict gluten-free diet, with patents secured and early-stage plans for commercialization via a biotechnology spin-off company.
Why It Matters: It provides a highly efficient, targeted intervention to mitigate the severe symptoms and physiological damage of celiac disease, overcoming the biological limitations of current nutritional supplements that fail to act as effective therapeutic alternatives to strict dietary restrictions.
A research project led by the Institute for Research in Nutrition and Food Safety (INSA) and the Faculty of Pharmacy and Food Sciences at the University of Barcelona, together with the Molecular Biology Institute of Barcelona (IBMB) of the CSIC (which stands for Consejo Superior de Investigaciones Científicas), has successfully designed and tested a gluten-degrading molecule that is a promising ally in the management of coeliac disease, an autoimmune disease whose symptoms are triggered by the consumption of gluten and other prolamins found in cereals. At present, there is a complete lack of treatment options beyond a diet free from gluten, which is difficult to maintain in Western societies where diets rely heavily on wheat products.
The major breakthrough is that the molecule is effective at very low concentrations and at a pH of 2—the pH of the stomach—a condition that none of the molecules currently available or under development had previously achieved with efficiency. Although some of them are marketed as nutritional supplements, they are not an effective alternative to gluten-free diets.
Counteracting the "Trigger" of Celiac Disease
The triggers for celiac disease are prolamins, proteins found in the most common cereals in our diet, such as wheat gluten. When these are digested in the stomach, they break down into smaller fragments (peptides). Some of these can be toxic, such as gluten immunogenic peptides (GIPs), which can withstand the stomach’s gastric acids and reach the small intestine. Among these, one of the most immunogenic is the "33-mer," a fragment of the α-gliadin in wheat gluten.
This poses a problem for people with celiac disease because once in the small intestine, the 33-mer and other GIPs bind particularly easily to a receptor of the immune system (the human leukocyte antigen, or HLA), triggering the inflammatory autoimmune response that causes the characteristic symptoms of the disease.
The results demonstrate that celiacase, a molecule stable in the stomach environment, could be an adjunctive therapeutic candidate to support a gluten-free diet.
Four years ago, the Proteolysis Group at IBMB-CSIC, led by F. Xavier Gomis-Rüth, described in an article in Nature Communications that nephrosin—a molecule found naturally in the digestive juices of the carnivorous plant Nepenthes ventrata—was capable of cleaving GIPs, building on results from the group of David Schriemer at the University of Alberta in Canada. In collaboration with the Autoimmunity, Immunonutrition, and Tolerance Group at the UB’s Faculty of Pharmacy and Food Sciences, led by Professor Francisco José Pérez-Cano, they demonstrated that nephrosin can degrade the 33-mer peptide and other GIPs before they reach the intestine, thereby potentially preventing this autoimmune inflammatory response.
Designed Using Molecular Engineering
In this study, the team designed and tested a molecule based on nephrosin. Named celiacase, this new molecule exhibits its maximum activity at the gastric pH of the stomach, where, in synergy with the pepsin in our digestive system, it breaks down the GIPs in cereals and the gliadin in wheat before they pass into the duodenum.
"There are other proteases, generically termed glutenases, which break down gluten, but they are not fully active at pH 2—the pH of the stomach—but rather at pH 7—the pH of the duodenum—when the bolus has already left the stomach," explains Gomis-Rüth. "Therefore, it is necessary to increase the doses to levels that make them unviable for therapeutic use."
The team tested the molecule in vivo using a mouse model developed by the University of Chicago, which is currently the model that most accurately replicates celiac disease. The results show that celiacase is effective at very low doses, mitigating the symptoms of the disease in gluten-fed mice, even at high gluten intake levels. "Intestinal atrophy, inflammation, the antibody response, and dysbiosis—that is, the alteration in the composition of the microbiota—were reduced," says Pérez-Cano. "Furthermore, immunoregulatory markers were restored to normal levels, as were microbial metabolic pathways."
Another advantage of celiacase is that it is no longer active once it reaches the duodenum. "Once it has accomplished its function, there is no need for it to remain active, so it does not interfere with other proteins in the body," adds Gomis-Rüth.
The molecule and its potential applications have been patented, and the team is taking the first steps toward setting up a spin-off company and taking the development to more advanced stages.
Funding: This study was partially funded by programs run by the Ministry of Science and Innovation, the Government of Catalonia’s Agency for Management of University and Research Grants (AGAUR), the Catalan Celiac Association, and the CSIC’s Conexión Trigo network.
Published in journal: EMBO Molecular Medicine
Title: Targeted enzymatic therapy for coeliac disease
Authors: Marina Girbal-González, Arturo Rodríguez-Banqueri, Hadeel Swaid, Soraia R Mendes, Laura Garzón-Flores, Juan Sebastián Ramírez-Larrota, Carolina Cueva, M Victoria Moreno-Arribas, Christof Regl, Christian G Huber, Katharina A Scherf, María José Rodríguez-Lagunas, Àngels Franch-Masferrer, Ulrich Eckhard, Francisco J Pérez-Cano, and F Xavier Gomis-Rüth
Source/Credit: University of Barcelona
Reference Number: bchm051426_01