KETI - Clinical development of transglutaminase-inhibitors for treating celiac disease

KETI - Clinical development of transglutaminase-inhibitors for treating celiac disease

Celiac disease is one of the most common autoimmune diseases, with a prevalence of 0.5-2%. It is triggered by the consumption of gluten proteins (gluten) from wheat, rye and barley. Gluten, which accounts for approximately 85% of the protein fraction in flour, is only incompletely digested and activates T-cells in the small intestine of patients with celiac disease and these T cells damage the resorptive mucosa . The consequences of this gluten-induced inflammation range from minor symptoms to severe malabsorption, with anemia and osteoporosis, to the development of intestinal and extraintestinal cancers. So far, the only treatment for celiac disease is strict adherence to a gluten-free diet. This is extremely challenging for patients and has a significant impact on the quality of life and socialization. Moreover, it is almost impossible to eliminate traces of gluten contained in almost all processed foods. Furthermore, a gluten-free diet often leads to inadequate intake of fiber, vitamins and trace elements.

The enzyme tissue transglutaminase (TG2), which modifies (deamidates) gluten peptides in the intestinal mucosa, plays a central role in triggering and maintaining active celiac disease. HLA-DQ2/DQ8-receptors on intestinal antigen-presenting cells recognize and bind these gluten peptides especially well after their TG2-mediated deamidation (all patients with celiac disease are carriers of HLA-DQ2/DQ8, which are the necessary genetic predisposition for the development of the disease, but are also found in 30-40 % of the normal population). The subsequent T-cell activation and intestinal inflammation is also accompanied by the formation of celiac disease-specific auto-antibodies against TG2. Furthermore, intestinal inflammation leads to an increase in the amount of TG2 released in the intestinal mucosa, which further fuels gluten deamidation.

The scientifically well-founded hypothesis of the project is that celiac disease can be treated prophylactically by inactivating the dysregulated TG2 in the inflamed intestinal mucosa, locally and non-systemically, by administrating a TG2-blocker. The thus inactivated TG2 can no longer catalyze the deamidation of gluten peptides. Therefore gluten peptides cannot be adequately bound and presented on antigen presenting cells, T cell activation cannot take place and the vicious cycle of intestinal inflammation and increased release of TG2 is interrupted.

The low-molecular weight TG2-inhibitor ZED1227 developed by Zedira and optimized to meet the requirements of celiac disease treatment is further developed preclinically and clinically by the project partners. After successful up-scaling of the manufacturing process and provision of GMP-grade compound, a galenic formulation for clinical trials with ZED1227 was developed. In parallel a program of pharmacological and toxicological examinations meeting the regulatory requirements for Phase 1 clinical trials was completed.

Keywords 

  • Celiac disease
  • Transglutaminase
  • pharmacological therapy

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