ERAAT

Alpha1-antitrypsin deficiency (ATD) is a rare disease caused by mutations in Αlpha1Antitrypsin (A1AT) leading to improperly folded protein products unable to be secreted, and that in some instances aggregate in hepatocyte endoplasmic reticulum (ER). The normal function of A1AT is to be transported to the lung where it acts as an inhibitor of neutrophil elastase. Z mutant Alpha1-Antitrypsin (ZA1AT) is retained in the ER by cellular quality control mechanisms and aggregates in this compartment. The consequences are severe health issues such as a loss-of-function defect in the lungs leading to lung emphysemas and chronic obstructive pulmonary disease (COPD) due the lack of circulating active A1AT. In the liver, the accumulation of ZA1AT through loop-sheet polymerization of soluble monomers leads to a proteotoxic gain-of-function, subsequently linked to deficient export from the ER. This aggregation can cause liver fibrosis, cirrhosis and subsequently hepatic failure. To date, there exists no effective pharmacological treatment alternative for ATD. Unpublished research from the Chevet laboratory (co-applicant) showed that selected activation of the IRE1 arm of the Unfolded Protein Response (UPR) improved the secretion of functionally active ZA1AT. This provides the proof of principle supporting the hypothesis that increasing ER proteostasis is a novel strategy to decrease proteotoxicity in the liver and to neutralize proteolytic activity in the lung in ATD. This project aims at identifying  IRE1 modulators in a cell-based high throughput screen (HTS) for their capacity to enhance ZA1AT secretion. We hypothesize that these molecules will restore secretion of ZA1AT and therefore ameliorate lung function as well as prevent liver toxicity and failure. Compounds will be validated in a cascade of functional assays that we have established. Validated hit compounds will be optimized by our experienced medicinal chemistry teams. Lead structures that fulfill the required parameters such as sufficient activity, selectivity, safety, will be tested in an animal model for ATD. The proposed ZA1AT modulators represent a highly promising approach to develop urgently needed drugs for the treatment of ATD, a strategy that we have applied successfully to correctors of cystic fibrosis.