Developing a unique single approach to the prevention and treatment of geneticZ alpha-1 antitrypsin-related emphysema and liver cirrhosis (360G-Wellcome-107717_Z_15_Z)

Z antitrypsin (Z-AT, severe alpha-1 antitrypsin deficiency) is an incurable and fatal genetic disorder. The mis-folded Z-AT promotes specific intermolecular polymerisation principally in the hepatocyte leading children and adults to develop liver cirrhosis and cancer which results in significant disability and death. The intracellular aggregation results in a failure of secretion which causes progressive COPD in the third decade of life, respiratory failure and death. There is a significant unmet need as current treatments are solely palliative; with only a fortunate minority receiving organ transplantation. Our work has identified a unique approach to treatment through compounds that inhibit Z-AT polymerisation and allow secretion of functional Z-AT. We have demonstrated proof of concept in cells for a lead compound and identified a hit series with a similar cellular effect This project aims to build detailed structure activity relationships on the most promising series, and secondly we will perform profiling of early prototype compounds in PiZ transgenic mice to obtain in vivo proof of concept. This work will bring us closer to a treatment for severe alpha-1 antitrypsin deficiency.