Engineering α-1 antitrypsin for augmentation therapy

α-1 antitrypsin (AAT) is used as augmentation therapy in patients with AAT deficiency (AATD)-related emphysema, and is a promising therapeutic for treatment of a wide range of inflammation and autoimmune diseases. However, patients undergoing weekly infusions of AAT augmentation therapy exhibit declining levels of circulating AAT, due to its propensity to aggregate and inactivate. AAT inactivation can be prevented by protein engineering, offering a route to pre-clinical candidates having superior therapeutic potential. This proposal will use protein engineering to create new variants of AAT that do not inactivate to the latent form or aggregate.