New therapeutic targets for alpha-1 antitrypsin deficiency

Abstract

Alpha-1antitrypsin deficiency (AATD) results from the intracellular polymerization and retention of mutant alpha-1antitrypsin (AAT) within the endoplasmic reticulum of hepatocytes. This causes cirrhosis whilst the deficiency of circulating AAT predisposes to early onset emphysema. This is an exciting time for researchers in the field with the development of novel therapies based on understanding the pathobiology of disease. I review here augmentation therapy to prevent the progression of lung disease and a range of approaches to treat the liver disease associated with the accumulation of mutant AAT: modifying proteostasis networks that are activated by Z AAT polymers, stimulating autophagy, small interfering RNA and small molecules to block intracellular polymerization, and stem cell technology to correct the genetic defect that underlies AATD.