Alpha1-antitrypsin deficiency: New therapies on the horizon

Abstract

Alpha1-antitrypsin deficiency (AATD) is caused by mutations in the SERPINA1 gene, coding for alpha1-antitrypsin (AAT). AAT is synthesised mainly in the liver and is released into bloodstream to protect tissues (particularly lung) with its antiprotease activity. The homozygous Pi∗Z mutation (Pi∗ZZ genotype) is the predominant cause of severe AATD. It interferes with AAT secretion thereby leading to AAT accumulation in the liver and lack of AAT in the circulation and the lung. Accordingly, Pi∗ZZ individuals are strongly predisposed to lung and liver injury. The former is treated by a weekly AAT augmentation therapy, but not medicinal products exist for the liver. Our review summarises the current approaches silencing AAT production, improving protein folding and secretion or promoting AAT degradation.

Trial registration: ClinicalTrials.gov NCT03945292 NCT04174118 NCT02168686 NCT03804021 NCT00377416.