Alpha-1 antitrypsin (AAT) deficiency is a common single-gene disorder among Northern Europeans and North Americans. The carrier frequency for the common missense mutation (Z-AAT) ranges from 4% in the US to nearly 25% in the Republic of Ireland. Severe AAT deficiency (plasma levels below 11 μm) is most commonly associated with an adult-onset
lung disease, with pan-acinar
emphysema and airway
inflammation, which is thought to be primarily owing to the loss of function of AAT in neutralizing
neutrophil elastase and other pro-inflammatory
enzymes. In 5-10% of patients, severe
liver disease may develop. This may occur at any time from infancy to adulthood, and is thought to be owing to toxicity from the Z-AAT
mutant protein that folds poorly and forms insoluble
polymers within the hepatocyte, which is the primary site for AAT production. Thus, gene therapy for AAT
lung disease is conceived of as augmentation of serum levels (a prolonged form of
protein replacement, which is currently in use), while gene therapy for
liver disease presents the problem of also having to downregulate the production of Z-AAT
protein. Over the years, numerous strategies have been employed for the gene therapy of both AAT-deficient
lung disease and
liver disease. These will be reviewed with an emphasis on modalities that have reached clinical trials recently.