Augmentation treatment for α1 antitrypsin deficiency.

www.thelancet.com Published online May 28, 2015 http://dx.doi.org/10.1016/S0140-6736(15)60036-8 1 α1 antitrypsin is a serine antiprotease secreted by the liver. Its main function is inhibition of neutrophil elastase, a non-specifi c protease released by activated or dying neutrophils. In individuals with healthy concentrations of α1 antitrypsin, the fragile alveolar structures of the lung parenchyma are protected from this protease (fi gure). α1 antitrypsin defi ciency, discovered by Laurell and Eriksson in 1963, is a common hereditary disorder, mainly of Caucasians, characterised by low serum concentrations of the protein, emphysema, and, in some cases, liver disease. Most cases are caused by homozygous inheritance of a single base mutation (Glu342Lys) in the α1 antitrypsin gene, referred to as the Z variant. The Z form of α1 antitrypsin produced by the liver aggregates in the endoplasmic reticulum of hepatocytes, with consequently decreased serum protein and, in some cases, liver cirrhosis. Because of these decreased serum concentrations, the lungs of Z homozygotes have little defence against neutrophil elastase and develop clinical manifestations of alveolar destruction (emphysema) aged 35–45 years in cigarette smokers, and aged 50–60 in non-smokers. In the 1980s, based on the concept that pathogenesis of emphysema can be caused by α1 antitrypsin defi ciency, my laboratory sought to develop a treatment to prevent the progressive loss of lung parenchyma that results in the clinical manifestations of emphysema. These studies led to approval in the USA of intravenous augmentation treatment for α1 antitrypsin defi ciency. First, using bronchoalveolar lavage, we showed that the epithelial surface of the lower respiratory tract of Z homozygotes was defi cient in α1 antitrypsin and, consequently, antineutrophil elastase capacity. Second, we purifi ed α1 antitrypsin from pooled human plasma and showed in individuals defi cient in α1 antitrypsin that intravenous administration of 60 mg/kg of purifi ed α1 antitrypsin once a week could re-establish healthy serum α1 antitrypsin concentrations and, importantly, re-establish healthy lung alveolar α1 antitrypsin concentrations and antineutrophil elastase capacity. On the basis of these studies, the US Food and Drug Administration approved use of augmentation treatment of α1 antitrypsin defi ciency. This approval, and the subsequent use of α1 antitrypsin augmentation treatment in more than 5000 patients with α1 antitrypsin defi ciency worldwide, was based entirely on biochemical effi cacy—ie, that α1 antitrypsin augmentation treatment is effi cacious because it re-establishes healthy serum and lung epithelial lining fl uid concentrations and antineutrophil elastase capacity. Despite the logic underlying the biochemical effi cacy of α1 antitrypsin augmentation treatment, no clinical evidence had existed that this treatment is effi cacious. Augmentation treatment for α1 antitrypsin defi ciency