The current therapy for AAT deficiency is augmentation with weekly infusions of purified AAT from pooled human plasma ( 9, 46– 48).
AAT in lung ELF of smokers has markedly reduced ability to inhibit NE compared with nonsmokers ( 34, 43, 44) this sensitivity of AAT to oxidants is the reason behind the early occurrence of emphysema in smokers with AAT deficiency ( 44, 45). Under oxidizing conditions, the M351 and M358 in the active site are oxidized to methionine sulfoxide, significantly reducing the ability of AAT to function ( 36– 42). These M residues in AAT are inactivated by exogenous oxidants, including cigarette smoke and air pollutants and endogenous oxidants from activated inflammatory cells ( 34, 35).
The Z allele causes the AAT protein to polymerize in hepatocytes, limiting secretion into the circulation, resulting in plasma levels 10% to 15% of the levels of normal M homozygotes ( 4, 5, 7, 29– 31).ĪAT binds serine proteases through its active site centered at methionine (M) 351 and 358 (M358, M351) through an irreversible interaction that inactivates both the protease and AAT ( 32, 33). Although there are more than 120 known alleles of AAT, individuals homozygous for the Z allele (E342K) account for more than 95% of clinically recognized cases of AAT deficiency ( 2, 4, 6, 23, 26– 28). The normal M alleles are present in more than 98% of the population ( 3, 5). Low serum levels of AAT, and thus in the alveolar structures and alveolar epithelial lining fluid (ELF), are associated with an imbalance between AAT and neutrophil-released proteases, leading to the slow destruction of the lung parenchyma ( 1, 2, 4, 6, 9, 14, 16, 23).ĪAT deficiency is caused by mutation in the SERPINA1 gene, a member of the serpin family of antiproteases ( 3, 5, 24, 25). However, hepatocytes produce the vast majority of functional AAT as AAT-deficient patients who receive liver transplants convert to the donor AAT phenotype ( 20– 22). In the lung, AAT is also produced locally by monocytes, macrophages, alveolar epithelial type 2 cells, and bronchial epithelial cells ( 17– 19). AAT is produced predominantly in the liver and diffuses across the lung from the circulation ( 1, 2, 4, 6, 9, 14– 16). AAT is a serine protease inhibitor that functions to inhibit neutrophil elastase (NE) as well as other neutrophil-released serine proteases, including proteinase 3, α-defensins, and cathepsin G ( 1, 2, 6, 9– 13). The disease, which is accelerated by smoking, presents at ages 35 to 40 in smokers compared with ages 55 to 60 in nonsmokers ( 1, 3, 6– 8). The primary manifestation of AAT deficiency is early-onset panacinar emphysema. Graphical AbstractĪlpha 1-antitrypsin (AAT) deficiency is a common autosomal recessive disorder affecting 1/2000 to 1/5000 individuals, about 90,000 people in the United States ( 1– 5). 8/AVL represents a second-generation gene therapy for AAT deficiency providing effective antiprotease protection even with oxidant stress.
8/AVL serum and ELF retained serine protease–inhibitory activity despite oxidant stress while 8/AMM function was abolished. High, dose-dependent AAT levels were found in the serum and lung epithelial lining fluid (ELF) of mice administered 8/AVL or 8/AMM by IV or IPL. 8/AVL was administered via intravenous (IV) and intrapleural (IPL) routes to C57BL/6 mice. We hypothesized that a onetime administration of a serotype 8 adeno-associated virus (AAV8) gene transfer vector coding for the oxidation-resistant variant AAT (A213/V351/元58 8/AVL) would maintain antiprotease activity under oxidant stress compared with normal AAT (A213/M351/M358 8/AMM). In vitro studies using amino acid substitutions demonstrated that replacing M351 with valine (V) and M358 with leucine (L) on a normal M1 alanine (A) 213 background provided maximum antiprotease protection despite oxidant stress. Cigarette smoke, pollution, and inflammatory cell–mediated oxidation of methionine (M) 351 and 358 inactivates AAT, limiting lung protection. AAT inhibits serine proteases, including neutrophil elastase, protecting the lung from proteolytic destruction. Alpha 1-antitrypsin (AAT) deficiency, a hereditary disorder characterized by low serum levels of functional AAT, is associated with early development of panacinar emphysema.
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