Why has it been so difficult to prove the efficacy of alpha-1-antitrypsin replacement therapy? Insights from the study of disease pathogenesis

Abstract

Alpha-1-antitrypsin is the most abundant circulating protease inhibitor. It is mainly produced by the liver and secreted into the circulation where it acts to prevent excessive proteolytic damage in the lungs by the enzyme neutrophil elastase. The most common severe deficiency allele is the Z mutation, which causes the protein to self-associate into ordered polymers. These polymers accumulate within hepatocytes to cause liver damage. The resulting lack of circulating α(1)-antitrypsin predisposes the Z homozygote to proteolytic lung damage and emphysema. Other pathways may also contribute to the development of lung disease. In particular, polymers of Z α(1)-antitrypsin can form within the lung where they act as a pro-inflammatory stimulus that may exacerbate protease-mediated lung damage. Researchers recognized in the 1980s that plasma α(1)-antitrypsin levels could be restored by intravenous infusions of purified human protein. Alpha-1-antitrypsin replacement therapy was introduced in 1987 but subsequent clinical trials have produced conflicting results, and to date there remains no widely accepted clinical evidence of the efficacy of α(1)-antitrypsin replacement therapy. This review addresses our current understanding of disease pathogenesis in α(1)-antitrypsin deficiency and questions why this treatment in isolation may not be effective. In particular it discusses the possible role of α(1)-antitrypsin polymers in exacerbating intrapulmonary inflammation and attenuating the efficacy of α(1)-antitrypsin replacement therapy.

Keywords: augmentation therapy; emphysema; α1-antitrypsin deficiency.

Figure 1

(A) Inhibition of neutrophil elastase by α₁-antitrypsin. After docking (left) the neutrophil elastase (grey) is inactivated by movement from the upper to the lower pole of the protein (right). This is associated with insertion of the reactive loop (red) as an extra strand into β-sheet A (green). Reproduced from Lomas et al with permission. (B) The structure of α₁-antitrypsin is centered on β-sheet A (green) and the mobile reactive center loop (red). Polymer formation results from the Z variant of α₁-antitrypsin (Glu342 Lys at P₁₇; arrowed) or mutations in the shutter domain (blue circle) that open β-sheet A to favor partial loop insertion (step 1) and the formation of an unstable intermediate (M^*). The patent β-sheet A can either accept the loop of another molecule (step 2) to form a dimer (D), which then extends into polymers (P). A small proportion of the unstable serpin molecules can accept their own loop (step 3) to form an inactive, thermostable, latent conformation (L). The individual molecules of α₁-antitrypsin within the polymer are colored red, yellow, and blue. Reproduced from Gooptu et al with permission.

Figure 2

(A) Electron microscopy (×20,000) of a hepatocyte from a Z homozygote showing a massive inclusion (arrowed) in the endoplasmic reticulum. Reproduced from Lomas et al with permission. (B) The intra-hepatic polymers of mutant Z α₁-antitrypsin have the appearance of beads on a string on electron microscopy. Reproduced from Lomas et al with permission.