Mysteries of α1-antitrypsin deficiency: emerging therapeutic strategies for a challenging disease

Abstract

The classical form of α1-antitrypsin deficiency (ATD) is an autosomal co-dominant disorder that affects ~1 in 3000 live births and is an important genetic cause of lung and liver disease. The protein affected, α1-antitrypsin (AT), is predominantly derived from the liver and has the function of inhibiting neutrophil elastase and several other destructive neutrophil proteinases. The genetic defect is a point mutation that leads to misfolding of the mutant protein, which is referred to as α1-antitrypsin Z (ATZ). Because of its misfolding, ATZ is unable to efficiently traverse the secretory pathway. Accumulation of ATZ in the endoplasmic reticulum of liver cells has a gain-of-function proteotoxic effect on the liver, resulting in fibrosis, cirrhosis and/or hepatocellular carcinoma in some individuals. Moreover, because of reduced secretion, there is a lack of anti-proteinase activity in the lung, which allows neutrophil proteases to destroy the connective tissue matrix and cause chronic obstructive pulmonary disease (COPD) by loss of function. Wide variation in the incidence and severity of liver and lung disease among individuals with ATD has made this disease one of the most challenging of the rare genetic disorders to diagnose and treat. Other than cigarette smoking, which worsens COPD in ATD, genetic and environmental modifiers that determine this phenotypic variability are unknown. A limited number of therapeutic strategies are currently available, and liver transplantation is the only treatment for severe liver disease. Although replacement therapy with purified AT corrects the loss of anti-proteinase function, COPD progresses in a substantial number of individuals with ATD and some undergo lung transplantation. Nevertheless, advances in understanding the variability in clinical phenotype and in developing novel therapeutic concepts is beginning to address the major clinical challenges of this mysterious disorder.

Keywords: Autophagy; Liver disease; α1-antitrypsin deficiency.

Fig. 1.

Pathophysiology of α1-antitrypsin and its deficiency (ATD). Synthesis, secretion and function of AT in the circulation and lungs of an unaffected individual (top) and illustration of how the liver and lungs are adversely affected in the classical form of ATD (bottom) (image used with permission from The University of Utah Genetic Science Learning Center, http://Learn.Genetics.utah.edu).

Fig. 2.

Pathways for the disposal of the mutant form of AT, ATZ, as potential therapeutic targets in ATD. Unlike wild-type AT, which efficiently traverses the conventional secretory pathway, the majority of mutant ATZ accumulates in the ER. Soluble forms of ATZ (ATZ monomers) are presumably degraded by the proteasomal pathway, whereas insoluble forms of ATZ (ATZ aggregates) are degraded by autophagy. Emerging candidate therapies that target these disposal pathways include carbamazepine, which has been shown to increase both proteosomal and autophagic disposal of ATZ. Autophagy enhancers such as certain phenothiazines and the novel Tat-beclin 1 peptide, an autophagy-inducing peptide, enhance autophagic disposal of ATZ. Ub, ubiquitin.