Novel treatment strategies for liver disease due to α1-antitrypsin deficiency

Abstract

Alpha1-antitrypsin (AT) deficiency is the most common genetic cause of liver disease in children and is also a cause of chronic hepatic fibrosis, cirrhosis, and hepatocellular carcinoma in adults. Recent advances in understanding how mutant AT molecules accumulate within hepatocytes and cause liver cell injury have led to a novel strategy for chemoprophylaxis of this liver disease. This strategy involves a class of drugs, which enhance the intracellular degradation of mutant AT and, because several of these drugs have been used safely in humans for other indications, the strategy can be moved immediately into clinical trials. In this review, we will also report on advances that provide a basis for several other strategies that could be used in the future for treatment of the liver disease associated with AT deficiency.

Figure 1

Two models for polymerization of ATZ. (A) Active serpins fold into a metastable state. Following the initial interaction with a target peptidase and reactive center loop (RCL) cleavage, the serpin undergoes a radical conformational change (RCL/s4A incorporation into b‐sheet A) that culminates in peptidase inhibition via distortion of the catalytic residues. (B) Loop‐sheet model of serpin polymerization. The RCL of one molecule is inserted into the open b‐sheet A of another. (C) Domain swapping model of serpin polymerization. This model is based on the structure of a domain‐swapped antithrombin dimer, where s5A and s4A (RCL) of a donor molecule insert into b‐sheet A of a recipient. (D) Normal serpins may fold through a polymerogenic intermediate that is stabilized by certain mutations. The black dotted arrow indicates a gap in b‐sheet A that accommodates s5A to form the s4A (RCL) exposed native molecule to A or the s5A and s4A domain‐swapped structure in C. Reproduced with permission from Figure 2 of Whisstock JC et al. J Biol Chem. 2010; 285: 24307–24312.

Figure 2

Effect of carbamazepine, fluphenazine, and pimozide on intracellular degradation of mutant ATZ. Soluble forms of ATZ (purple) are degraded by the proteasomal pathway (top right) and insoluble aggregates of ATZ (gold) are degraded by autophagy (bottom right). Carbamazepine appears to enhance autophagy and also the proteasome. Fluphenazine and pimozide enhance the autophagic degradation of ATZ.