2 The massive formation of insoluble aggregates of mutant ATZ proteins in the hepatocytic ER results in apoptosis, hepatic inflammation, and fibrosis/cirrhosis and strongly predisposes patients to hepatocellular carcinoma (Fig. 1B).3 The diagnosis of AAT deficiency is established by low serum AAT levels, which are measured

for the screening of suspected patients; this is followed by genotyping (with PiZZ-specific polymerase chain reaction) and protein phenotyping (with isoelectric focusing gel) as verification tests.4 In liver histology, MG132 periodic acid-Schiff–positive, diastase-resistant globules containing ATZ protein polymers in hepatocytes are typically seen with AAT deficiency.3 Therapeutic options for AAT deficiency are limited at present. Patients with pulmonary manifestations are treated with standard chronic obstructive pulmonary disease drugs. In addition, augmentation therapy with regular intravenous administrations of partially purified plasma preparations

highly enriched with AAT is available (Prolastin, Zemaira, and Aralast), but this therapy is expensive (ca. $60,000-$150,000 per year), and data on its effectiveness are less robust.1 Clinical trials with augmentation therapy have indicated that emphysema progression might be moderately Selleckchem STA-9090 reduced,5, 6 but large studies with mortality as an endpoint are lacking at present. There is currently no therapeutic medical option available for treating liver diseases associated with AAT deficiency. Ultimately, liver transplantation is a causative therapy for AAT deficiency because it reverts the peripheral AAT deficiency and hepatic disease manifestation. Graft and patient survival rates after liver transplantation due to AAT deficiency are similar Calpain to those for other etiologies of cirrhosis.7 Several new therapeutic strategies for AAT deficiency have been proposed and investigated in the past. For instance, intravenous augmentation therapy might be replaced

by intranasal drug formulations in the future, and in experimental settings, protective AAT serum levels may also be reached with gene therapy approaches (e.g., viral gene transfer into muscle cells).1, 8 Targeting AAT deficiency–related liver disease has turned out to be more complex. Efficient inhibition of mutant protein polymerization is feasible in vitro but is difficult to translate into nontoxic, liver-specific drugs.9 An initial clinical trial with phenylbutyric acid as a chemical chaperone that enhanced AAT secretion in cell culture and mouse models failed because of a lack of efficacy and severe side effects in patients.10 David Perlmutter’s group investigated an alternative strategy: enhancing the cellular pathways responsible for the degradation of these aberrant molecules (Fig. 1C).