Chemical Chaperones Mediate Increased Secretion of Mutant α 1-Antitrypsin(α 1-AT) Z: A Potential Pharmacological Strategy for Prevention of Liver Injury and Emphysema in α 1-AT Deficiency

In α 1-AT deficiency, a misfolded but functionally active mutant α 1-ATZ(α 1-ATZ) molecule is retained in the endoplasmic reticulum of liver cells rather than secreted into the blood and body fluids. Emphysema is thought to be caused by the lack of circulating α 1-AT to inhibit neutrophil elastase in the lung. Liver injury is thought to be caused by the hepatotoxic effects of the retained α 1-ATZ. In this study, we show that several "chemical chaperones," which have been shown to reverse the cellular mislocalization or misfolding of other mutant plasma membrane, nuclear, and cytoplasmic proteins, mediate increased secretion of α 1-ATZ. In particular, 4-phenylbutyric acid (PBA) mediated a marked increase in secretion of functionally active α 1-ATZ in a model cell culture system. Moreover, oral administration of PBA was well tolerated by PiZ mice (transgenic for the human α 1-ATZ gene and consistently mediated an increase in blood levels of human α 1-AT reaching 20-50% of the levels present in PiM mice and normal humans. Because clinical studies have suggested that only partial correction is needed for prevention of both liver and lung injury in α 1-AT deficiency and PBA has been used safely in humans, it constitutes an excellent candidate for chemoprophylaxis of target organ injury in α 1-AT deficiency.