Chemical chaperones mediate increased secretion of mutant α1-antitrypsin (α1-AT) Z:: A potential pharmacological strategy for prevention of liver injury and emphysema in α1-AT deficiency

In alpha 1-AT deficiency, a misfolded but functionally active mutant alpha 1-ATZ (alpha 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 alpha 1-AT to inhibit neutrophil elastase in the lung. Liver injury is thought to be caused by the hepatotoxic effects of the retained alpha 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 alpha 1-ATZ. In particular, 4-phenylbutyric acid (PBA) mediated a marked increase in secretion of functionally active alpha 1-ATZ in a model cell culture system. Moreover, oral administration of PEA was well tolerated by PiZ mice (transgenic for the human alpha 1-ATZ gene) and consistently mediated an increase in blood levels of human alpha 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 alpha 1-AT deficiency and PEA has been used safely in humans, it constitutes an excellent candidate for chemoprophylaxis of target organ injury in alpha 1-AT deficiency.