Chemical chaperones mediate increased secretion of mutant alpha 1-antitrypsin (alpha 1-AT) Z: A potential pharmacological strategy for prevention of liver injury and emphysema in alpha 1-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 li ver 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 neut rophil elastase in the lung. Liver injury is thought to be caused by the he patotoxic effects of the retained alpha 1-ATZ. In this study, we show that several "chemical chaperones," which have been shown to reverse the cellula r mislocalization or misfolding of other mutant plasma membrane, nuclear, a nd cytoplasmic proteins, mediate increased secretion of alpha 1-ATZ. In par ticular, 4-phenylbutyric acid (PBA) mediated a marked increase in secretion of functionally active alpha 1-ATZ in a model cell culture system. Moreove r, oral administration of PEA was well tolerated by PiZ mice (transgenic fo r the human alpha 1-ATZ gene) and consistently mediated an increase in bloo d levels of human alpha 1-AT reaching 20-50% of the levels present in PIM m ice and normal humans. Because clinical studies have suggested that only pa rtial 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 constitute s an excellent candidate for chemoprophylaxis of target organ injury in alp ha 1-AT deficiency.