A novel model and molecular therapy for Z alpha-1 antitrypsin deficiency.

Animal models that closely resemble human disease can present a challenge. Particularly so in alpha-1 antitrypsin deficiency (α(1)ATD), as the mouse alpha-1 antitrypsin (α(1)AT) cluster encodes five highly related genes compared with the one in humans. The mouse PI2 homologue is closest to the α(1)AT human gene. We have changed the equivalent mouse site that results in the Z variant in man (Glu342Lys) and made both the "M" and "Z" mouse PI2 α(1)AT proteins. We have tested the ability of a small-molecular-weight compound CG to alleviate polymerisation of these mouse α(1)AT proteins as it has been shown to reduce aggregates of Z α(1)AT in man. We found that (1) CG specifically reduces the formation of polymers of recombinant mouse "Z" protein but not "M" protein; (2) whereas there is significantly more α(1)AT secreted from Chinese Hamster Ovary cells transfected with the mouse "M" α(1)AT gene than with the "Z" (20.8 ± 3.9 and 6.7 ± 3.6, respectively; P < 0.005), CG increased the α(1)AT levels secreted from "Z" cells (21.2 ± 0.01) to that of "M" (20.2 ± 0.02). The data support the concept that the murine "Z" gene is a potential model for the study of α(1)ATD and that mice expressing this gene would be relevant for testing treatments in vivo.