A novel model and molecular therapy for Z alpha-1 antitrypsin deficiency
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- McNab, G.L., Dafforn, T.R., Wood, A. et al. Mamm Genome (2012) 23: 241. doi:10.1007/s00335-011-9370-2
Animal models that closely resemble human disease can present a challenge. Particularly so in alpha-1 antitrypsin deficiency (α1ATD), as the mouse alpha-1 antitrypsin (α1AT) cluster encodes five highly related genes compared with the one in humans. The mouse PI2 homologue is closest to the α1AT 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 α1AT proteins. We have tested the ability of a small-molecular-weight compound CG to alleviate polymerisation of these mouse α1AT proteins as it has been shown to reduce aggregates of Z α1AT 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 α1AT secreted from Chinese Hamster Ovary cells transfected with the mouse “M” α1AT gene than with the “Z” (20.8 ± 3.9 and 6.7 ± 3.6, respectively; P < 0.005), CG increased the α1AT 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 α1ATD and that mice expressing this gene would be relevant for testing treatments in vivo.