Our studies have focused on determining the molecular basis of alpha1-antitrypsin (alpha1AT) deficiency variants and utilizing natural mutations of the alpha1AT gene to assess structure-function relationships of alpha1AT and to explore regulatory mechanisms of alpha1AT gene expression. In the past year the laboratory has begun characterization of an alpha1AT intronic sequence that enhances alpha1AT gene expression, characterized the molecular basis of QOtrastevere (an alpha1AT null variant), begun the characterization of a group of frameshift mutations that terminate in the same structural region of the alpha1AT protein and identified a new null variant QObonny blue. We have developed an adenoviral-alpha1AT vector that expresses six times more alpha1AT than previous vectors and established an emphysema animal model to evaluate the biochemical efficacy of alpha1AT gene therapy. To evaluate the hypothesis that the liver disease associated with alpha1AT deficiency is the result of hepatitis from a common enteric virus we screened liver samples from alpha1AT deficient individuals post transplant for the presence of viral nucleic acid sequences.
