a1-antitrypsin (AAT;A1AT) deficiency is a common debilitating hereditary disorder. The condition is characterized by reduced serum levels of AAT, a 52-kDa glycoprotein synthesized chiefly in the liver and, to a lesser extent, by macrophages and neutrophils. AAT acts as an antiprotease and is the physiological inhibitor of neutrophil serine proteases such as neutrophil elastase, cathepsin G and protease 3, all detectable in the lung. Inherited deficiency of AAT predisposes individuals to early onset hereditary emphysema. In addition, AAT deficiency also contributes to conditions such as emphysema caused by smoking, cystic fibrosis, pulmonary hypertension, pulmonary fibrosis, and chronic obstructive pulmonary disease (COPD). AAT isolated from human plasma has been used for treating hereditary emphysema for nearly 20 years. However, because of the limited supply of the plasma purified AAT, there are no AAT therapeutics available to treat other, more common diseases, such as COPD or smokers'emphysema;individuals with these conditions could benefit from AAT therapy. Despite the urgent need for AAT therapeutics, the progress toward recombinant AAT (rAAT) development has been hampered by difficulties in producing large quantity, high quality, and affordable AAT recombinant drug. This proposal is based on the preliminary data generated from the unique protein refolding technology, and toward the goal of producing highly stable, long in vitro half life, pharmaceutical grade mutant and peggylated rAAT from refolded E. coli inclusion bodies.
This project is to develop new mutant and peggylated forms of recombinant a1-antitrypsin (AAT) to treat medical conditions such as hereditary emphysema, chronic obstructive pulmonary disease (COPD), and other diseases caused by AAT deficiency. The ultimate goal is to produce high quality, affordable AAT drug to benefit patients who could not be treated by AAT because of the insufficient supply of the medicine isolated from human serum.
