High Density Lipoprotein Targeting Protease Inhibitors for Preservation of Lung Function

Alpha-1-antitrypsin (A1AT) deficiency can result in clinically significant loss of lung function as a result of excessive elastase activity in the lungs. Elastase is a proteolytic enzyme that is naturally regulated by A1AT. Current treatment for A1AT deficiency involves replacement therapy by infusion of purified A1AT, however, the clinical benefit gained from this treatment is modest. This may be due to an inability of the infused A1AT to access the lungs where it can prevent elastase mediated damage. Recently, high density lipoproteins (HDL) in the circulation have been found to bind to A1AT. HDL-bound A1AT can be transported to the lung more efficiently than free A1AT and prevents elastase induced damage to the lung in mouse models of emphysema. We have recently designed an HDL-targeting elastase inhibitor peptide that can mimic the function of A1AT. This peptide binds to HDL in the plasma and confers potent elastase inhibitor activity to the HDL. In this Pilot and Feasibility Study proposal, we plan to evaluate this peptide as a potential therapeutic in a mouse model of elastase induced emphysema. Outcome measures will include inflammatory markers in the blood and lung fluids as well as measurements of lung function and analysis of lung morphology. We anticipate the HDL-targeting elastase inhibitor peptide will suppress inflammation and display better preservation of lung function than free A1AT because of its smaller size, increased potency, and efficient HDL-targeting.