Chemical Activation of Protein Phosphatase 2A Slows Progression of Alpha-1 Antitrypsin Deficiency Associated Loss of Lung Function

Abstract

Introduction/rationale to the study: We previously reported that the activity of protein phosphatase 2A (PP2A), a serine threonine phosphatase, is reduced in cells from alpha‐1 antitrypsin (AAT) deficient patients. Our group recently demonstrated that chemical activation of PP2A reduces loss of lung function in smoke‐exposed mice. Here we hypothesis that treatment with a PP2A activator would reduce loss of lung function decline in aged AAT deficient mice. Methods used: Male and female age‐matched Serpina1a‐e knockout mice daily received 5 mg/kg of an improved small molecule activator of PP2A, ATUX‐792, by oral administration for 4 months. Forced oscillation and expiratory measurements were recorded in each animal using the Scireq Flexivent System. Airspace enlargements were quantified by mean linear intercept measurements. The PP2A activator utilized here, ATUX‐792, is a tricyclic‐sulfonamide compound with improved metabolic stability and oral bioavailability compared to the prototype PP2A activator used in our previous study. Results of the study: Long‐term ATUX‐792 administration resulted in no notable toxicity in mice, with external appearance, behavior, and body weight similar to vehicle groups. As expected, aged AAT deficient animals receiving a placebo had changes in pressure volume loops, airway inflammation, lung compliance, inspiratory capacity and FEV0.05/FVC compared to wild type age matched controls. Importantly, treatment with ATUX‐792 reduced progression of these disease parameters in AAT deficient mice. ATUX‐792 treated animals had enhanced PP2A activity within their lungs and reduced phosphorylation of MAP kinases. Conclusions of the study: Our study indicates that the decrease in PP2A activity that occurs in AAT deficiency could be restored by PP2A