Aro-Aat Reduces Z-AAT Protein in Pizz Patients and Leads to Improvements in Clinically Relevant Liver Biomarkers

Background Homozygous PiZZ alpha-1 antitrypsin deficiency (AATD) is an autosomal co-dominant genetic disorder causing pulmonary and liver disease in children and adults. Wild type alpha-1 antitrypsin (AAT) is synthesized by hepatocytes and secreted into circulation to protect the lung during inflammation by inhibition of neutrophil proteases. The mutant Z protein (Z-AAT) misfolds and is retained in the hepatocyte rather than secreted. This triggers liver injury which can lead to cirrhosis and the reduced serum activity can lead to lung injury. Intracellular proteolysis pathways are activated in the hepatocyte to reduce Z-AAT accumulation, but liver injury still results in some individuals. ARO-AAT is a hepatocyte targeted RNAi therapeutic designed to silence expression of Z-AAT mRNA leading to reduced Z-AAT protein synthesis. Herein, we report initial results from Cohort 1 in the AROAAT2002 phase 2 clinical trial.