Tackling the biological complexity of AATD

Alpha-1-antitrypsin deficiency (AATD) is the most common genetic cause of liver disease in children and the most frequent genetic diagnosis for which children undergo liver transplantation. AAT is synthesized in the liver and released into the plasma where it is the most abundant circulating protease inhibitor. The most common genetic cause of AAT deficiency is a mutation that renders the AAT protein prone to form aggregates in liver cells, causing liver injury and increased risk of hepatocellular carcinoma (HCC). However, the severity of the liver damage among homozygotes is dependent on genetic and/or environmental modifiers. The only curative treatment available for hepatic failure or cirrhosis associated with AATD is liver transplantation.
Despite several studies that have contributed to better understanding the pathophysiology of AATD, major knowledge gaps still remain. Thus, in our lab we aim to tackle some of these gaps by focusing on aspects of liver pathology that have not yet been addressed or remain unclear. In particular, we are interested in identifying pathways responsible for altered liver metabolism and cancer development observed in later stages of the disease. We combine expression and imaging studies in cellular and murine models of the disease. Moreover, we take advantage of long-lived primary liver organoid technology and genome editing to understand how accumulation of the mutant AAT protein alters cell biology, differentiation, and metabolism and how dysregulation of these processes is involved in the pathogenesis of the disease. The final goal of our research efforts will be to evaluate possible exploitation or modulation of the identified pathways as therapeutic approaches for affected patients.

The "Total Award" amount indicated for this project represents the share of the funding of the Telethon Foundation for research by the Tigem institute from January 2022 until last budget year, calculated based on the size of the research group.