Hereditary Angioedema iPSC Models Implicate ER-Associated Degradation as a Potential Therapeutic Target.

BACKGROUND: Hereditary angioedema (HAE) is a rare congenital disorder characterized by recurrent episodes of subcutaneous and submucosal swelling, which can progress to life-threatening laryngeal obstruction. The most common form of HAE results from mutations in the SERPING1 gene, which encodes C1-esterase inhibitor (C1-INH). HAE belongs to the broader category of serpinopathy, in which misfolded serine protease inhibitors polymerize and are retained within the endoplasmic reticulum, leading to both loss-of-function and toxic gain-of-function effects. OBJECTIVE: This study aims to develop a stable patient-derived cell line that accurately represent the molecular and cellular processes underlying HAE and serves as a replicable platform for drug discovery and therapy. METHODS: Two HAE patients were recruited; peripheral blood mononuclear cells were obtained to generate patient-specific induced pluripotent stem cell (iPSC) lines. The HAE-iPSC cell lines were verified for their pluripotency and differentiated into hepatocytes for further physio-pathological studies. RESULTS: The generated iPSC lines were genetically identical to the donors, expressed canonical pluripotency markers, and demonstrated trilineage differentiation potential through embryoid body formation and expression of germ layer markers. Importantly, immunohistochemical analysis revealed intracellular retention and aggregation of C1-INH protein. We also demonstrated that the dominant-negative effect of the mutant C1-INH could be ameliorated by androgen treatment, a well-established agent in long-term prophylactic therapy for HAE. CONCLUSION: This is the first development of patient-derived iPSC models of HAE. These models not only exhibit key molecular features of HAE but also provide a versatile platform for mechanistic studies and preclinical drug testing.