Hereditary Angioedema: From Gene to Gene Therapy

Abstract Hereditary angioedema (HAE) (OMIM #106100) is a rare genetic, autosomal dominant condition characterised by recurrent, unpredictable episodes of cutaneous and submucosal swelling (mainly facial, abdominal, extremity) that are debilitating and potentially life‐threatening. The great majority of HAE patients carry a pathogenic variant in the SERPING1 gene, coding for the C1‐esterase inhibitor (C1‐INH) protein. This leads to uncontrolled Factor XII/plasma kallikrein activation and overproduction of the vasoactive peptide bradykinin, resulting in tissue swelling. About 5% of HAE patients have normal quantitative and functional C1‐INH levels. Variants in a small number of genes related to bradykinin signalling have been associated with this form of HAE. For many years, only symptomatic or prophylactic therapies have been available to reduce clinical manifestations. Recently, new targeted therapies based on molecular strategies (antisense oligonucleotides, gene editing) have been developed in order to achieve complete control of the disease and a number of clinical trials are ongoing. Key Concepts Hereditary angioedema (HAE) is caused by quantitative or qualitative C1 inhibitor deficiency, which is due to the presence of a defective copy of the SERPING1 gene. Patients with angioedema are often misdiagnosed and may therefore receive ineffective medical treatments or undergo unnecessary invasive diagnostic procedures. The application of high‐throughput next‐generation sequencing (NGS) technologies in routine clinical settings allows a timely and accurate molecular diagnosis for most HAE patients. The implementation of genomic approaches in HAE will contribute to the identification of specified targets for therapeutic intervention. Recent advances in gene editing techniques could open a new era of precision medicine in the individualised management of HAE.