The Future of Therapeutic Options for Hereditary Angioedema.

Hereditary angioedema (HAE) is a rare, genetic condition causing unpredictable and severe episodes of angioedema that are debilitating and life-threatening. HAE can be classified into HAE due to C1INH deficiency (HAE-C1INH), or HAE with normal C1INH (HAE-nl-C1INH). HAE-C1INH is subcategorized as type I and II based upon deficient or dysfunctional circulating C1INH protein resulting from inherited or spontaneous mutations in the SERPING1 gene leading to uncontrolled Factor XII(FXII)/plasma kallikrein activation and excessive bradykinin production. Bradykinin-2 receptor activation leads to vasodilation, increased vascular permeability and smooth muscle contractions, resulting in subcutaneous or submucosal fluid extravasation that can affect the face, extremities, airway, gastrointestinal and genitourinary systems. HAE-nl-C1INH is caused by either a known or unknown genetic mutation and the mechanisms are less well-established but most forms are thought to be related to bradykinin signaling with a similar presentation as HAE-C1INH despite normal levels of C1INH protein and function. Current HAE management strategies include on-demand and prophylactic treatments which replace C1INH, reduce kallikrein activity or block bradykinin binding to the bradykinin B2 receptor (BDKRB2). With the advent of additional small molecule inhibitors, monoclonal antibodies, RNA-targeted therapies, gene therapies and gene modification approaches, preclinical studies and human clinical trials are underway to further expand therapeutic options in HAE. This review article will briefly summarize current HAE treatments and provide an overview of potential future therapies for HAE.