Specific Targeting of Plasma Kallikrein for Treatment of Hereditary Angioedema: A Revolutionary Decade.

Hereditary angioedema (HAE) is a rare, chronic, genetic disease that presents with nonpruritic angioedema of the face, extremities, airway (can be life-threatening), genitourinary system, and abdomen. These symptoms can significantly impair daily activities. Hereditary angioedema is classified into HAE owing to a deficiency of functional C1INH (HAE-C1INH) or HAE with normal C1INH (HAE-nl-C1INH). Both type I and II HAE-C1INH result from inherited or spontaneous mutations in the SERPING1 gene, which encodes for C1INH. These mutations result in C1INH dysfunction, leading to uncontrolled plasma kallikrein activity with excessive bradykinin production. Bradykinin receptor activation leads to vasodilation, increased vascular permeability, and smooth muscle contractions, resulting in submucosal angioedema through fluid extravasation. Hereditary angioedema nl-C1INH is caused by either a known or unknown genetic mutation. The underlying mechanism of HAE-nl-C1INH is less well understood but is thought to be related to bradykinin signaling. Plasma kallikrein inhibitors have been developed to inhibit the kallikrein-kinin pathway to prevent (prophylactic) and treat on-demand (acute) HAE attacks. Several of these medications are delivered through subcutaneous or intravenous injection, although new and emerging therapies include oral formulations. This article provides a historical review and describes the evolving landscape of available kallikrein inhibitors to treat HAE-C1INH.