Hereditary Angioedema as a Metabolic Liver Disorder: Novel Therapeutic Options and Prospects for Cure

Abstract

Hereditary angioedema (HAE) is a rare autosomal dominant disorder caused by mutations of the SERPING1 or the Factor 12 genes. It is potentially fatal, particularly if not identified at an early stage. Apart from androgens, which are contraindicated in children and in pregnant women, a range of effective, albeit very expensive treatments have recently become available for HAE patients. The cost of these new treatments is beyond the reach of most developing countries. At this time, there is no cure for the disorder. In spite of mutations of the SERPING1 gene, autoimmunity and infections are not prominent features of the condition. Here, we present the argument that HAE should be viewed primarily as a metabolic liver disorder. This conceptual paradigm shift will stimulate basic research and may facilitate new therapeutic approaches to HAE outlined in this paper. We suggest several novel potential treatment options for HAE from the perspectives of clinical immunology, molecular biology, and liver transplantation. Many of these offer the prospect of curing the disorder. The effectiveness of these options is rapidly improving in many cases, and their risks are decreasing. Given the very high costs of treating HAE, some of these curative options may become feasible in the next decade.

Genetic variants of SERPING1 gene in Polish patients with hereditary angioedema due to C1 inhibitor deficiency

“…After initial recognition in the 80-s, the mutation of SER-PING1 gene encoding C1-inhibitor (C1-INH) is responsible for C1-INH-HAE [3,4], and introducing genetic studies in patients with C1-INH-HAE [5] has become an essential part of molecular researches conducted on this disease [4,6,7]. Previous genetic studies indicated a wide spectrum of disease-associated variants in the SERPING1 gene and often lack of correlation with the phenotype in patients with this disease [8][9][10][11]. Over 500 different SERPING1 mutations [4] in patients with C1-INH-HAE have been detected and described according to the Human Genome Mutation Database (HGMD) (http://www.hgmd.cf.ac.uk/ac/index.php).…”

Hereditary angioedema in children and adolescents – A consensus update on therapeutic strategies for German‐speaking countries

“…Conversely, it is discussed whether HAE could be cured by transplanting a healthy liver. 51 To date, no such case is known.…”

All Patients With Common Variable Immunodeficiency Disorders (CVID) Should Be Routinely Offered Diagnostic Genetic Testing

“…CRISPR-Cas9 has been used to repair CYBB gene mutations in X-linked chronic granulomatous disease cells (50). As discussed previously, off-target effects of the CRISPR-Cas9 system may limit its in vivo use (51), although there has been progress to mitigate these risks (52). We are unaware of any current in vivo trials of retroviral gene therapy or CRISPR-Cas9 gene editing studies in patients with CVID-like disorders.…”