Future treatments for hereditary hemorrhagic telangiectasia
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(2020) 15:4
REVIEW
Open Access
Future treatments for hereditary hemorrhagic telangiectasia Florian Robert1, Agnès Desroches-Castan1, Sabine Bailly1†, Sophie Dupuis-Girod1,2,3† and Jean-Jacques Feige1*†
Abstract Hereditary Hemorrhagic Telangiectasia (HHT), also known as Rendu-Osler syndrome, is a genetic vascular disorder affecting 1 in 5000–8000 individuals worldwide. This rare disease is characterized by various vascular defects including epistaxis, blood vessel dilations (telangiectasia) and arteriovenous malformations (AVM) in several organs. About 90% of the cases are associated with heterozygous mutations of ACVRL1 or ENG genes, that respectively encode a bone morphogenetic protein receptor (activin receptor-like kinase 1, ALK1) and a co-receptor named endoglin. Less frequent mutations found in the remaining 10% of patients also affect the gene SMAD4 which is part of the transcriptional complex directly activated by this pathway. Presently, the therapeutic treatments for HHT are intended to reduce the symptoms of the disease. However, recent progress has been made using drugs that target VEGF (vascular endothelial growth factor) and the angiogenic pathway with the use of bevacizumab (anti-VEGF antibody). Furthermore, several exciting high-throughput screenings and preclinical studies have identified new molecular targets directly related to the signaling pathways affected in the disease. These include FKBP12, PI3kinase and angiopoietin-2. This review aims at reporting these recent developments that should soon allow a better care of HHT patients. Keywords: Hereditary hemorrhagic telangiectasia, Vascular malformations, Bone morphogenetic protein signaling, Drug repositioning, Bevacizumab, Tacrolimus, ALK1, High throughput screening
Background Hereditary Hemorrhagic Telangiectasia (HHT), also known as Rendu-Osler syndrome, is a genetic vascular disorder affecting 1 in 5000–8000 individuals worldwide, with regional differences and higher prevalence areas associated with founder effects [1–4]. This rare disease (ORPHA774; https://www.orpha.net/consor/cgi-bin/index.php?lng=EN) is characterized by various vascular defects including epistaxis, blood vessel dilations (telangiectasia) and arteriovenous malformations (AVM) in lungs, liver and brain. Epistaxis is the most frequent clinical manifestation of HHT, affecting more than 95% of patients [5]. Pulmonary AVMs are observed in 15–45% of patients but remain frequently undiagnosed and asymptomatic. Hepatic AVMS are observed in more than 70% of patients depending on the screening technique used but only 8% of patients will * Correspondence: [email protected] † Sabine Bailly, Sophie Dupuis-Girod and Jean-Jacques Feige contributed equally to this work. 1 Univ. Grenoble Alpes, Inserm, CEA, Laboratory Biology of Cancer and Infection, F-38000 Grenoble, France Full list of author information is available at the end of the article
develop symptomatic liver disease [6]. Gastrointestinal telangiectasias are quite frequent (70% of patients) and may lead to hemorrha
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