Future treatments for hereditary hemorrhagic telangiectasia

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, PI3-kinase and angiopoietin-2. This review aims at reporting these recent developments that should soon allow a better care of HHT patients.

Keywords: ALK1; Bevacizumab; Bone morphogenetic protein signaling; Drug repositioning; Hereditary hemorrhagic telangiectasia; High throughput screening; Tacrolimus; Vascular malformations.

Fig. 1

Mutated genes in HHT encode members of the BMP9/BMP10 signaling pathway. The cartoon depicts the BMP9/BMP10 signaling pathway in endothelial cells. After ligand binding to cell surface receptors, signal transduction proceeds through phosphorylation of the type 1 receptor ALK1, phosphorylation of Smad 1/5/9, translocation of the Smad complex to the nucleus and transcriptional effects on target genes, as indicated by blue arrows. The left part of the Figure lists the names of the genes that are mutated in HHT patients and the arrows point to their gene products. The frequency of the mutations is indicated in % between the parentheses

Fig. 2

BMP9 and BMP10 induce vascular quiescence by various mechanisms. Through ALK1 phosphorylation of Smad1/5/9, BMP9 or BMP10 triggers transcriptional effects that induce vascular quiescence, including repression of ANGPT2 (angiopoietin 2) and induction of VEGFR1 expressions. In parallel, BMP9 inhibits the phosphorylation of the phosphatase PTEN (which is active in its unphosphorylated form), thereby inhibiting the activity of PI3K, a downstream effector of both VEGF and ANGPT2. ANGPT2 signaling is complex: when ANGPT1 (angiopoietin 1) is present, ANGPT2 acts as an antagonist of ANGPT1 and prevents the phosphorylation of the Tie2 receptor and the activation of PI3K. When ANGPT2 is present in large excess over ANGPT1, it acts as an agonist of the Tie2 receptor and stimulates PI3 Kinase. Tie2 activation is pro-angiogenic. VEGF activates different signaling pathways (PI3K/AKT, PLCγ/ERK, src/p38MAPK) which trigger a variety of biological responses (EC (endothelial cell) survival, permeability, proliferation and migration). VEGFR1, whose expression is increased by BMP9, acts as a decoy VEGF receptor, thereby shutting down the pro-angiogenic VEGF signaling mediated by VEGFR2 Altogether, BMP9 and BMP10 maintain vascular quiescence by shutting down the pro-angiogenic VEGF and ANGPT2 signaling pathways.

Fig. 3

Future treatments for HHT. The HHT-causing mutations of genes encoding components of the BMP9/BMP10 signaling pathway (indicated by red asterisks), result in decreased downstream signaling (indicated by thinner arrows than in Fig. 2) and increased activity of the VEGF and ANGPT2 signaling pathways (indicated by thicker arrows than in Fig. 2). Several drugs that target these pathways are already in use in clinical trials (blue boxes) or under evaluation in preclinical studies (parma boxes) for HHT treatment. Currently evaluated HHT treatments target VEGF via anti-VEGF antibodies (bevacizumab) or VEGFR2 tyrosine kinase inhibitors (VEGFR2-TKI such as pazopanib). Tacrolimus and sirolimus were identified through recent high-throughput screening of FDA-approved drugs as activators of ALK1 (and ALK3) signaling. They are under phase I/II trials as clinical treatments for HHT. Preclinical studies are investigating the beneficial effects of anti-ANGPT2 antibodies (LC-10) and PI3-kinase inhibitors (wortmannin or LY294002). As shown on this cartoon, all these treatments aim at restoring the balance between the BMP9 pathway and the VEGF/ANGPT2 pathways in order to re-establish vascular quiescence