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Orphanet Journal of Rare Diseases
Published in: Orphanet Journal of Rare Diseases 1/2020

Open Access 01-12-2020 | Epistaxis | Review

Future treatments for hereditary hemorrhagic telangiectasia

Authors: Florian Robert, Agnès Desroches-Castan, Sabine Bailly, Sophie Dupuis-Girod, Jean-Jacques Feige

Published in: Orphanet Journal of Rare Diseases | Issue 1/2020

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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.
Literature
1.
2.
Guttmacher AE, Marchuk DA, White RI Jr. Hereditary hemorrhagic telangiectasia. N Engl J Med. 1995;333:918–24.PubMedCrossRef
3.
Lesca G, Genin E, Blachier C, Olivieri C, Coulet F, Brunet G, et al. Hereditary hemorrhagic telangiectasia: evidence for regional founder effects of ACVRL1 mutations in French and Italian patients. Eur J Hum Genet. 2008;16:742–9.PubMedCrossRef
4.
Plauchu H, de Chadarevian JP, Bideau A, Robert JM. Age-related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population. Am J Med Genet. 1989;32:291–7.PubMedCrossRef
5.
Dupuis-Girod S, Bailly S, Plauchu H. Hereditary hemorrhagic telangiectasia: from molecular biology to patient care. J Thromb Haemost. 2010;8:1447–56.PubMedCrossRef
6.
Buscarini E, Plauchu H, Garcia Tsao G, White RI Jr, Sabba C, Miller F, et al. Liver involvement in hereditary hemorrhagic telangiectasia: consensus recommendations. Liver Int. 2006;26:1040–6.PubMedCrossRef
7.
Kjeldsen AD, Kjeldsen J. Gastrointestinal bleeding in patients with hereditary hemorrhagic telangiectasia. Am J Gastroenterol. 2000;95:415–8.PubMedCrossRef
8.
Johnson DW, Berg JN, Baldwin MA, Gallione CJ, Marondel I, Yoon SJ, et al. Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet. 1996;13:189–95.PubMedCrossRef
9.
McAllister KA, Grogg KM, Johnson DW, Gallione CJ, Baldwin MA, Jackson CE, et al. Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet. 1994;8:345–51.PubMedCrossRef
10.
11.
Seki T, Yun J, Oh SP. Arterial endothelium-specific activin receptor-like kinase 1 expression suggests its role in arterialization and vascular remodeling. Circ Res. 2003;93:682–9.PubMedCrossRef
12.
Gougos A, Letarte M. Primary structure of endoglin, an RGD-containing glycoprotein of human endothelial cells. J Biol Chem. 1990;265:8361–4.PubMed
13.
Saito T, Bokhove M, Croci R, Zamora-Caballero S, Han L, Letarte M, et al. Structural basis of the human Endoglin-BMP9 interaction: insights into BMP signaling and HHT1. Cell Rep. 2017;19:1917–28.PubMedPubMedCentralCrossRef
14.
Gallione CJ, Repetto GM, Legius E, Rustgi AK, Schelley SL, Tejpar S, et al. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet. 2004;363:852–9.PubMedCrossRef
15.
Gallione CJ, Richards JA, Letteboer TG, Rushlow D, Prigoda NL, Leedom TP, et al. SMAD4 mutations found in unselected HHT patients. J Med Genet. 2006;43:793–7.PubMedPubMedCentralCrossRef
16.
Lesca G, Burnichon N, Raux G, Tosi M, Pinson S, Marion MJ, et al. Distribution of ENG and ACVRL1 (ALK1) mutations in French HHT patients. Hum Mutat. 2006;27:598.PubMedCrossRef
17.
Hernandez F, Huether R, Carter L, Johnston T, Thompson J, Gossage JR, et al. Mutations in RASA1 and GDF2 identified in patients with clinical features of hereditary hemorrhagic telangiectasia. Hum Genome Var. 2015;2:15040.PubMedPubMedCentralCrossRef
18.
Wooderchak-Donahue WL, McDonald J, O'Fallon B, Upton PD, Li W, Roman BL, et al. BMP9 mutations cause a vascular-anomaly syndrome with phenotypic overlap with hereditary hemorrhagic telangiectasia. Am J Hum Genet. 2013;93:530–7.PubMedPubMedCentralCrossRef
19.
David L, Mallet C, Mazerbourg S, Feige JJ, Bailly S. Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells. Blood. 2007;109:1953–61.PubMedCrossRef
20.
Scharpfenecker M, van Dinther M, Liu Z, van Bezooijen RL, Zhao Q, Pukac L, et al. BMP-9 signals via ALK1 and inhibits bFGF-induced endothelial cell proliferation and VEGF-stimulated angiogenesis. J Cell Sci. 2007;120:964–72.PubMedCrossRef
21.
Tillet E, Ouarne M, Desroches-Castan A, Mallet C, Subileau M, Didier R, et al. A heterodimer formed by bone morphogenetic protein 9 (BMP9) and BMP10 provides most BMP biological activity in plasma. J Biol Chem. 2018;293:10963–74.PubMedPubMedCentralCrossRef
22.
Garcia de Vinuesa A, Abdelilah-Seyfried S, Knaus P, Zwijsen A, Bailly S. BMP signaling in vascular biology and dysfunction. Cytokine Growth Factor Rev. 2016;27:65–79.PubMedCrossRef
23.
Goumans MJ, Zwijsen A, Ten Dijke P, Bailly S. Bone morphogenetic proteins in vascular homeostasis and disease. Cold Spring Harb Perspect Biol. 2017;10:a031989.CrossRef
24.
Tillet E, Bailly S. Emerging roles of BMP9 and BMP10 in hereditary hemorrhagic telangiectasia. Front Genet. 2014;5:456.PubMed
25.
Damjanovich K, Langa C, Blanco FJ, McDonald J, Botella LM, Bernabeu C, et al. 5'UTR mutations of ENG cause hereditary hemorrhagic telangiectasia. Orphanet J Rare Dis. 2011;6:85.PubMedPubMedCentralCrossRef
26.
Ricard N, Bidart M, Mallet C, Lesca G, Giraud S, Prudent R, et al. Functional analysis of the BMP9 response of ALK1 mutants from HHT2 patients: a diagnostic tool for novel ACVRL1 mutations. Blood. 2010;116:1604–12.PubMedCrossRef
27.
Mallet C, Lamribet K, Giraud S, Dupuis-Girod S, Feige JJ, Bailly S, et al. Functional analysis of endoglin mutations from hereditary hemorrhagic telangiectasia type 1 patients reveals different mechanisms for endoglin loss of function. Hum Mol Genet. 2015;24:1142–54.PubMedCrossRef
28.
Gallione C, Aylsworth AS, Beis J, Berk T, Bernhardt B, Clark RD, et al. Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP-HHT syndrome. Am J Med Genet A. 2010;152A:333–9.PubMedCrossRef
29.
McDonald J, Wooderchak-Donahue W, VanSant WC, Whitehead K, Stevenson DA, Bayrak-Toydemir P. Hereditary hemorrhagic telangiectasia: genetics and molecular diagnostics in a new era. Front Genet. 2015;6:1.PubMedPubMedCentralCrossRef
30.
Park SO, Wankhede M, Lee YJ, Choi EJ, Fliess N, Choe SW, et al. Real-time imaging of de novo arteriovenous malformation in a mouse model of hereditary hemorrhagic telangiectasia. J Clin Invest. 2009;119:3487–96.PubMedPubMedCentral
31.
Hao Q, Su H, Marchuk DA, Rola R, Wang Y, Liu W, et al. Increased tissue perfusion promotes capillary dysplasia in the ALK1-deficient mouse brain following VEGF stimulation. Am J Physiol Heart Circ Physiol. 2008;295:H2250–6.PubMedPubMedCentralCrossRef
32.
Snellings D, Gallione C, Clark D, Vozoris N, Faughnan M, Marchuk D. Somatic mutations in vascular malformations of hereditary hemorrhagic telangiectasia results in biallelic loss of ENG or ACVRL1. Am J Hum Genet. 2019;105:894–906.
33.
Bidart M, Ricard N, Levet S, Samson M, Mallet C, David L, et al. BMP9 is produced by hepatocytes and circulates mainly in an active mature form complexed to its prodomain. Cell Mol Life Sci. 2012;69:313–24.PubMedCrossRef
34.
David L, Mallet C, Keramidas M, Lamande N, Gasc JM, Dupuis-Girod S, et al. Bone morphogenetic protein-9 is a circulating vascular quiescence factor. Circ Res. 2008;102:914–22.PubMedPubMedCentralCrossRef
35.
Wood JH, Guo J, Morrell NW, Li W. Advances in the molecular regulation of endothelial BMP9 signalling complexes and implications for cardiovascular disease. Biochem Soc Trans. 2019;47:779–91.PubMedCrossRef
36.
Larrivee B, Prahst C, Gordon E, del Toro R, Mathivet T, Duarte A, et al. ALK1 signaling inhibits angiogenesis by cooperating with the notch pathway. Dev Cell. 2012;22:489–500.PubMedPubMedCentralCrossRef
37.
Thalgott JH, Dos-Santos-Luis D, Hosman AE, Martin S, Lamande N, Bracquart D, et al. Decreased expression of vascular endothelial growth factor receptor 1 contributes to the pathogenesis of hereditary hemorrhagic telangiectasia type 2. Circulation. 2018;138:2698–712.PubMedCrossRef
38.
Crist AM, Zhou X, Garai J, Lee AR, Thoele J, Ullmer C, et al. Angiopoietin-2 inhibition rescues Arteriovenous malformation in a Smad4 hereditary hemorrhagic telangiectasia mouse model. Circulation. 2019;139:2049–63.PubMedCrossRefPubMedCentral
39.
Ruiz S, Zhao H, Chandakkar P, Chatterjee PK, Papoin J, Blanc L, et al. A mouse model of hereditary hemorrhagic telangiectasia generated by transmammary-delivered immunoblocking of BMP9 and BMP10. Sci Rep. 2016;5:37366.PubMedPubMedCentralCrossRef
40.
Alsina-Sanchis E, Garcia-Ibanez Y, Figueiredo AM, Riera-Domingo C, Figueras A, Matias-Guiu X, et al. ALK1 loss results in vascular hyperplasia in mice and humans through PI3K activation. Arterioscler Thromb Vasc Biol. 2018;38:1216–29.PubMedCrossRef
41.
Iriarte A, Figueras A, Cerda P, Mora JM, Jucgla A, Penin R, et al. PI3K (phosphatidylinositol 3-kinase) activation and endothelial cell proliferation in patients with hemorrhagic hereditary telangiectasia type 1. Cells. 2019;8:971.PubMedCentralCrossRef
42.
Ola R, Dubrac A, Han J, Zhang F, Fang JS, Larrivee B, et al. PI3 kinase inhibition improves vascular malformations in mouse models of hereditary haemorrhagic telangiectasia. Nat Commun. 2016;7:13650.PubMedPubMedCentralCrossRef
43.
Ola R, Kunzel SH, Zhang F, Genet G, Chakraborty R, Pibouin-Fragner L, et al. SMAD4 prevents flow induced Arteriovenous malformations by inhibiting casein kinase 2. Circulation. 2018;138:2379–94.PubMedPubMedCentralCrossRef
44.
Sommer N, Droege F, Gamen KE, Geisthoff U, Gall H, Tello K, et al. Treatment with low-dose tacrolimus inhibits bleeding complications in a patient with hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension. Pulm Circ. 2019;9:2045894018805406.PubMedCrossRef
45.
Parambil JG, Woodard TD, Koc ON. Pazopanib effective for bevacizumab-unresponsive epistaxis in hereditary hemorrhagic telangiectasia. Laryngoscope. 2018;128:2234–6.PubMedCrossRef
46.
Faughnan ME, Gossage JR, Chakinala MM, Oh SP, Kasthuri R, Hughes CCW, et al. Pazopanib may reduce bleeding in hereditary hemorrhagic telangiectasia. Angiogenesis. 2019;22:145–55.PubMedCrossRef
47.
Kovacs-Sipos E, Holzmann D, Scherer T, Soyka MB. Nintedanib as a novel treatment option in hereditary haemorrhagic telangiectasia. BMJ Case Rep. 2017;2017:219393.
48.
Droege F, Thangavelu K, Lang S, Geisthoff U. Improvement in hereditary hemorrhagic telangiectasia after treatment with the multi-kinase inhibitor Sunitinib. Ann Hematol. 2016;95:2077–8.PubMedCrossRef
49.
Geisthoff UW, Nguyen HL, Hess D. Improvement in hereditary hemorrhagic telangiectasia after treatment with the phosphoinositide 3-kinase inhibitor BKM120. Ann Hematol. 2014;93:703–4.PubMedCrossRef
50.
Flieger D, Hainke S, Fischbach W. Dramatic improvement in hereditary hemorrhagic telangiectasia after treatment with the vascular endothelial growth factor (VEGF) antagonist bevacizumab. Ann Hematol. 2006;85:631–2.PubMedCrossRef
51.
Mitchell A, Adams LA, MacQuillan G, Tibballs J, vanden Driesen R, Delriviere L. Bevacizumab reverses need for liver transplantation in hereditary hemorrhagic telangiectasia. Liver Transpl. 2008;14:210–3.PubMedCrossRef
52.
Dupuis-Girod S, Ginon I, Saurin JC, Marion D, Guillot E, Decullier E, et al. Bevacizumab in patients with hereditary hemorrhagic telangiectasia and severe hepatic vascular malformations and high cardiac output. JAMA. 2012;307:948–55.PubMedCrossRef
53.
Buscarini E, Botella LM, Geisthoff U, Kjeldsen AD, Mager HJ, Pagella F, et al. Safety of thalidomide and bevacizumab in patients with hereditary hemorrhagic telangiectasia. Orphanet J Rare Dis. 2019;14:28.PubMedPubMedCentralCrossRef
54.
55.
Fleagle JM, Bobba RK, Kardinal CG, Freter CE. Iron deficiency anemia related to hereditary hemorrhagic telangiectasia: response to treatment with bevacizumab. Am J Med Sci. 2012;343:249–51.PubMedCrossRef
56.
Follner S, Ibe M, Schreiber J. Bevacizumab treatment in hereditary hemorrhagic teleangiectasia. Eur J Clin Pharmacol. 2012;68:1685–6.PubMedCrossRef
57.
Lupu A, Stefanescu C, Treton X, Attar A, Corcos O, Bouhnik Y. Bevacizumab as rescue treatment for severe recurrent gastrointestinal bleeding in hereditary hemorrhagic telangiectasia. J Clin Gastroenterol. 2013;47:256–7.PubMedCrossRef
58.
Iyer VN, Apala DR, Pannu BS, Kotecha A, Brinjikji W, Leise MD, et al. Intravenous Bevacizumab for refractory hereditary hemorrhagic telangiectasia-related epistaxis and gastrointestinal bleeding. Mayo Clin Proc. 2018;93:155–66.PubMedCrossRef
59.
Kim YH, Kim MJ, Choe SW, Sprecher D, Lee YJ, S PO. Selective effects of oral antiangiogenic tyrosine kinase inhibitors on an animal model of hereditary hemorrhagic telangiectasia. J Thromb Haemost. 2017;15:1095–102.PubMedPubMedCentralCrossRef
60.
Esposito A, Viale G, Curigliano G. Safety, tolerability, and Management of Toxic Effects of phosphatidylinositol 3-kinase inhibitor treatment in patients with Cancer: a review. JAMA Oncol. 2019;5:1347–54.CrossRefPubMed
61.
Korchynskyi O, ten Dijke P. Identification and functional characterization of distinct critically important bone morphogenetic protein-specific response elements in the Id1 promoter. J Biol Chem. 2002;277:4883–91.PubMedCrossRef
62.
Zilberberg L, ten Dijke P, Sakai LY, Rifkin DB. A rapid and sensitive bioassay to measure bone morphogenetic protein activity. BMC Cell Biol. 2007;8:41.PubMedPubMedCentralCrossRef
63.
Ruiz S, Chandakkar P, Zhao H, Papoin J, Chatterjee PK, Christen E, et al. Tacrolimus rescues the signaling and gene expression signature of endothelial ALK1 loss-of-function and improves HHT vascular pathology. Hum Mol Genet. 2017;26:4786–98.PubMedPubMedCentralCrossRef
64.
Spiekerkoetter E, Tian X, Cai J, Hopper RK, Sudheendra D, Li CG, et al. FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension. J Clin Invest. 2013;123:3600–13.PubMedPubMedCentralCrossRef
65.
Albinana V, Sanz-Rodriguez F, Recio-Poveda L, Bernabeu C, Botella LM. Immunosuppressor FK506 increases endoglin and activin receptor-like kinase 1 expression and modulates transforming growth factor-beta1 signaling in endothelial cells. Mol Pharmacol. 2011;79:833–43.PubMedCrossRef
66.
67.
Skaro AI, Marotta PJ, McAlister VC. Regression of cutaneous and gastrointestinal telangiectasia with sirolimus and aspirin in a patient with hereditary hemorrhagic telangiectasia. Ann Intern Med. 2006;144:226–7.PubMedCrossRef
68.
Dupuis-Girod S, Chesnais AL, Ginon I, Dumortier J, Saurin JC, Finet G, et al. Long-term outcome of patients with hereditary hemorrhagic telangiectasia and severe hepatic involvement after orthotopic liver transplantation: a single-center study. Liver Transpl. 2010;16:340–7.PubMed
69.
Salloum R, Fox CE, Alvarez-Allende CR, Hammill AM, Dasgupta R, Dickie BH, et al. Response of blue rubber bleb nevus syndrome to Sirolimus treatment. Pediatr Blood Cancer. 2016;63:1911–4.PubMedCrossRef
70.
Yesil S, Tanyildiz HG, Bozkurt C, Cakmakci E, Sahin G. Single-center experience with sirolimus therapy for vascular malformations. Pediatr Hematol Oncol. 2016;33:219–25.PubMedCrossRef
71.
Gibson CC, Zhu W, Davis CT, Bowman-Kirigin JA, Chan AC, Ling J, et al. Strategy for identifying repurposed drugs for the treatment of cerebral cavernous malformation. Circulation. 2015;131:289–99.PubMedCrossRef
Metadata
Title
Future treatments for hereditary hemorrhagic telangiectasia
Authors
Florian Robert
Agnès Desroches-Castan
Sabine Bailly
Sophie Dupuis-Girod
Jean-Jacques Feige
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Orphanet Journal of Rare Diseases / Issue 1/2020
Electronic ISSN: 1750-1172
DOI
https://doi.org/10.1186/s13023-019-1281-4

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