title: Bazedoxifene, a new orphan drug for the treatment of bleeding in hereditary haemorrhagic telangiectasia.
abstract: Hereditary haemorrhagic telangiectasia (HHT), or Rendu-Osler-Weber syndrome, is a dominant genetic vascular disorder. In HHT, blood vessels are weak and prone to bleeding, leading to epistaxis and anaemia, severely affecting patients' quality of life. Development of vascular malformations in HHT patients is originated mainly by mutations in ACVRL1/ALK1 (activin receptor-like kinase type I) or Endoglin (ENG) genes. These genes encode proteins of the TGF-β signalling pathway in endothelial cells, controlling angiogenesis. Haploinsufficiency of these proteins is the basis of HHT pathogenicity. It was our objective to study the efficiency of Bazedoxifene, a selective estrogen receptor modulator (SERM) in HHT, looking for a decrease in epistaxis, and understanding the underlying molecular mechanism. Plasma samples of five HHT patients were collected before, and after 1 and 3 months of Bazedoxifene treatment. ENG and ALK1 expression in activated mononuclear cells derived from blood, as well as VEGF plasma levels, were measured. Quantification of Endoglin and ALK1 mRNA was done in endothelial cells derived from HHT and healthy donors, after in vitro treatment with Bazedoxifene. Angiogenesis was also measured by tubulogenesis and wound healing assays. Upon Bazedoxifene treatment, haemoglobin levels of HHT patients increased and the quantity and frequency of epistaxis decreased. Bazedoxifene increased Endoglin and ALK1 mRNA levels, in cells derived from blood samples and in cultured endothelial cells, promoting tube formation. In conclusion, Bazedoxifene seems to decrease bleeding in HHT by partial compensation of haploinsufficiency. The results shown here are the basis of a new orphan drug designation for HHT by the European Medicine Agency (EMA).
authors.forename: Roberto
authors.initials: R
authors.lastname: Zarrabeitia
authors.forename: Luisa
authors.initials: L
authors.lastname: Ojeda-Fernandez
authors.forename: Lucia
authors.initials: L
authors.lastname: Recio
authors.forename: Carmelo
authors.initials: C
authors.lastname: Bernabéu
authors.forename: Jose A
authors.initials: JA
authors.lastname: Parra
authors.forename: Virginia
authors.initials: V
authors.lastname: Albiñana
authors.affiliation: Luisa M. Botella, Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu, 9, Madrid, 28040 Spain, E-mail: cibluisa@cib.csic.es.
authors.forename: Luisa M
authors.initials: LM
authors.lastname: Botella
mesh_terms: D030301:Activin Receptors, Type II / Q000235:genetics; D000368:Aged; D002478:Cells, Cultured; D000071063:Endoglin / Q000235:genetics; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006470:Hemorrhage / Q000097:blood / Q000188:drug therapy / Q000209:etiology; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D008875:Middle Aged; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009965:Orphan Drug Production; D010865:Pilot Projects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000627:therapeutic use; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000235:genetics; D014945:Wound Healing / Q000187:drug effects
chemical_list: C064206:ENG protein, human; D000071063:Endoglin; D007211:Indoles; D012333:RNA, Messenger; D020845:Selective Estrogen Receptor Modulators; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II; C447119:bazedoxifene
keywords: ALK1 protein; Bazedoxifene; ENG protein; hereditary haemorrhagic telangiectasia; selective estrogen receptor modulator