Bazedoxifene, a new orphan drug for the treatment of bleeding in hereditary haemorrhagic telangiectasia

Roberto Zarrabeitia; Luisa Ojeda-Fernandez; Lucia Recio; Carmelo Bernabéu; José A. Parra; Virginia Albiñana; Luisa M. Botella

doi:10.1160/TH15-03-0239

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2016; 115(06): 1167-1177
DOI: 10.1160/TH15-03-0239

Endothelium and Angiogenesis

Schattauer GmbH

Bazedoxifene, a new orphan drug for the treatment of bleeding in hereditary haemorrhagic telangiectasia

Roberto Zarrabeitia

²Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain

³Medicina Interna Hospital de Sierrallana, Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain

,

Luisa Ojeda-Fernandez

¹Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain

²Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain

,

Lucia Recio

¹Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain

,

Carmelo Bernabéu

¹Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain

²Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain

,

José A. Parra

⁴Servicio de Radiodiagnóstico, Hospital Universitario Marqués de Valdecilla, Santander, Spain

,

Virginia Albiñana

¹Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain

,

Luisa M. Botella

¹Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain

²Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain

› Institutsangaben

Abstract

Summary

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).

Keywords

Bazedoxifene - selective estrogen receptor modulator - ENG protein - ALK1 protein - hereditary haemorrhagic telangiectasia

Volltext

Referenzen

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