Genotype Expression and Phenotype of Endothelial Cells, Carrying an ACVRL1, ENG or SMAD4 Mutation, in Response to BMP9 for the Identification of New Therapeutic Targets in Hereditary Haemorrhagic Telangiectasia

NCT05632484 | Completed

• 2 other identifiers: 69HCL20_02502021-A01792-39
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 3

Brief Summary

Hereditary hemorrhagic telangiectasia (HHT) or Osler-Weber-Rendu syndrome patients are carriers of a heterozygous mutation of the activin receptor-like kinase 1 (ACVRL1), Endoglin (ENG) or Mothers against decapentaplegic homolog 4 (SMAD4) gene. HHT involves the Bone Morphogenetic Protein 9 (BMP9)/Activin receptor-Like Kinase 1 (ALK1)-endoglin signalling pathway. BMP9 is a growth factor that binds to ALK1 receptor and to endoglin its co-receptors and physiologically activates Smad signaling pathway. Endothelial cells in HHT patients display half expression of functional ALK1 receptors or endoglin co-receptors or of the transcription factor SMAD4, which should lead to effects on the functions of these cells. The identification of differences in gene expression between endothelial cells from HHT patients and healthy donors will allow the identification of new functions or new target pathways for therapy. Circulating endothelial cells are rare in the bloodstream in adults, but are present in greater quantities in cord blood.

Conditions

Hereditary Haemorrhagic Telangiectasia

Keywords

hereditary haemorrhagic telangiectasia; endothelial cell

Outcome Measures

Primary Outcomes (2)

• Number of Endothelial Colony Forming Cells (ECFC) from cord blood

  The primary outcome is the obtention of at least one clone of 10 000 cells from the cord blood after 3 weeks from the time of isolation. Number of viable cells is measured by Trypan blue test.

  up to 3 weeks after cells isolation

• Number of Human Umbilical Vein Endothelial Cells(HUVEC) from cord

  For the cord, the primary outcome is the obtention of 500 000 cells after one week from the isolation. Number of viable cells is measured by Trypan blue test.

  up to one week

Secondary Outcomes (2)

• cell freezing and thawing

  Through study completion, an average of 5 years.

• Gene expression quantification after RNA extraction from cells

  Through study completion, an average of 5 years.

Study Arms (1)

Newborns with a parent with HHT disease

EXPERIMENTAL

16 newborns with one parent suffering HHT disease and carrying a mutation in the ACVRL1, ENG or SMAD4 gene will be included in this study.

Biological: Cord blood sampling; Biological: Cord sampling

Interventions

Cord blood sampling BIOLOGICAL

Collection of 2 milliliters (mL) of cord blood on an Ethylenediaminetetraacetic acid (EDTA) tube, on the day of delivery and after cutting the umbilical cord, for genetic testing

Newborns with a parent with HHT disease

Cord sampling BIOLOGICAL

Collection of 20 centimeters (cm) of umbilical cord

Newborns with a parent with HHT disease

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Newborn whose parents :
• are adults
• are affiliated to a social security or similar
• are not subject to any legal protection measures
• Newborn child with one parent who has monitored for HHT confirmed by molecular biology (carrier of a mutation of the SMAD4, ENG or ACVRL1 gene).
• Consent signed by the two representatives of parental authority

You may not qualify if:

• One of the two parents opposes donating the umbilical cord blood and the umbilical cord for research
• One of the two parents opposes genetic testing
• Patient for whom it was not possible to obtain umbilical cord blood after delivery for technical or medical reasons.

Sponsors & Collaborators

• Hospices Civils de Lyon: lead

Study Sites (3)

Hôpital Femme-mère-Enfant

Bron, 69677, France

Location

Hôpital Estaing

Clermont-Ferrand, 63100, France

Location

Hôpital St Eloi

Montpellier, 34295, France

Location

Related Publications (2)

• Al Tabosh T, Al Tarrass M, Tourvieilhe L, Guilhem A, Dupuis-Girod S, Bailly S. Hereditary hemorrhagic telangiectasia: from signaling insights to therapeutic advances. J Clin Invest. 2024 Feb 15;134(4):e176379. doi: 10.1172/JCI176379.

  PMID: 38357927 BACKGROUND

• Al Tabosh T, Liu H, Koca D, Al Tarrass M, Tu L, Giraud S, Delagrange L, Beaudoin M, Riviere S, Grobost V, Rondeau-Lutz M, Dupuis O, Ricard N, Tillet E, Machillot P, Salomon A, Picart C, Battail C, Dupuis-Girod S, Guignabert C, Desroches-Castan A, Bailly S. Impact of heterozygous ALK1 mutations on the transcriptomic response to BMP9 and BMP10 in endothelial cells from hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension donors. Angiogenesis. 2024 May;27(2):211-227. doi: 10.1007/s10456-023-09902-8. Epub 2024 Jan 31.

  PMID: 38294582 BACKGROUND

MeSH Terms

Conditions

Telangiectasia, Hereditary Hemorrhagic

Interventions

Cordocentesis

Condition Hierarchy (Ancestors)

Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Telangiectasis; Hemorrhagic Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Vascular Malformations; Cardiovascular Abnormalities; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Blood Specimen Collection; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Paracentesis; Punctures; Therapeutics; Surgical Procedures, Operative; Investigative Techniques

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 21, 2022
• First Posted: November 30, 2022
• Study Start: March 10, 2023
• Primary Completion: May 20, 2023
• Study Completion: May 20, 2023
• Last Updated: September 3, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

FR (3)