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 (CAERO)

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.

Study Overview

• Status: Completed
• Conditions: Hereditary Haemorrhagic Telangiectasia
• Intervention / Treatment: Biological: Cord blood sampling; Biological: Cord blood sampling; Biological: Cord sampling

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Sophie DUPUIS-GIROD, MD, PhD; Phone Number: +33 04 27 85 65 25; Email: sophie.dupuis-girod@chu-lyon.fr

Study Locations

• France
  • Bron, France, 69677
    • Hôpital Femme-Mère-Enfant
    • Contact: Sophie Dupuis-Girod, MD, PhD; Phone Number: +33 04.27.85.65.22; Email: sophie.dupuis-girod@chu-lyon.fr
    • Principal Investigator: Sophie Dupuis-Girod, MD, PhD
  • Clermont-Ferrand, France, 63100
    • Hopital Estaing
    • Contact: Vincent Grosbost, MD, PhD; Phone Number: +33 04 73 75 00 85; Email: vincent.grobost@gmail.com
    • Principal Investigator: Vincent Grosbost, MD, PhD
  • Montpellier, France, 34295
    • Hôpital St Eloi
    • Contact: Sophie Rivière, MD, PhD; Phone Number: +33 04 67 33 73 37; Email: s-riviere@chu-montpellier.fr
    • Principal Investigator: Sophie Rivière, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Newborns with a parent with HHT disease; 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; 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; Biological: Cord blood sampling; Collection of 50 to 100 mL of cord blood from the cord blood collection bag; Biological: Cord sampling; Collection of 20 centimeters (cm) of umbilical cord

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
cell freezing and thawing	After isolation and amplification, cells from cord or from clones from the cord blood are frozen in vials. The cells viability (50 to 70% of alive cells after thawing) is a criteria of successful experiment.	Through study completion, an average of 5 years.
Gene expression quantification after RNA extraction from cells	The third outcome is reached when we obtain up to 5 µg of RNA after cell seeding and stimulation with growth factors. Gene expression is measured by real-time polymerase chain reaction (RT-qPCR) and Ribonucleic acid Sequencing (RNAseq).	Through study completion, an average of 5 years.

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon

Study record dates

Study Major Dates

• Study Start (Actual): March 10, 2023
• Primary Completion (Actual): May 20, 2023
• Study Completion (Actual): May 20, 2023

Study Registration Dates

• First Submitted: October 21, 2022
• First Submitted That Met QC Criteria: November 21, 2022
• First Posted (Actual): November 30, 2022

Study Record Updates

• Last Update Posted (Actual): June 2, 2023
• Last Update Submitted That Met QC Criteria: June 1, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: hereditary haemorrhagic telangiectasia; endothelial cell
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Congenital Abnormalities; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Cardiovascular Abnormalities; Vascular Malformations; Telangiectasis; Telangiectasia, Hereditary Hemorrhagic
• Other Study ID Numbers: 69HCL20_0250; 2021-A01792-39 (Other Identifier: ID-RCB)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No