SAINBIOSE INSERM U1059Pharmacology & Thrombosis

Research axe

Pharmacology & Thrombosis

medicament

This axis focuses on hemostasis pharmacology, multiparametric personalized pharmacology, and pulmonary pharmacology and engineering (see Inhaled Particles & Aerosols axis).

What these three pharmacological topics have in common is the need to evaluate, understand, and optimize the use of therapies in thromboembolic, pulmonary, and hemorrhagic pathologies. Optimization naturally implies stratified and personalized medicine. These three developments require expertise in the acquisition and analysis of data from a variety of sources: in vitro, in vivo, clinical trials, and existing literature, with mastery of different modeling tools: population approaches in pharmacology, meta-analysis and meta-regression, Bayesian estimation, modeling, statistical learning, and engineering.

The clinical fields concerned include vascular pharmaco-therapeutics in high-risk situations (e.g., analyzing anticoagulant treatment failures in cancer patients, determining sources of variability, etc.), multiparametric pharmacology (e.g., modeling live monitoring of data in intensive care anesthesia to guide treatments according to several targets), and developing an ex vivo platform to reproduce specific clinical situations (intensive care, smoking cessation, COPD, etc.) for estimating the pharmacokinetics of inhaled therapies.

Projects

Proteomic Pattern Associated With the Diagnosis of Chronic Thromboembolic Pulmonary Hypertension

PROTEO-CTEPH
Description

Chronic ThromboEmbolic Pulmonary Hypertension (CTEPH) is a rare but severe complication of pulmonary embolism (PE). CTEPH is evoked in patients with persistent dyspnea. According to international guidelines, symptomatic patients with perfusion defects on lung scan and Pulmonary Hypertension (PH)-likely transthoracic echo (TTE) must be evaluated in Pulmonary Hypertension (PH)-centers with right heart catheterism, to confirm or rule out the presence of precapillary Pulmonary Hypertension (PH), and precise the group of Pulmonary Hypertension (PH). However, persistent dyspnea and perfusion defects are frequent after pulmonary embolism (PE), and the accuracy of transthoracic echo (TTE) is not great for precapillary Pulmonary Hypertension (PH). This study proposed to seek for a specific proteomic pattern in patients admitted for a suspicion of Chronic ThromboEmbolic Pulmonary Hypertension (CTEPH).

Members

Project Leader : Pr. Laurent Bertoletti

Researchers involved :  

Lab scientists involved:

Sophie Hodin

Student involved :

TBA

ISS from MSD
http://sainbiose-lab.fr/wp-content/uploads/2024/03/logo-MSD.png

Haemophilia and bone loss

PHILEOS
Description

Introduction Two meta-analyses showed lower bone mineral density (BMD) in patients with haemophilia (haemophilia type and severity were often not specified) compared with healthy controls. This finding could be related to reduced mobility and sedentary lifestyle, and/or hepatitis C or HIV infection. The aim of this study is to determine osteoporosis prevalence in patients with haemophilia classified in function of the disease type (A or B) and severity, and to evaluate the potential role of regular prophylactic factor replacement (early vs delayed initiation) in preserving or restoring BMD.

Methods and analysis The haemoPHILia and ostEoporOSis Study is a prospective, controlled, multicentre study that will include patients in France (13 haemophilia treatment centres), Belgium (1 centre) and Romania (1 centre). In total, 240 patients with haemophilia and 240 matched healthy controls will be recruited (1:1). The primary objective is to determine osteoporosis prevalence in patients with severe haemophilia A and B (HA and HB) without prophylaxis, compared with healthy controls. Secondary outcomes include: prevalence of osteoporosis and osteopenia in patients with mild, moderate and severe HA or HB with prophylaxis (grouped in function of their age at prophylaxis initiation), compared with healthy subjects; BMD in patients with HA and HB of comparable severity; correlation between BMD and basal factor VIII/IX levels and thrombin potential; and quantification of plasmatic markers of bone remodelling (formation and resorption) in patients with haemophilia.

Ethics and dissemination The protocol was approved by the French Ethics Committee and by the French National Agency for Medicines and Health Products Safety (number: 2019-A03358-49). The results of this study will be actively disseminated through scientific publications and conference presentations.

Trial registration number NCT04384341.

Members

Project Leader : Pr. Brigitte Tardy

Researchers involved :  

  • Pr Thierry Thomas (CIC INSERM 1408)
  • Dr Anne Devillard (CIC INSERM 1408)

Lab scientists involved:

Mégane Rubio (DRCI – Unité de Recherche Clinique)

Aurélie Montmartin 

Sylvie Spinar

Carine Labruyère (CIC INSERM 1408)

Hervé Locrel

Student involved :

TBA

Funding

PHRC

financements indus

autres grant

Temporal characterization of Extracellular Vesicles during cellular therapy using CAR-T cells and during the occurrence of Immune effector Cell-Associated Neurotoxicity Syndrom.

VESICANS
Description

Extracellular vesicles (EVs) are active biological entities that participate in a wide range of cellular processes and functions, including intercellular communication, angiogenesis, coagulation and cell survival. Immune effector Cell-Associated Neurotoxicity (ICANS) is a new toxicity mainly described with immunotherapies as CAR-T cell. ICANS affects approximately a third of patients who receive this treatment. The ICANS mechanism has not yet been well understood. Autopsy studies showed endothelial activation markers and multifocal vascular abnormalities. It is hypothesized that activation of endothelial cells by systemic inflammation occurs when the release of pro-inflammatory cytokines at the time of CAR-T treatment increases the permeability of the blood-brain barrier (BBB). Indeed, it was shown in vitro that after exposure of brain endothelial cells to pro-inflammatory cytokines, these cells emitted EVs capable of modulating several functions and cellular partners (expression of junction zone proteins, resistance of endothelial cells brain, of the transcriptome modulation (pericytes), or increased adhesion of T lymphocytes to endothelial cells). In vivo, it has been demonstrated that endothelial EVs of cerebral origin are increased in the plasma of patients with other neuroinflammatory disorders such as multiple sclerosis during exacerbations of the disease. In patients treated with CAR T cells, only one team has published to date on the analysis of EVs. They showed an increase in CAR T EVs in the plasma of patients with ICANS and a higher proportion of senescent CD8+ T cells and M-MDSCs correlated with early signs of neuroaxonal damage before receiving CAR T cells, suggesting that ICANS could be the final event of a process that begins before infusion. However, no study analysed EVs of endothelial origin in these patients. Thus, we conduct a prospective study with the aim of characterizing the EVs secreted in patients treated with CAR-T cells, in particular EVs of endothelial origin, their presence and their possible role of EVs in the appearance of ICANS type neurological complications. Through this study, we combine three analysis methods to refine the phenotype of EVs : analysis using Nano Tracking Analysis, flow cytometry and electron microscopy. The cytokine profile and its kinetics during treatment and in the event of ICANS occurrence will be correlated to the analyzes of EVs. Patients carry out neuropsychological assessment and brain MRI to analyze the BBB permeability. This study, ultimately, could facilitate the detection, prevention and treatment of ICANS.

Members

Project Leader : Dr. Emilie Chalayer

Researchers involved :  

Lab scientists involved:

Student involved :

Sébastien Charles

Funding
Ligue contre le cancer

Ligue contre le cancer

Fond d'action du CHU

Fond d'action du CHU

Aire

Aire

Team

Fabrice Cognasse
Head of DVH & Pharmocology and ThrombosisSilvy Laporte, PhD
PU-PH
Hind Hamzeh-Cognasse
ProfessorPatrick Mismetti, PhD
PU-PH
Amelie
Assistant ProfessortJean Escal, PharmD, PhD
Assistant Professort
Maïlys Portier
TechnicianValerie Bin
Technician
Marco Heestermans
StatisticianCeline Chapelle, PhD
Statistician
Marco Heestermans
Lab scientistSophie Hodin
Lab scientist
Marco Heestermans
TechnicianAurélie Montmartin
Technician
Amelie
StatisticianEmilie PRESLES-BOULARD
Statistician
Maïlys Portier
PhD studentAnne-Noelle Heizmann
PhD student
Marco Heestermans
PhD studentSebastien Charles
PhD student
Marco Heestermans
Prenom nom
Marco Heestermans
name