Le fucoïdane: un polysaccharide sulfaté pour l'imagerie moléculaire de l'athérosclérose, la thrombose et l'inflammation vasculaire

L'objectif de mon projet de thèse est de développer des agents de contraste permettant l'imagerie moléculaire de l'athérosclérose, la thrombose et l'inflammation vasculaire pour répondre au besoin de la radiologie courante en matière de diagnostic et d'évaluation des traitements des pathologies cardiovasculaires. La cible moléculaire choisie est la P-sélectine, protéine exprimée lors de l'activation plaquettaire ou endothéliale lié à ces troubles cardiovasculaires. L'hypothèse de travail est qu'une famille de polysaccharides sulfatés naturels, peu coûteux, aux nombreuses propriétés biologiques, les fucoïdanes, déjà décrits comme interagissant avec la P-sélectine pourrait servir de plateforme de développement d'agents de contraste ciblant cette molécule. Après avoir démontré qu un fucoïdane de bas poids moléculaire était capable d'interagir fortement avec la P-sélectine, nous l'avons associé à un radiotraceur et à deux traceurs d'imagerie par résonnance magnétique. Nous avons ensuite évalué in vitro l'interaction de ces produits avec des plaquettes activées et/ou in vivo sur des modèles animaux d'activation plaquettaire ou endothéliale. Plusieurs produits de contraste ont été développés. L'un d'entre eux nous a permis de détecter in vivo en scintigraphie les zones d'activation plaquettaire dans des modèles animaux. L'ensemble des résultats obtenus au cours de cette thèse et les perspectives qu'ils engendrent ont encouragé l'INSERM à déposer un brevet sur l'utilisation de fucoïdane comme ligand pour le diagnostic de pathologies mettant en jeu une activation plaquettaire ou endothéliale.The objective of my thesis project is to developcontrast agents for molecular imaging of atherosclerosis,thrombosis and vascular inflammation in response to the need ofcurrent radiology for the diagnosis and the assessmentof cardiovascular diseases therapeutics.The molecular target chosen is the P-selectin (also known as CD62P)protein expressed during platelet or endothelial activation bound tothese cardiovascular disorders.The working hypothesis is that a family of natural sulfated polysaccharides, inexpensive, with many biological properties, fucoidan, already described as interacting with the P-selectin couldserve as a platform for development of contrast agents targeting thismolecule.After demonstration that a low weight molecular fucoidan wasable to interact strongly with the P-selectin, we have associatedthis polysaccharide to a radiotracer and two contrast agents for magnetic resonance imaging. We then evaluated in vitro the interaction of theseagents with activated platelets and / or in vivo on animal modelsof platelet or endothelial activation.Several contrast agents have been developed. One of them enabled to detect in vivo areas of platelet or endothelial activation onanimal models.All the results obtained and the perspectives of these works have encouraged the INSERM to file a patent about the use of fucoidan as a ligand for the diagnosis of disorders involving platelet or endothelial activation.PARIS13-BU Sciences (930792102) / SudocSudocFranceF

Abdominal Aortic Aneurysms Targeted by Functionalized Polysaccharide Microparticles: a new Tool for SPECT Imaging

International audienc

Ultrasmall superparamagnetic iron oxide nanoparticles coated with fucoidan for molecular MRI of intraluminal thrombus

International audienc

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

BackgroundWe previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in similar to 80% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P=1.1x10(-4)) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70[95%CI 1.3-8.2], P=2.1x10(-4)). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR=19.65[95%CI 2.1-2635.4], P=3.4x10(-3)), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR=4.40[9%CI 2.3-8.4], P=7.7x10(-8)). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68x10(-5)).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old