CE14 - Physiologie et physiopathologie

Von Willebrand Disease in the 21st century: towards a shift in paradigm – VISTA

Submission summary

Von Willebrand disease (VWD) is an inherited bleeding disorder resulting from quantitative or qualitative deficiencies in von Willebrand factor (VWF), a plasma glycoprotein, crucial to platelet thrombus formation during primary hemostasis. Despite existing treatment options, quality of life is significantly altered in VWD patients. Treatment options include replacement therapy (for severe VWD) or endothelial storage mobilization (for moderate or qualitative forms of VWD). Such approaches do not consider VWD heterogeneity nor the molecular mechanisms underlying the disease in specific patient’s subgroups. VWD management leaves room for improvement, notably in women who are most affected due to gynecological-related
challenges.
We have 2 main objectives:
1) To perform an unprecedented assessment of the burden of VWD in terms of public health by crossing data from the French Reference Center on VWD with the French health data hub which contains medical health insurance data for the entire population. In a first instance, we will focus on women, assessing hospital stays, surgeries, drug consumption, gynecological visits, sick leaves, related to bleeding events. Our goal is to identify patients, who despite an accurate diagnosis and standard management of their pathology, still experience significant bleeding events.
Second, we will focus on patients with suspected accelerated clearance of VWF. Similar to what we described for women, we will compare individual bleeding trajectories with VWF half-life calculations. Establishing such a correlation will allow us to identify a target population who could potentially benefit from a more personalized medical approach, and in this particular case an approach aiming to prolong VWF half-life.
2) This last point represents an important link with our second main objective which consists in developing novel treatment options for VWD, based on the identification of unmet clinical needs evidenced/confirmed in our first objective. The approaches we propose to develop are based on the use of single-domain antibodies (nanobodies) or platelet-mimetic particles.
Based on our current knowledge of VWF catabolism, we will develop bispecific nanobodies that will be used to ameliorate plasma concentrations of VWF. In addition, another series of bispecific nanobodies will be generated that will enhance or normalize the hemostatic activity of dysfunctional VWF mutants. These different nanobodies-based approaches are based on a fully operational platform within the consortium and on largely pre-existing nanobodies.
Besides nanobodies, we will also used bioengineered lipid particles decorated with bioactive peptides, mimicking platelet function. Such particles have previously demonstrated their hemostatic efficacy in trauma models wand will be used in a particular VWD subtype characterized by a defective platelet function.
Dedicated murine models of VWD as well as biochemical approaches will be used to test these different approaches.
Our project proposes a disruptive approach to VWD, an often neglected bleeding disorder which, if not deadly anymore in our modern times, still impacts significantly the lives of patients. We are building this project on an important expertise in VWD both at the clinical and basic research level, available study models, solid preliminary data as well as an official health data hub access authorization.

Project coordination

Cecile DENIS (Hémostase, Inflammation, Thrombose)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

HITh Hémostase, Inflammation, Thrombose
Case Western Reserve University / Department of Biomedical Engineering
U1011 Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires

Help of the ANR 453,032 euros
Beginning and duration of the scientific project: February 2022 - 42 Months

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