Funding transnational collaborative research through joint transnational calls is one of the major objectives of E-Rare. This is the most important and effective joint activity to enhance the cooperation between European scientists working on rare diseases and thus reducing the fragmentation of research in this field. E-Rare launches calls on a yearly basis. The topic and eligibility criteria are specified every year and therefore may vary from one call to the other.

France
Germany
Italy
WHIM-Thernet
WHIM syndrome: Pathological basis and development of therapeutic molecules

Project Coordinator

Institut Pasteur Department of Virology
Paris
France

Partners

Jan Münch Insitute of Molecular Virology Ulm University Medical Center Ulm, Germany
Jean-Luc Galzi Biotechnologie et Signalisation Cellulaire Ecole Supérieure de Biotechnologie Illkrich, France
Silvano Sozzani Instituto Clinico Humanitas Rozzano, Italy

The chemokine/chemokine receptor CXCL12/CXCR4 axis is essential during embryonic life and regulates leukocyte homeostasis through the control of homing/retention/egress between lymphoid organs such as the bone marrow (BM), thymus, spleen and lymph nodes and periphery. Dysfunctions of the CXCL12/CXCR4 axis were found to be responsible for an unusual form of neutropenia associated with hyperplasia of mature neutrophils in the BM (myelokathexis) and reported as the WHIM syndrome (WS). Beside, WS derives its acronym from the manifestations of warts due to Human PapillomaVirus infections, hypogammaglobulinemia, and bacterial infections, but the clinical presentation of patients is heterogeneous as well as the severity and onset of the disease. WS is also genetically heterogeneous. For many patients, dysfunctions of the CXCL12/CXCR4 axis are linked to inherited heterozygous autosomal dominant mutations in the CXCR4 locus and for the others, who are carrying a wild-type CXCR4, the underlying genetic defects remain unknown. Management of WS is prophylactic, and none of the treatments are fitted to the diagnostic, efficient and safe on the long run, and specifically target CXCL12/CXCR4 axis although there is strong support for the responsibility of dysfunctions of this axis in WS pathogenesis. The goal of this project is to shed light on the pathophysiological role of CXCL12/CXCR4 dysfunctions, to identify key markers of the disease, to improve patients’ access to diagnosis and treatment, and to provide the bases for therapies. This will be achieved by means of transeuropean network between clinicians and scientists including established patient-registries to gather a critical mass of patients for studies and treatment. Comprehensive investigations of candidate drug and the beneficial therapeutic effect of their chronic use will be developed following three axes. A mouse model of the WS now available will permit to evaluate the efficiency/safety of the chronic administration of new and known antagonists of the CXCL12 axis. This includes the CXCL12/CXCR4 antagonist Mozobil® patented for its use in clinic for mobilization of BM stem cells. We plan to enroll the European WS cohort for a phase I/II clinical trial based on acute administration of Mozobil®. An innovative feature of WHIM-Thernet is the characterization and optimization of antagonists of the CXCL12 axis based on the development of recently discovered-antichemokine drug and -endogenous CXCR4 antagonists. Functional studies will be performed in relevant in vitro and in vivo model systems. 

E-Rare 2012 - Created by Toussaint Biger