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.

The Netherlands
Novel treatment strategies for autosomal dominant chronic mucocutaneous candidiasis

Project Coordinator

Radboud University Medical Center
The Netherlands


Anne Puel Inserm, Laboratory of Human Genetics of Infectious Diseases Paris, France
Bodo Grimbacher University Medical Center Freiburg Freiburg, Germany
Toni Cathomen University Medical Center Freiburg Freiburg, Germany

Autosomal dominant chronic mucocutaneous candidiasis (AD-CMC) is a rare and severe primary immunodeficiency that is characterized by mucocutaneous fungal infection, autoimmune phenomena, cerebral aneurysms, and oropharyngeal and esophageal cancer. Recently it was discovered by members of this consortium that STAT1 mutations are responsible for AD-CMC. These mutations lead to the inability of STAT1 to be dephosphorylated resulting in hyperphosphorylation, increased binding to the DNA and gain of function (GOF) of STAT1 signaling. Furthermore, a characteristic feature of AD-CMC patients is a deficiency in the T-helper 17 response (Th17), which is the cause of the mucocutaneous fungal infection. No targeted treatment other than lifelong antifungal therapy exists for AD-CMC and the discovery of the genetic defect and functional immunological defects make it now possible to explore new treatment strategies, which is the aim of this project.
Several key objectives will be pursued:
1. Restore STAT1 hyperphosphorylation in AD-CMC by epigenetic modification.
2. Inhibition of STAT1 hyperactivity with pharmacological inhibitors and inhibition of specific cytokines with antibodies to restore Th17 deficiency.
3. Explore treatment of AD-CMC patients with GOF mutations in STAT1 with G-CSF and M-CSF.
4. Investigate the use of Gene Therapy/Gene Surgery in patients with AD-CMC with GOF STAT1 mutation.
We anticipate that we will identify interventions that can restore the functional defects associated with STAT1 GOF mutations that can be used to conduct clinical studies.

E-Rare 2012 - Created by Toussaint Biger