EURO-CMC

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.