Periodic Reporting for period 2 - V-EPC (Inherited disfunctions of brain microcirculation)
Reporting period: 2019-03-01 to 2020-08-31
The loss-of-function mutations in anyone of three genes, namely CCM1 (also known as KRIT1), CCM2 (OSM) and CCM3 (PDCD10) result in CCM lesion formation.
Why is it important for society?
In many cases patients require continuous assistance. The prevalence of the hereditary form is low (less than 1 out of 10,000) while the sporadic form is quite frequent ( 1 out of 200). There is no pharmacological treatment available for CCM patients and the only possible intervention is surgery. The consequences of the disease are seizures, strong headache, paralysis and others.
What are the overall objectives?
The major objectives of our work are:
-the development of murine models closer to the human disease to be used to understand the evolution of the pathology and to find specific inhibitors
-to identify pharmacological therapeutics able to delay or even induce regression of the vascular malformations.
Based on these observations, translational studies are under way to identify pharmaceutical agents able to reduce the formation of cavernomas and eventually induce their regression.
We also combined different techniques to comprehensively characterize sub-clusters of endothelial cells in both normal conditions and after deletion of CCM3 at early postnatal stage. We identified a specific cluster of endothelial cells resistant to CCM transformation. Conversely, a subset of mitogenic endothelial progenitors and venous capillary endothelial cells appears to be at the origin of CCM lesions.