BMI1 INHIBITION REDUCES LESION BURDEN AND BLOCKS DISEASE PROGRESSION IN A CHRONIC MOUSE MODEL OF CEREBRAL CAVERNOUS MALFORMATION

Cerebral Cavernous Malformation (CCM) is a neurovascular disease characterized by the formation of capillary-venous vascular lesions known as cavernomas. Such lesions develop from the clonal expansion of a subset of brain-resident endothelial progenitor cells. Both sporadic and familial forms of CCM exist. Familial CCM is a rare disease with a prevalence of 0.02%, and is typically associated with mutations in either Ccm1, Ccm2 or Ccm3 genes. Cavernomas are prone to develop intracerebral hemorrhages leading to severe neurological damage. The current gold standard is surgical resection of cavernomas and symptom management, with no pharmacological treatments available. Our group recently discovered that the Polycomb group protein BMI1 is aberrantly upregulated in endothelial cells lining human cavernomas, crucially contributing to their transcriptional rewiring. We showed that pharmacological inhibition of BMI1 with the PTC209 inhibitor ameliorates multiple pathological phenotypes, both in vitro and in an acute mouse model of CCM, suggesting BMI1 as a promising therapeutic target for CCM treatment. Nevertheless, the safety of PTC209 in human patients has not been fully assessed yet. Notably, the BMI1 inhibitor Unesbulin has been positively evaluated in terms of safety and efficacy in several clinical trials for the treatment of hard-to-treat cancers. Here, we implemented a slow-progression chronic mouse model of CCM to recapitulate more closely the onset and progression of cavernomas in human patients, and evaluated the effects of Unesbulin. We found that treatment with Unesbulin significantly reduces lesion burden, impacting both de novo lesion formation and, most importantly, arresting the progression of pre-established cavernomas. These findings, and the favorable risk-benefit profile that the drug has demonstrated in humans, support its potential as a therapeutic approach to block cavernomas progression, offering critical benefits for patients’ quality of life.