BMI1 inhibition reduces lesion burden and slows down disease progression in a chronic mouse model of cerebral cavernous malformation

Cerebral Cavernous Malformation (CCM) is a neurovascular disease characterized by 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 and are typically due to mutations in either Ccm1, Ccm2 or Ccm3 genes. CCMs are prone to develop intracerebral hemorrhages leading to severe neurological damage. The current gold standard is surgical resection 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 PTC209 ameliorates multiple pathological phenotypes, both in vitro and in acute CCM mouse models, suggesting BMI1 as a promising therapeutic target for CCM treatment. Nevertheless, because of its poor safety and pharmacokinetics profiles, PTC209 is not suitable for use in patients. 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 that more faithfully reflects the onset and progression of cavernomas observed in patients. Single-cell profiling of brain endothelial cells revealed transcriptional changes consistent with CCM molecular features, supporting the relevance of this disease model. Using this model, we found that treatment with Unesbulin substantially reduces lesion burden, affecting both de novo lesion formation and arresting the progression of pre-existing cavernomas. The treatment also reduces erythrocyte extravasation, a critical process contributing to the worsening of clinical symptoms. Single-cell transcriptomics further suggests modulation of CCM-associated programs in specific endothelial subpopulations in treated chronic CCM mice. These findings, and the favorable risk-benefit profile of the drug in humans, support its potential as a therapeutic approach to block cavernomas progression, offering potential critical benefits for the patients' quality of life.