Rebastinib inhibits cerebral cavernous malformation in a chronic mouse model

Area of Science:

• Neuroscience
• Vascular Biology
• Pharmacology

Background:

• Cerebral cavernous malformations (CCMs) arise from mutations in CCM genes (CCM1-3) or MAP3K3, leading to aberrant MEKK3 signaling.
• MEKK3 signaling is pathologically activated in CCMs, making it a key therapeutic target.
• Previous studies show MEKK3 inhibition suppresses CCM formation in mouse models.

Purpose of the Study:

• To identify and evaluate MEKK3 inhibitors for CCM treatment.
• To assess the therapeutic efficacy of rebastinib in a preclinical mouse model of CCM.
• To determine if rebastinib can suppress CCM lesion formation, progression, and improve survival.

Main Methods:

• In silico screening identified rebastinib as a MEKK3 inhibitor.
• Therapeutic efficacy was tested in a Ccm3-deficient mouse model (Ccm3^BECKO).
• Evaluations included micro-CT, MRI, gene expression analysis, and survival studies.

Main Results:

• Rebastinib potently inhibited MEKK3 kinase activity and downstream gene expression.
• Rebastinib reduced CCM lesion formation and growth in both initiation and established stages.
• Treatment prolonged survival in Ccm3^BECKO mice, with significant benefits when started after lesion establishment.

Conclusions:

• Oral rebastinib effectively suppresses CCM lesion development and progression in a mouse model.
• MEKK3 inhibition via rebastinib demonstrates therapeutic potential for CCM disease.
• Rebastinib treatment offers a promising strategy for managing CCMs and improving patient outcomes.