Cerebral cavernous malformations (CCMs) are vascular lesions in the central nervous system, affecting ~0.5% of the population. CCM patients experience debilitating neurological problems, which worsen as lesions expand and progress. CCMs are triggered by endothelial cell germline and/or somatic mutations in one of the 3 genes (i.e. KRIT1, CCM2 or PDCD10) that encode components of the CCM complex. Disruption of the CCM complex in endothelial cells drives clonal expansion and an “epithelial-to-mesenchymal-like” transition, resulting in CCM formation. Symptomatic CCMs are usually treated by surgical removal, which is invasive and risky. Pharmacological treatments for CCM are being tested. However, significant physical barriers exist for the transport of systemically-administered drugs to the CCM microenvironment, especially for so-called “biologics”, which typically exceed 1KDa in molecular weight. Indeed, human CCMs have little to no vascular access via the CCM “lumen”. Growing CCMs do recruit a microvasculature that offers an alternative drug access route; however, it retains significant blood-brain barrier (BBB) function, which will limit drug delivery.

In the Price Lab, we are developing MR image-guided strategies for targeted drug delivery to CCMs via transient permeabilization of this perilesional microvasculature with focused ultrasound (FUS) and microbubbles (MBs). To set a foundation for this project, we previously developed and characterized transgenic mouse models of CCM that recapitulate hallmarks of human disease, optimized longitudinal MR imaging to monitor CCM progression, and confirmed via MRI that perilesional microvessels retain barrier function. In newer studies, we deployed MRI-guided FUS+MBs to safely permeabilize perilesional microvessels. Given our FUS infrastructure and expertise, as well as our experience with translating FUS treatments to clinical trials, we are exceptionally well-positioned to translate successful results to the clinic.