Pioneering MRI-Guided Focused Ultrasound Platforms for the Treatment of Cerebral Cavernous Malformation 443 views

Cerebral cavernous malformations (CCMs) are vascular lesions affecting approximately 0.5% of the population, resulting from bi-allelic mutations in genes encoding components of the CCM complex. Disruption of this complex leads to altered signaling, causing endothelial permeability and increased proliferation, contributing to the multi-cavern morphology of CCMs. Patients with CCMs experience progressive neurological symptoms due to recurrent hemorrhage, and surgical removal, the primary treatment, poses high risks. This lack of treatment options motivates the goal of this dissertation: developing non-invasive therapeutic platforms using MRI-guided focused ultrasound (FUS) for CCM treatment. In the first dissertation aim, we adapt clinically-representative MRI sequences to inform the progression of CCMs in a pre-clinical mouse model. These optimized MRI sequences reveal age-related increases in CCM volume and permeability, with varying individual lesion trajectories. CCM permeability is inversely correlated with cell density, and optimal treatment intervention is identified between 2 and 3 months of age. These MRI sequences enable detection of lesion growth and bleeding associated with CCM exacerbation in the mouse model. In the second aim, we employ this MRI platform to design and evaluate FUS blood-brain barrier opening (BBBO) for CCM. FUS BBBO enhances MR contrast agent accumulation within the CCM microenvironment without inducing growth or bleeding of sonicated CCMs. Remarkably, FUS BBBO arrests CCM growth and repeat BBBO reduces the formation of new CCMs. FUS BBBO is presented as a non-invasive, independently beneficial treatment for CCM. In the third aim, we leverage our MRI platform to assess the ability of FUS BBBO to augment model drug delivery to the CCM microenvironment. FUS BBBO significantly increases the delivery of small and biologic model drugs in the lesion core and perilesional space. We find that FUS BBBO differentially enhances the delivery of the contrast agents, predominately increasing small molecule delivery in the perilesional space and model biologic delivery in the intralesional space. Combined with our prior demonstration of its independent efficacy in halting CCM growth and formation, these findings highlight the unprecedented potential of FUS BBBO to generate transformative treatment paradigms for CCM.

PHD (Doctor of Philosophy)

focused ultrasound; cerebral cavernous malformation; minimally-invasive; blood-brain barrier opening; drug delivery; magnetic resonance imaging

English

2024-02-12