MR Image-Guided Drug Delivery to Cerebral Cavernous Malformations with Focused Ultrasound

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. Here, we will develop 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 preliminary studies, we deployed MRI-guided FUS+MBs to safely permeabilize perilesional microvessels. Furthermore, we determined that, remarkably, CCMs exposed to FUS+MBs alone are chronically stabilized, providing a powerful

platform that may offer therapeutic synergy with augmented drug delivery. Given this premise and these preliminary data, we are well-positioned to propose three specific aims. In Aim 1, we will develop a robust MR image-guided approach for the safe and effective delivery of drugs to the CCM microenvironment with FUS and

MBs. We will define relationships between acoustic feedback control systems, contrast agent delivery, and safety. In Aim 2, we will leverage this information to define CCM-drug exposure curves for anti-angiogenic [Anti- VEGF-A; 3TSR (Thrombospondin-1 fragment)] and anti-neuroinflammatory (Anti-CSF1R) biologics we

hypothesize will be efficacious in controlling CCMs, using ImmunoPET imaging. In Aim 3, we will control CCM progression and its associated neuroinflammation via FUS+MB-mediated delivery of these biologics. Based on the ImmunoPET measurements from Aim 2, we will tailor and implement protocols for delivery of each drug to

the CCM microenvironment. CCM progression, neuroinflammation, oxidative stress, and survival will be examined. 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.