Abstract The Brain Vascular Malformation Consortium (BVMC) focuses on three rare vascular diseases with brain involvement: Cerebral Cavernous Malformation (CCM), Sturge-Weber Syndrome (SWS), and Hereditary Hemorrhagic Telangiectasia (HHT). Each is poorly understood in terms of biological mechanisms leading to progression to clinical symptoms, are resource-intensive to manage effectively, and has high probability of serious neurological morbidity. All three share a common biological theme: a brain vascular phenotype based on failure of the normal physiological mechanisms of blood vessel formation or maintenance. There is considerable overlap in the nature of the neurological morbidity of these disorders: hemorrhage, seizures and focal neurological deficits are common causes of poor functional outcome and significantly affect patient quality of life. Recent advances have also identified several dysregulated cell-signaling pathways in common, which has treatment implications. Over the past 5 years, rapid basic and translational advances have identified several candidate therapeutics, many of which are already FDA-approved for other indications and could be repurposed for use in CCM, SWS or HHT. However, much work is still needed to prepare for pending drug trials in patients with these rare diseases. In the next cycle, our projects propose to focus on clinical trial readiness issues to help inform trials, by identifying and validating biologically relevant biomarkers that can be used for monitoring drug response and identifying measurable outcomes for trial development. The overall goal of the BVMC is to facilitate and advance high-quality clinical research in CCM, SWS, and HHT by providing research infrastructure and maintaining longitudinal patient registries and biorepositories (Aim 1), by identifying and validating clinical outcomes and biomarkers for use in clinical trials (Aim 2), and by training the next generation of rare disease researchers and funding high-risk/high-payoff pilot studies (Aim 3). These aims will be accomplished through our three Projects, Cores, pilot project and training components; active collaborations with the Patient Advocacy Groups – Angioma Alliance, Sturge Weber Foundation, Cure HHT; and the RDCRN Data Management and Coordinating Center. Establishment of the BVMC has been a major step forward in promoting cross-disease collaborations, providing a centralized clinical research infrastructure for studying these three rare diseases, and generating a valuable resource for the larger neurovascular community.

Project Narrative Rare brain vascular malformations are costly and difficult to treat, have high probability of serious neurological complications, and lack specific medical therapies, although promising candidates are emerging. The identification of biomarkers for disease progression would significantly improve patient surveillance, optimize management, and provide critical data for pending drug therapeutic trials.