Brain Vascular Malformation Consortium: Predictor's of Clinical Course

摘要 脑血管畸形联合会(BVMC)关注三种罕见的脑血管疾病 受累范围：脑海绵状血管畸形(CCM)、斯特奇-韦伯综合征(SWS)和遗传性 出血性毛细血管扩张(HHT)。每一种都不太清楚导致的生物学机制 进展到临床症状，是资源密集型的有效管理，并有很高的可能性 严重的神经系统疾病。这三者都有一个共同的生物学主题：基于脑血管表型的 关于血管形成或维持的正常生理机制的失败。的确有 这些疾病的神经系统发病率的性质有相当大的重叠：出血、癫痫发作 局灶性神经功能缺陷是导致功能预后不良的常见原因，并对患者产生重大影响 生活质量。最近的进展也发现了几个调控失调的细胞信号通路。 常见，这具有治疗意义。 在过去的5年里，快速的基础和翻译进步已经确定了几种候选疗法， 其中许多已经被FDA批准用于其他适应症，并可以重新用于CCM，SWS 或者HHT。然而，仍需要做大量的工作来准备对这些罕见的患者进行悬而未决的药物试验 疾病。在下一个周期中，我们的项目建议将重点放在临床试验准备情况上，以帮助为试验提供信息， 通过识别和验证可用于监测药物反应和 确定试验开发的可衡量结果。BVMC的总体目标是促进和促进 通过提供研究基础设施和维护，在CCM、SWS和HHT方面进行高质量的临床研究 纵向患者登记和生物信息库(目标1)，通过确定和验证临床结果和 用于临床试验的生物标记物(目标2)，并通过培训下一代罕见疾病研究人员和 资助高风险/高回报的试点研究(目标3)。这些目标将通过我们的三个项目来实现， 核心、试点项目和培训部分；与患者倡导团体--Angioma积极合作 联盟、斯特奇·韦伯基金会、Cure HHT以及RDCRN数据管理和协调中心。 BVMC的建立是促进跨疾病合作的重要一步，提供了 一个集中的临床研究基础设施，用于研究这三种罕见疾病，并产生有价值的 为更大的神经血管社区提供资源。

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.