Integrated Longitudinal Studies to Identify Biomarkers and Therapeutic Strategies for Sturge-Weber Syndrome

识别斯特奇-韦伯综合征生物标志物和治疗策略的综合纵向研究

• 批准号: 10673820
• 负责人: JEFFREY A LOEB
• 金额: $ 36.73万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10673820
• 关键词: Affect; Anticonvulsants; Aspirin; Atrophic; Biological Markers; Blood; Blood Vessels; Brain; Brain Vascular Malformation; Brain imaging; Cerebral Calcification; Cerebrovascular Disorders; Clinical; Clinical Trials; Data; Databases; Disease; Disease Progression; Early Diagnosis; Eye; Fetal Development; Foundations; Future; GNAQ gene; GTP-Binding Protein alpha Subunits, Gs; Glaucoma; Gliosis; Grant; Headache; Hemangioma; Image; Inflammation; Inflammatory; Leptomeninges; Lesion; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Migraine; Mutation; Neurologic Symptoms; Online Systems; Patients; Pharmaceutical Preparations; Plasma; Port-Wine Stain; Prospective Studies; Quality of life; Radiology Specialty; Refractory; Retrospective Studies; Risk; Sampling; Seizures; Skin; Spider nevus; Structure; Sturge-Weber Syndrome; Surrogate Markers; Symptoms; Testing; Therapeutic; Time; Tissues; Veins; Visualization; angiogenesis; biomarker identification; brain arteriovenous malformations; brain parenchyma; calcification; cerebral cavernous malformations; clinical care; clinical predictors; clinical trial readiness; dashboard; data integration; data registry; data visualization; drug repurposing; imaging biomarker; imaging study; longitudinal database; malformation; member; participant enrollment; patient biomarkers; patient engagement; patient registry; predictive marker; prevent; recruit; stroke-like episode; stroke-like outcome; synergism; tool

Sturge-Weber Syndrome (SWS) is a skin, eye, and brain vascular disorder of capillary angiomas resulting in port wine stain angiomas affecting the skin, angiomas and glaucoma of the eye, and leptomeningeal angiomas surrounding the brain. In 2013, members of the Brain Vascular Malformations Consortium (BVMC) co-identified a somatic, activating mutation in the GNAQ gene (which encodes the G alpha subunit) in affected vascular tissue. This mutation occurs during fetal development and thus, even with early diagnosis, the vascular malformation is already present and may not be reversible. However, as with many vascular brain lesions, serious complications can arise from the effects of the vascular malformation and the surrounding brain parenchyma. Recently, the Sturge-Weber Foundation (SWF) brought together patients and clinicians to identify unmet needs for patients. While neurological symptoms including seizures and headaches are common, stroke-like episodes, severe bouts of seizures, and migraine headaches were felt to significantly impact patient quality of life. Current treatments used to prevent these symptoms include aspirin and seizure medications, but neither is well supported by longitudinal studies. Nor is it clear exactly what causes stroke-like symptoms or how to identify SWS patients at risk for these symptoms. Elegant serial brain imaging studies from our previous grant period have provided important clues showing changes in the vascular structures themselves as well as surrounding brain parenchyma, including dense brain calcifications that could underlie these symptoms. Hence, another potentially exciting treatment is to target brain calcifications through a repurposed drug. Here, we will address pressing needs for clinical trial readiness through the identification of at risk patients, analysis of current treatments, and identification of robust, clinically useful and predictive biomarkers. We plan to extend our patient registry data to integrate longitudinal clinical, radiological, and blood biomarkers of patients to identify those at most risk to have severe neurological symptoms and to identify potential treatments (Aim 1). We will identify imaging biomarkers that will change over time and correlate with severe neurological symptoms (Aim 2). Finally, for enrolled patients who present with severe neurological symptoms, plasma samples will be screened for inflammatory changes at baseline, during, and after the severe symptoms to identify predictive biomarkers for clinical trials (Aim 3). A major deliverable will be a clinically useful, integrated longitudinal database and dashboard tool to help visualize data that will help clinicians better understand progression of disease course following the SWS mutation.

斯特奇-韦伯综合征 (SWS) 是一种皮肤、眼睛和脑血管毛细血管疾病 血管瘤导致葡萄酒色斑 血管瘤影响皮肤、血管瘤和青光眼 眼睛和大脑周围的软脑膜血管瘤。 2013年，脑血管协会成员 畸形联盟 (BVMC) 共同鉴定出 GNAQ 基因的体细胞激活突变 （编码 G α 亚基）存在于受影响的血管组织中。这种突变发生在胎儿时期 因此，即使早期诊断，血管畸形也已经存在 并且可能不可逆转。然而，与许多血管性脑损伤一样，会出现严重的并发症 可能是由血管畸形和周围脑实质的影响引起的。 最近，斯特奇-韦伯基金会 (SWF) 将患者和临床医生聚集在一起， 确定患者未满足的需求。虽然神经系统症状包括癫痫发作和 头痛很常见，有中风样发作、严重癫痫发作和偏头痛 被认为显着影响患者的生活质量。目前用于预防这些的治疗方法 症状包括阿司匹林和癫痫药物，但这两种药物都没有得到纵向的充分支持 研究。目前尚不清楚到底是什么原因导致中风样症状或如何识别 SWS 患者 有出现这些症状的风险。我们之前资助期间的优雅的连续脑成像研究 提供了重要的线索，显示血管结构本身的变化以及 周围的脑实质，包括可能位于这些实质之下的致密脑钙化 症状。因此，另一种潜在的令人兴奋的治疗方法是通过靶向脑钙化 重新调整用途的药物。在这里，我们将通过以下方式解决临床试验准备的迫切需求： 识别有风险的患者，分析当前的治疗方法，并识别稳健的、 临床上有用的和预测性的生物标志物。 我们计划扩展我们的患者注册数据，以整合纵向临床、放射学和 患者的血液生物标志物，以识别那些最有可能出现严重神经系统症状的人 并确定潜在的治疗方法（目标 1）。我们将确定会改变的成像生物标志物 随着时间的推移，并与严重的神经系统症状相关（目标 2）。最后，对于入组患者 对于出现严重神经系统症状的人，将对血浆样本进行筛查 基线、严重症状期间和之后的炎症变化以确定预测性 用于临床试验的生物标志物（目标 3）。主要交付成果将是一个临床上有用的、集成的 纵向数据库和仪表板工具可帮助可视化数据，从而更好地帮助临床医生 了解 SWS 突变后疾病进程的进展。