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: 10442416
• 负责人: JEFFREY A LOEB
• 金额: $ 37.41万
• 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/10442416
• 关键词: Address; Affect; Anticonvulsants; Aspirin; Atrophic; Biological Markers; Blood; Blood Vessels; Brain; Brain Vascular Malformation; Brain imaging; Cerebral Calcification; Cerebrovascular Disorders; Clinical; Clinical Trials; Clinical/Radiologic; Data; Databases; Disease; Disease Progression; Early Diagnosis; Enrollment; Eye; Fetal Development; Foundations; Future; GNAQ gene; GTP-Binding Protein alpha Subunits, Gs; Glaucoma; Gliosis; Grant; Headache; Hemangioma; Hemangioma of skin; Image; Inflammation; Inflammatory; 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; Refractory; Retrospective Studies; Risk; Sampling; Seizures; Skin; Spider nevus; Structure; Sturge-Weber Syndrome; Surrogate Markers; Symptoms; Testing; Therapeutic; Time; Tissues; Veins; angiogenesis; brain arteriovenous malformations; brain parenchyma; calcification; cerebral cavernous malformations; clinical care; clinical predictors; clinical trial readiness; dashboard; data registry; drug repurposing; imaging biomarker; imaging study; longitudinal database; malformation; member; patient biomarkers; patient engagement; patient registry; predictive marker; prevent; recruit; stroke-like episode; stroke-like outcome; 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.

Sturge-Weber综合征（SWS）是一种皮肤、眼和脑血管疾病， 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 畸形协会（BVMC）共同鉴定了GNAQ基因中的体细胞激活突变 （其编码G α亚基）在受影响的血管组织中。这种突变发生在胎儿期。 因此，即使早期诊断，血管畸形也已经存在 并且可能不可逆。然而，与许多脑血管病变一样， 可由血管畸形和周围脑实质的影响引起。 最近，Sturge-Weber基金会（Sturge-Weber Foundation）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 头痛是常见的，中风样发作，严重的癫痫发作和偏头痛 会显著影响患者的生活质量。目前用于预防这些疾病的治疗方法 症状包括阿司匹林和癫痫药物，但纵向研究也没有很好的支持。 问题研究也不清楚究竟是什么原因导致中风样症状或如何识别SWS患者 这些症状的风险。我们上一个资助期的系列脑成像研究 提供了重要的线索，显示血管结构本身的变化， 周围的脑实质，包括密集的脑钙化，可能是这些 症状因此，另一种潜在的令人兴奋的治疗方法是通过一种靶向治疗脑钙化的方法。 重新使用的药物在这里，我们将通过以下方式满足临床试验准备的迫切需求： 风险患者的识别，当前治疗的分析，以及稳健的， 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登记数据，以整合纵向临床、放射学和 患者的血液生物标志物，以确定那些最有可能出现严重神经系统症状的患者 并确定潜在的治疗方法（目标1）。我们将确定成像生物标志物， 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患者，将筛查血浆样本， 在基线、严重症状期间和之后的炎症变化，以确定预测 用于临床试验的生物标志物（目标3）。一个主要的可交付成果将是一个临床上有用的， 纵向数据库和仪表板工具，帮助可视化数据，帮助临床医生更好地 了解SWS突变后疾病进程的进展。