Modifiers of Disease Severity and Progression in Cerebral Cavernous Malformation

摘要 家族性脑海绵状血管畸形(FCCM)是一种罕见的常染色体显性遗传病，由 三个CCM基因突变，并在MRI上典型地诊断为多个病变。这些漏水的血管 损伤可导致过早出血性中风、反复癫痫发作和其他致残缺陷。这个 触发神经症状的机制或事件仍不清楚。此外，FCCM患者存在 疾病负担的巨大变异性，即使在那些具有相同基因突变、家族或年龄的人中也是如此。这个变种 对于那些管理或生活在这种终生疾病中的人来说，这是一个棘手的难题。目前只有神经外科 治疗方案可供选择。然而，针对CCM信号通路的几种有前景的治疗药物 (血管内皮生长因子、RhoA激酶、转化生长因子、炎症)正在积极的临床前研究中，新的1/2期 阿托伐他汀治疗慢性粒细胞白血病的临床试验正在进行中。为迎接第三阶段临床试验，我们建议 利用我们在过去9年中取得的长足进步来建立、招募、表型和识别修饰物 关注FCCM疾病严重程度和进展，关注知识差距和临床试验障碍 FCCM的准备工作。我们的长期目标是确定可测量的结果和强大的生物标记物， 帮助选择高危患者，并帮助监测临床试验中的药物反应。 在上一个项目期间，我们确定脑损伤负担是FCCM严重程度的一个重要表型，并且 无论是在基因水平还是在mRNA水平，炎症都是损伤负担的关键调节因素。动物中的平行工作 模型证实了我们人类发现的重要性，并揭示了与肠道微生物组之间意想不到的联系。 此外，最近的研究报道，循环血浆中炎性细胞因子的水平可以用来 对患者进行风险分层的可靠生物标志物。我们建议利用我们之前的努力，现在专注于以下因素 影响疾病进展到临床症状和结果，包括患者报告的生活质量，以及 表型障碍损害(目标1)，研究一种新的环境调节剂-肠道微生物组(目标2)， 并扩大我们对临床试验血液生物标记物开发的关注(目标3)。脑血管 畸形联盟的FCCM队列是同类中规模最大的，将用于实现这些目标 与血管瘤联盟-患者倡导组织、我们的7个BVMC招聘网站和Rare 疾病临床研究网络。我们的研究结果将表征生活质量结果并确定 疾病风险修饰物和有助于分层或监测药物治疗的生物标记物，从而建立 FCCM患者的临床试验准备情况。

Abstract Familial cerebral cavernous malformation (FCCM) is a rare autosomal dominant disease caused by mutations in three CCM genes, and classically diagnosed by multiple lesions on MRI. These leaky vascular lesions can cause premature hemorrhagic strokes, recurrent seizures, and other disabling deficits. The mechanisms or events triggering neurological symptoms remain unknown. Further, FCCM patients present with huge variability in disease burden, even among those with the same gene mutation, family, or age. This variation presents a difficult conundrum for those managing or living with this lifelong disease. Currently only neurosurgical treatment options are available. However, several promising therapeutics targeting CCM signaling pathways (VEGF, RhoA kinase, TGF-ß, inflammation) are under active pre-clinical investigation, and a new Phase 1/2 clinical trial of atorvastatin in CCM patients is underway. In anticipation of Phase 3 clinical trials, we propose to leverage our considerable progress over the past 9 years to establish, recruit, phenotype, and identify modifiers of FCCM disease severity and progression to focus on gaps in knowledge and barriers to clinical trial preparedness in FCCM. Our long-term goal is to identify measurable outcomes and robust biomarkers that will help select high-risk patients and help monitor drug response in clinical trials. In the last project period, we identified brain lesion burden as an important phenotype of FCCM severity, and that inflammation is a key modifier of lesion burden at both the genetic and mRNA levels. Parallel work in animal models confirmed the importance of our human findings and revealed an unexpected link to the gut microbiome. Moreover, recent studies have reported that circulating plasma levels of inflammatory cytokines can be used as reliable biomarkers to risk-stratify patients. We propose to leverage our prior efforts to now focus on factors that influence disease progression to clinical symptoms and outcomes, including patient-reported quality of life, and barriers to phenotyping lesions (Aim 1), investigate a new environmental modifier – the gut microbiome (Aim 2), and expand our focus on blood biomarker development for clinical trials (Aim 3). The Brain Vascular Malformations Consortium’s FCCM cohort, the largest of its kind, will be used to accomplish these aims in collaboration with the Angioma Alliance - patient advocacy group, our 7 BVMC recruitment sites, and the Rare Diseases Clinical Research Network. Results of our study will characterize quality of life outcomes and identify modifiers of disease risk and biomarkers useful for stratification or monitoring drug therapy, thus establishing clinical trial readiness for FCCM patients.