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， 三个CCM基因突变，并通过MRI上的多个病变进行经典诊断。这些渗漏的血管 损伤可引起过早出血性中风、复发性癫痫发作和其它致残缺陷。的 触发神经症状的机制或事件仍然未知。此外，FCCM患者存在 疾病负担的巨大差异，即使是在具有相同基因突变、家庭或年龄的人群中。这种变化 对于那些管理或患有这种终身疾病的人来说，这是一个难题。目前只有神经外科 治疗方案可用。然而，一些有前途的治疗靶向CCM信号通路， (VEGF，RhoA激酶，TGF-β，炎症）正在积极的临床前研究中， 阿托伐他汀在CCM患者中的临床试验正在进行中。在3期临床试验的预期中，我们建议 利用我们在过去9年中取得的巨大进展，建立、招募、表型和鉴定修饰物 FCCM疾病的严重程度和进展，重点关注知识差距和临床试验障碍 在FCCM的准备。我们的长期目标是确定可测量的结果和可靠的生物标志物， 帮助选择高风险患者，并帮助监测临床试验中的药物反应。 在上一个项目期间，我们确定脑损伤负荷是FCCM严重程度的重要表型， 炎症在基因和mRNA水平上都是病变负荷的关键调节剂。动物平行作业 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的意外联系。 此外，最近的研究已经报道，炎性细胞因子的循环血浆水平可以用作 可靠的生物标志物来对患者进行风险分层。我们建议利用我们以前的努力，现在把重点放在以下因素上： 影响疾病进展至临床症状和结局，包括患者报告的生活质量，以及 表型病变的障碍（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志物开发的关注（目标3）。脑血管 畸形联盟的FCCM队列是同类队列中最大的，将用于实现这些目标。 与血管瘤联盟合作-患者倡导小组，我们的7个BVMC招募网站，以及罕见的 疾病临床研究网络。我们的研究结果将描述生活质量的结果，并确定 用于分层或监测药物治疗的疾病风险修饰物和生物标志物，从而建立 为FCCM患者准备临床试验。

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.