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-, 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.
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