Serum exosomes as disease severity biomarkers in familial cerebral cavernous malformations and hereditary hemorrhagic telangiectasia

University Of California, San Francisco, San Francisco CA

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Abstract

PROJECT SUMMARY This application is being submitted in response to NOT-TR-18-019. The Brain Vascular Malformation Consortium (BVMC, U54 NS065705) investigates determinants of clinical course and disease progression in 3 diseases that feature cerebrovascular malformations. Two of these diseases, Familial Cerebral Cavernous Malformations (CCM) and Hereditary Hemorrhagic Telangiectasia (HHT), are familial autosomal dominant syndromes with variable expressivity, which share features of disease course including a variable lesion burden and a risk of intracerebral hemorrhage with profound clinical consequences. Over the past 9 years since the inception of the BVMC, we have assembled large well- characterized cohorts with clinical data and DNA samples and other biospecimens, and identified epidemiologic and genetic influences on CCM and HHT disease progression. We now propose to extend these studies by utilizing banked specimens and extensive clinical datasets from CCM and HHT cohorts previously enrolled by the BVMC to investigate circulating exosomal miRNA levels as potential biomarkers of disease severity in CCM and HHT. Exosomes, small membrane-bound particles released by cells into the circulation, serve as an avenue for cell-cell communication, and can represent tissue specific disease processes. Circulating miRNA are a promising diagnostic and prognostic biomarker for many diseases, including inflammatory and vascular diseases and stroke, and studies suggest that isolation of exosomes is important for accurate quantification of circulating miRNA. We now propose to utilize banked CCM and HHT serum samples and the accompanying clinical datasets in a novel way that was not envisioned in the original BVMC application. We will 1) isolate exosomes from 12 CCM and 12 HHT patients of varying phenotype severity, 2) measure exosomal miRNA expression by RNAseq and 3) correlate exosomal miRNA expression patterns with CCM and HHT disease severity phenotypes and validate significant findings in a replication cohort. The long term goals are to develop specific and accessible biomarkers for disease severity and progression in longitudinal studies, in order to guide clinical management and risk stratification of patients affected with the diseases, as well as provide surrogate biomarkers of disease progression for clinical trial development.