CNS-Derived Fetal Extracellular Vesicles for the Non-Invasive Diagnosis of Fetal CNS CMV Infection

摘要

Abstract Congenital cytomegalovirus (CMV) infection affects 1 in every 150 infants born in the US and is responsible for more long-term sequelae than either Down syndrome or Fetal Alcohol Syndrome. Despite this, there are no current diagnostic methods to individualize early treatment towards those pregnancies most likely to benefit nor existing methods to non-invasively follow treatment efficacy. Traditional methods of ultrasound and amniocentesis delay accurate diagnosis of congenital CMV until mid-gestation and may not detect fetal infection early enough to prevent developmental sequelae. Exosomes/extracellular vesicles are nanovesicles that package and protect proteins and freely cross the blood brain barrier and the placenta bearing specific and discriminatory surface markers from their cell of origin. Purification of vesicles from maternal blood using markers unique to the fetal brain non-invasive evaluation of neurologic morbidity from CMV infection. We hypothesize that nanovesicles can be isolated from maternal serum that contain both protein markers of neurologic injury and inflammation and miRNA markers specific to mechanisms of CMV. We further hypothesize that changes in exosome levels of these target biomarkers will correlate with clinical outcomes. Successful completion of the aims of this proposal has to potential to transform the clinical approach to congenital viral infections. Nanovesicles may be able to detect pre-clinical injury prior to the development of ultrasound findings – enabling earlier treatment prior to irreversible damage and therefore potentially increasing the effectiveness of any treatment strategy. The results would determine if novel assays developed under this proposal can be used to predict morbidity, clinically to counsel parents and in future therapeutic trials to follow response. The ultimate goal is to guide individualized treatment in affected pregnancies while limiting unnecessary drug exposure/side effects in unaffected pregnancies.