Central Nervous System Derived Exosomes: A Novel Source of Biomarkers for Neonatal Hypoxic Ischemic Encephalopathy

ABSTRACT Neonatal hypoxic-ischemic encephalopathy (HIE) affects 1-8 in 1000 live births. Therapeutic hypothermia (TH) improves survival but 35% of surviving treated neonates have significant residual disability. Monitoring of HIE at the bedside currently relies on neurological exam, ultrasound, and aEEG, but these methods do not adequately identify hypothermia non- responders. Multiple biomarkers have been tested for prediction of neurological outcome, however none have translated into a clinically used test to guide therapy or to predict prognosis. In part this is because markers may be blocked by the blood brain barrier or non-specific to the central nervous system (CNS). PA-18-485 highlights that the development of “biomarkers to provide accurate estimate of the timing, nature and extent of brain injury for infants at risk for neonatal encephalopathy” is a critical research goal of the NICHD. Assay development and neuroprotective treatment must be tailored to the unique clinical phases of HIE: acute (0-6 hrs), latent (6-12 hrs), secondary (12-72 hrs) & tertiary (>72 hrs). Central nervous system-derived exosomes (CNSEs) are nanovesicles that freely cross the blood brain barrier and contain surface markers from their cell of origin (neurons/astrocytes); purification of CNSEs essentially allows non-invasive sampling of the neonatal CNS without contamination from non-CNS sources. We hypothesize that CNSE based assays from the acute, latent and early secondary clinical phases of HIE in term neonates can a) predict short term clinical outcomes (vEEG) as well as MRI changes associated with neurodevelopmental (ND) outcomes at 2-years and b) identify the relative contribution of various pathologic processes to adverse outcomes in the individual neonate. Further, we hypothesis that CNSE based assays can be used to quantify the effects of therapeutic neuroprotectants in target cells (neurons/astrocytes) in real time, potentially augmenting future HIE pharmacology studies.