Targeted Therapies for Neonatal White Matter Injury

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PROJECT SUMMARY ABSTRACT Neonatal White Matter Injury (NWMI) is the leading cause of neurologic and developmental disabilities in children born prematurely. Neuroinflammation, following an initial ischemic/hypoxic-ischemic or infectious insult, mediated by activated microglia and astrocytes, is implicated in the pathogenesis resulting in diffuse white matter injury. Targeted drug delivery to attenuate neuroinflammation may greatly improve therapeutic outcomes. However, delivery of drugs for the treatment of diffuse brain injury in the neonate is a major challenge. Our preliminary studies suggest that intravenous administration of dendrimers (tree-like nanostructured polymers, 4 nm) results in their selective accumulation in activated microglia/macrophages and astrocytes in the brain of injured animals. Importantly, a single, intravenous 10 mg/kg dose of N-acetyl cysteine (NAC) conjugated to the dendrimer (D-NAC), administered after neonatal ischemia resulted in a significant improvement in myelination in the short-term, and attenutation of neuroinflammation. First, we seek to attenuate neuroinflammation in NWMI in a targeted manner. However, target drug delivery for the treatment of diffuse brain injury is a major challenge. We have previously shown that systemic administration of dendrimers (tree-like nanostructured polymers, 4nm) results in their selective accumulation in activated microglia and astrocytes, and in oligodendrocytes in our ischemic NWMI mouse model. Furthermore, dendrimer conjugated to N-acetylcysteine (D-NAC), systemically administered at 24h and 5 days post neonatal ischemia, resulted in sustained attenuation of inflammatory cytokines and reduction of white matter injury at postnatal day 14. Second, we seek to use targeted D-NAC nanotherapy to improve Glial restricted precursor (GRP) survival. GRP cell transplantation is currently being investigated as a therapeutic strategy in a number of neurologic diseases, and we have previously shown that transplanted GRPs exert some restorative effect in the same ischemic mouse model of NWMI, but have limited survival and differentiation capacity when injected into injured brain. Building on these promising findings, the objective of this application is to (i) provide sustained drug release by D-NAC to prolong therapeutic effect, (ii) determine the therapeutic window for D-NAC treatment in the postnatal period and (iii) determine whether D-NAC can enhance survival and restorative capacity of transplanted GRP cells. Our hypotheses are that (1) ongoing neuroinflammation will facilitate selective accumulation of D-NAC in activated microglia/macrophages and astrocytes even at later time points following neonatal ischemia in NWMI; (2) Targeted cellular delivery and sustained release of NAC by dendrimer nanodevices will result in (a) reduction of neuroinflammation/oxidative stress, and (b) improve long term neurobehavioral and neuropathological outcomes in NWMI; (3) D-NAC therapy will reduce inflammation and oxidative stress and allow a permissive environment for GRPs to survive, migrate and restore myelination and axonal injury in NWMI. These hypotheses will be tested using three specific aims, relating to the preparation of dendrimer-NAC nanodevice, identifying the therapeutic window in the post-natal period, and assessing the sustained efficacy of dendrimer. This study is significant because, it explores the potential of targeted post-natal therapy in a clinically relevant model of NWMI for improvement in neurological outcomes, and it will help us to develop a better understanding of how modulating the role of microglial activation and chronic neuroinflammation affects neonatal brain injury and the capacity of precursor cells to remyelinate an injured brain.