Combinatorial Neuroprotective Strategies for Preterm Brain Injury

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PROJECT SUMMARY Preterm birth remains a major cause of mortality and morbidity globally and in the United States. Fortunately, over the past several decades, mortality has decreased such that survival is now over 90% in high income countries. Unfortunately, commensurate improvements in neurodevelopmental outcomes of extremely preterm infants (EP, born <28 weeks’ gestation) remain elusive, with more than 60% of survivors developing at least one disability such as cerebral palsy, autism, ADHD, or cognitive, hearing, or visual impairment. There are no targeted neuroprotective interventions for preterm infants in current clinical use, driving a significant clinical need to develop therapies that reduce the mortality and long-term morbidity seen in EP infants. To evaluate promising therapeutics in the preterm infant, we have developed complementary in vitro and in vivo techniques in the developing ferret. Our preliminary data in the inflammation sensitized hypoxic-ischemic-hyperoxic (HIH) ferret model of preterm brain injury shows injury patterns and behavioral changes consistent with those seen in infants born prematurely. In cultured organotypic ferret brain slices exposed to oxygen-glucose deprivation (OGD), we have also shown regionally dependent injury, similar to the preterm human, and regional and treatment- dependent transcriptome changes associated with neuroprotection. The fact that we see regionally dependent responses to therapy suggests that an optimal therapeutic approach will require combinatorial therapies to provide global neuroprotection and improve long-term neurodevelopmental outcomes. This is particularly relevant considering the recent publication of the PENUT trial, which found no significant neuroprotective effect of erythropoietin (Epo) monotherapy – one of the most promising therapies in the pipeline – in EP infants. Organotypic brain slices can provide a platform to screen combinatorial therapeutics including their interactions. For example, our preliminary data in EP-equivalent ferret brain slices shows Epo in combination with the anti- inflammatory antibiotic azithromycin results in synergistic benefit in the subcortical white matter, a region that is specifically at risk in EP infants, but this combination does not result in benefit in all brain regions. Building on these findings, the objectives of our proposed research are to (1) determine the regional specificity and efficacy of multiple promising neurotherapeutics in vitro, (2) evaluate combined neurotherapeutics to optimize regional and global neuroprotection in vitro, and (3) develop a cocktail of neurotherapeutics optimizing neuroprotection in vivo in a ferret model of EP brain injury. Our overarching hypotheses are that: (1) neurotherapeutics that provide complementary region-specific neuroprotection in vitro will increase global neuroprotection in vivo, and (2) that compared to monotherapy, combining complementary neurotherapeutics will result in greater neuroprotection across the entire brain that persists into adolescence. Data resulting from this proposal could support a clinical trial in this population for which no specific neuroprotective therapies are currently available.