Inter-alpha Inhibitors in Hypoxic-Ischemic Brain Injury

Perinatal brain injury resulting in mental retardation and cerebral palsy is the most severe disability in children and affects 40-148 in preterm and 1–2/1000 in full term infants. This places a huge burden on society, emphasizing the critical need for improved prevention/treatment strategies to decrease perinatal brain injury. Hypothermia (HT) is the only FDA approved therapy to attenuate brain damage in infants. This therapy is only partially protective, has a narrow therapeutic window, can only be used to treat hypoxic-ischemic encephalopathy (HIE) in full term infants, and is not approved for use in preterm infants. Therefore, additional adjunctive therapies are urgently needed. Inter-alpha Inhibitor Proteins (IAIPs) are naturally derived glycoproteins that have been demonstrated to play an important role in modulating host inflammatory responses by targeting multiple, diverse inflammatory pathways. IAIPs down-regulate cytokines, inhibit serine proteases, block complement activation, maintain neutrophils in a resting state, reduce ROS production, and bind nuclear proteins that are released from dying cells. Our encouraging results from the recently completed SBIR Phase II project showed that IAIPs markedly attenuate brain volume loss under normothermic conditions in experimental neonatal HI brain injury, and that treatment with IAIPs offered equivalent neuroprotective efficacy to HT in neonatal rats. The results of MRI imaging correlated very well with the brain volume loss in the injured rat brains when they became young adults, facilitating efficient and long-term study of treatment effects. We treated the rats with IAIPs immediately after the exposure to HI followed by HT. In this proposal, we will modify our previous study paradigm to enhance IAIPs effect by providing longer sequential repeated doses after exposure to HT. This strategy specifically targets the prolonged secondary inflammatory phase that last for days to weeks after HI brain injury. The goal of this project is to advance the drug development process by confirming and further developing effective therapeutic strategies using IAIPs as an alternative or adjunctive to HT to prevent and/or attenuate HI-related brain damage in neonates. We will also explore blood IAIP levels and other inflammatory markers as potential biomarkers to assist in future human trials. The specific aims are: 1) To optimize the treatment strategy with IAIPs in treating moderate and severe HI alone and/or after treatment with HT: We hypothesize that multiple repeated IAIP doses after HT augments the beneficial effects of HT by reducing the secondary inflammatory phase and improves long term histopathological and behavioral outcomes; 2) To identify pharmacodynamic biomarkers to use in animal toxicology and clinical studies: We hypothesize that the levels of IAIPs and the associated target proteins (HMGB1 and extracellular histones) are altered in infants with HIE and could serve as useful predictive biomarkers in addition to Apgar/Sarnat scores, aEEG and blood gas values to guide clinical therapy in infants. The proposed translational project is designed to obtain robust key preclinical data in support of future early human safety and efficacy testing.