Inter-alpha Inhibitors in Hypoxic-Ischemic Brain Injury

Neonatal hypoxia ischemiaHIremains a major cause of acute perinatal brain injuryleading ultimately to neurologic dysfunction manifesting as cerebral palsymental retardationand epilepsyUnfortunatelycurrent treatment and prevention strategies in newborns are limitedThere are no currently available therapies to prevent treat and or attenuate brain damage in premature infants other than supportive care and the only available therapeutic intervention for full term infants is hypothermiawhich is only partially protectiveInteralpha Inhibitor ProteinsIAIPare naturally derived glycoproteins that have been shown to play an important role in modulating inflammatory responses by down regulating pro inflammatory cytokines in several experimental models of newborn and adult systemic inflammation and in models of inflammation induced premature laborOur recent investigations strongly demonstrate that IAIP reduced neuroanatomical injury in the brain of neonatal rats and improves long term behavioral indices of learning and memory tasksIn the Phase I SBIR studywe confirmed the beneficial effects of IAIP in neonatal rats after HIparticularly in male subjectsMore recentlywe obtained supporting evidence that IAIP also has long term beneficial effects on behavioral function in female ratssuggesting that IAIP has durable neuroprotective effects in both males and females depending upon test and the duration after the HI insultThese findings suggest unique beneficial effects of IAIP on long term outcomes in males and femalesin spite our histopathological beneficial findings mainly in male neonatal ratsThe goal of this Phase II SBIR project is to obtain robust preclinical and manufacturing process data of human plasma derived IAIP to support the development as a novel adjunctive neuroprotective strategy to the current standard of care of hypothermia for the treatment of hypoxic ischemic encephalopathy in newbornsWe hypothesize that treatment with IAIP as an adjunctive therapy to hypothermia further enhances the effectiveness of hypothermia as a neuroprotective strategy and improves long term outcomes after HI brain injury in neonatesThe Specific Aims of the studies areto develop an efficient scalable bioprocess of plasma derived IAIP and carry out formulationviral safety and long term stability studies of purified IAIPato determine the pharmacokineticsPKof IAIP in male and female rats under conditions of hypoxic ischemicHIand hypothermiaHTand to perform dose response studiesbto assess the neuroprotective effects of IAIP as an adjunctive treatment strategy to HT in moderate or severe HI brain injury in newborn rats andto determine the long term neuroprotective efficacy of IAIP treatment with combined HT after HI in the newborn ratsThe proposed studies have significant translational potential to develop IAIP as a novel agent to prevent attenuate brain damage in full term as well as in preterm infants at risk for mental retardation