SBIR-STTR Award

Neonatal hypoxia-ischemia (HI) remains a major cause of acute perinatal brain injury, leading ultimately to neurologic dysfunction manifesting as cerebral palsy, mental retardation, and epilepsy. Cerebral oxygen deprivation and/or reduced blood flow due to umbilical cord occlusion, prolonged labor, and/or intracranial hemorrhage produce an inflammatory response contributing to neuronal cell death. Unfortunately, current treatment and prevention strategies in newborns are lacking and inadequate. There are no currently available therapies to prevent/treat and/or attenuate brain damage in premature infants and the only available therapeutic intervention for full term infants is hypothermia, which is onlypartially protective. Inter-alpha Inhibitor Proteins (IAIP) are naturally derived molecules that have been shown to play an important role in modulating inflammatory response by down-regulating pro-inflammatory cytokines in several experimental models of newborn and adult systemic inflammation and in models of inflammation- induced premature labor. Moreover, decreased IAIP has been shown to accurately predict the development of sepsis in premature infants and decreases in IAIP have been detected following induced ischemia in the ovine fetus brains. Thus, exogenous treatment with IAIP is likely to attenuate inflammation-induced brain injury in neonatal incidences of cerebral ischemia. Our recent data strongly demonstrate the beneficial effects of early administration of IAIP in established models of HI injury in the ovine fetus, neonatal rats and adult mice. Not only does IAIP treatment reduce neuroanatomical injury in the brain of experimental animals, but long-term improvement on learning and memory tasks was achieved. The goal of this Phase I SBIR project is to confirm and obtain proof-of-concept of the neuroprotective effects of IAIP in newborn brain injuries. We hypothesize that IAIP treatment will reduce neuronal death and attenuate the development of ischemic-reperfusion injury in the brain. The Specific Aims of the study are to examine the therapeutic effects and long-term behavioral outcome of delayed IAIP treatment in neonatal rat hypoxic-ischemic brain injury model. The proposed studies have significant translational potential to develop IAIP as a novel agent to prevent/attenuate brain damage in infants at risk for mental retardation.

Thesaurus Terms:
Acute;Adult;Animals;Anti-Inflammatory;Anti-Inflammatory Agents;Attenuated;Base;Behavioral;Blood;Blood Flow;Brain;Brain Hypoxia-Ischemia;Brain Injuries;Brain Ischemia;Cerebral Ischemia;Cerebral Ischemia-Hypoxia;Cerebral Palsy;Cerebrum;Cessation Of Life;Clinically Relevant;Cognitive Deficits;Cytokine;Cytokine Suppression;Data;Deprivation;Development;Epilepsy;Experimental Models;Fetus;Fresh Frozen Plasmas;Goals;Health;Human;Hypoxia;Immunoglobulins;Immunomodulators;Incidence;Infant;Inflammation;Inflammation Mediators;Inflammatory;Inflammatory Response;Injury;Inter-Alpha-Inhibitor;Intracranial Hemorrhages;Ischemia;Ischemic-Hypoxic Encephalopathy;Kidney;Language Development;Learning;Life;Light;Longitudinal Studies;Measures;Memory;Mental Retardation;Modeling;Mus;Natural Hypothermia;Neonatal;Neonatal Brain Injury;Neonatal Hypoxic-Ischemic Brain Injury;Neonate;Neurologic;Neurologic Dysfunctions;Neuron Loss;Neurons;Newborn Infant;Novel;Novel Therapeutics;Outcome;Oxygen;Patients;Perinatal Brain Injury;Phase;Plasma;Play;Premature;Premature Birth;Premature Infant;Premature Labor;Prevent;Prevention Strategy;Protein Biosynthesis;Proteins;Public Health Medicine (Field);Public Health Relevance;Rattus;Reperfusion Injury;Reperfusion Therapy;Risk;Role;Sepsis;Sepsis Syndrome;Sheep;Shock;Short-Term Memory;Small Business Innovation Research Grant;Testing;Therapeutic;Therapeutic Effect;Therapeutic Intervention;Translating;Treatment Strategy;Umbilical Cord Structure;

Neonatal hypoxia-ischemia (HI) remains a major cause of acute perinatal brain injury, leading ultimately to neurologic dysfunction manifesting as cerebral palsy, mental retardation, and epilepsy. Unfortunately, current treatment and prevention strategies in newborns are limited. There 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 hypothermia, which is only partially protective. Inter- alpha Inhibitor Proteins (IAIP) are 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 labor. Our 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 tasks. In the Phase I SBIR study, we confirmed the beneficial effects of IAIP in neonatal rats after HI, particularly in male subjects. More recently, we obtained supporting evidence that IAIP also has long-term beneficial effects on behavioral function in female rats, suggesting that IAIP has durable neuroprotective effects in both males and females depending upon test and the duration after the HI insult. These findings suggest unique beneficial effects of IAIP on long-term outcomes in males and females, in spite our histopathological beneficial findings mainly in male neonatal rats. The 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 newborns. We 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 neonates. The Specific Aims of the studies are: 1) to develop an efficient scalable bioprocess of plasma-derived IAIP and carry out formulation, viral safety and long-term stability studies of purified IAIP; 2a) to determine the pharmacokinetics (PK) of IAIP in male and female rats under conditions of hypoxic-ischemic (HI) and hypothermia (HT) and to perform dose-response studies; 2b) to assess the neuroprotective effects of IAIP as an adjunctive treatment strategy to HT in moderate or severe HI brain injury in newborn rats and 3) to determine the long-term neuroprotective efficacy of IAIP treatment with combined HT after HI in the newborn rats. The 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.

Public Health Relevance Statement:
Cerebral hypoxia-ischemia (HI) and associated inflammation is a profound neurological problem in neonatal infants leading to poor health conditions. This proposal will advance public health by developing novel anti-inflammatory therapeutic strategy to complement current standard therapy of body cooling in infants with HI brain injury.

Project Terms:
Acute; Adult; Animals; Anti-inflammatory; Anti-Inflammatory Agents; Attenuated; attenuation; behavior test; Behavioral; behavioral outcome; bioprocess; Brain; Brain Hypoxia-Ischemia; Brain Injuries; brain volume; Cell Death; Cerebral Ischemia-Hypoxia; Cerebral Palsy; Clinical; clinically relevant; Combined Modality Therapy; Complement; cytokine; Cytoprotection; Data; Development; dexterity; Dose; Drug Kinetics; Effectiveness; Epilepsy; Experimental Models; Female; field study; Formulation; Functional disorder; Glycoproteins; Goals; Health; Histologic; Human; human data; Hypoxia; Hypoxic-Ischemic Brain Injury; improved; indexing; Industrialization; Infant; Inflammation; Inflammatory; Inflammatory Response; Injury; inter-alpha-inhibitor; Investigation; Ischemia; Laboratories; Learning; Magnetic Resonance Imaging; male; Manufacturer Name; manufacturing process; Measurement; Measures; medical specialties; Memory; Mental Retardation; Modeling; morris water maze; Motor; natural hypothermia; Neonatal; neonatal brain; neonatal hypoxic-ischemic brain injury; neonate; Neuroglia; Neurologic; Neurologic Dysfunctions; Neurons; Newborn Infant; novel; Outcome; Pathologic; Patients; Perinatal Brain Injury; Phase; Plasma; Plasma Proteins; Play; pre-clinical; Premature Infant; Premature Labor; preterm newborn; prevent; Prevention strategy; Procedures; Process; Proteins; Public Health; Rattus; Recovery; Reflex action; Reperfusion Therapy; response; Risk; Role; Safety; skills; Small Business Innovation Research Grant; Source; standard of care; Supportive care; Term Birth; Testing; Therapeutic; Therapeutic Intervention; Treatment Efficacy; treatment strategy; Viral; way finding