PreImplantation Factor plus hypothermia to treat neonatal brain injury

ABSTRACTPerinatal hypoxic ischemic encephalopathyHIEaffectstoinfants per everybornMortality from HIE can be up toand approximatelyof survivors suffer significant longterm disability including cerebral palsyepilepsyand developmental disordersDamage during the acute phase of HIE is caused by a deficit in oxygen and glucose in the brainHoweverincreasing evidence indicates that secondary and tertiary phases are responsible for significant ongoing damageAfter an initial insultoxidative stress increases and signaling cascades lead to cell deathElevated inflammation and epigenetic changes may be present months to years after initial injury as evidenced by myelin deficitsreduced plasticityand altered cell numberRecentlyhypothermia has been used to significantly reduce mortality and developmental complications in term infants with HIEHoweverthere are several limitations to this approachTreatment must be initiated withinhours of injury to reduce metabolic damage and oxidative stressandof infants still die or suffer severe disabilityThe National Institute of Child Health and Human Development recently reported an urgent need to develop neuroprotective combination therapies to be used hours to days after the insult in combination with hypothermiaSeveral known neuroprotective compoundserythropoietinstem cellsxenonetcare being investigated alone or in combination with hypothermiabutto datenone have emerged as a more effective treatment for HIEOverallthere is need for new adjuvant therapies in HIEThis project will test the efficacy of moderate hypothermia plus an immunomodulatory compoundsynthetic PreImplantation FactorsPIFin a rat model of HIE that is equivalent in development to a term human infant brainsPIF regulates both the innate and adaptive immune response and reverses chronic neuroinflammationsPIF co localizes with neuronal and macrophage cells and crosses the blood brain barrier during inflammationIn HIE model of prematurity sPIF reversed neuro axonal injuryactivating neuronal stems cells proliferation and differentiation to myelin coated cellsIn this projectwe will first perform a short termdose ranging study with sPIF plus hypothermia to determine what dose is most effectiveThenwe will perform a longer term comparison of the selected sPIF dose plus hypothermia combination and compare the results to hypothermia aloneWe will use histologyneurofunctional tests to compare the different treatments Overallwe anticipate sPIF plus hypothermia will affect all injury phases and will create an additive neuroprotective effect since these treatments target different pathwaysClinical translation of sPIF as a first line HIE treatment is promising if these preclinical evaluations are successfulBioIncept received Fast Track FDA designation for sPIF and a safety trial in patients with autoimmune hepatitis was completed successfully PROJECT NARRATIVE Perinatal hypoxic ischemic encephalopathyHIEcan result in newborn death or longterm disability including cerebral palsyepilepsyincreased hyperactivityand developmental disordersRecentlyhypothermia treatment has been used to significantly reduce mortality and developmental complications from HIEbutof infants still die or suffer severe disabilityThe National Institute of Child Health and Human DevelopmentNICHDrecently reported an urgent need to develop neuroprotective combination therapies to be used hours to days after the insult in combination with hypothermiaThis project will test the efficacy of hypothermia plus a novel immunomodulatory compoundPreimplantation FactorPIFto develop a more effective combination treatment to prevent brain injury