PreImplantation Factor plus hypothermia to treat neonatal brain injury

ABSTRACT
Perinatal hypoxic ischemic encephalopathy HIE affects to infants per every born Mortality
from HIE can be up to and approximately of survivors suffer significant long term disability including
cerebral palsy epilepsy and developmental disorders Damage during the acute phase of HIE is caused by a
deficit in oxygen and glucose in the brain However increasing evidence indicates that secondary and tertiary
phases are responsible for significant ongoing damage After an initial insult oxidative stress increases and
signaling cascades lead to cell death Elevated inflammation and epigenetic changes may be present months
to years after initial injury as evidenced by myelin deficits reduced plasticity and altered cell number
Recently hypothermia has been used to significantly reduce mortality and developmental complications
in term infants with HIE However there are several limitations to this approach Treatment must be initiated
within hours of injury to reduce metabolic damage and oxidative stress and of infants still die or
suffer severe disability The 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 hypothermia A number of known neuroprotective compounds erythropoietin stem cells
xenon etc are being investigated alone or in combination with hypothermia but to date none have emerged
as a more effective treatment for HIE Overall there is need for new adjuvant therapies in HIE
This project will test the efficacy of moderate hypothermia plus an immunomodulatory compound
synthetic PreImplantation Factor sPIF in a rat model of HIE that is equivalent in development to a term
human infant brain BioIncept has published data demonstrating that PIF regulates both the innate and
adaptive immune response Significantly PIF reversed neurological damage in a multiple sclerosis model and
protected against oxidative stress in multiple disease models Recent studies in a model of encephalopathy of
prematurity showed that PIF provided protection against neuro axonal injury
In this project we will first perform a short term dose ranging study with sPIF plus hypothermia to
determine what dose is most effective Then we will perform a longer term comparison of the selected sPIF
dose plus hypothermia combination and compare the results to hypothermia alone We will use histology
neurofunctional tests and magnetic resonance imaging MRI to compare the different treatments Overall we
anticipate PIF plus hypothermia will affect all injury phases and will create an additive neuroprotective effect
since these treatments target different pathways Clinical translation of PIF as a first line HIE treatment is
promising if these preclinical evaluations are successful as BioIncept received FDA Fast Track designation for
PIF treatment of autoimmune hepatitis clinical trial began in and Yale University collaborators provide
additional obstetric and clinical expertise PROJECT NARRATIVE
Perinatal hypoxic ischemic encephalopathy HIE can result in newborn death or long term disability
including cerebral palsy epilepsy increased hyperactivity and developmental disorders Recently
hypothermia treatment has been used to significantly reduce mortality and developmental complications
from HIE but of infants still die or suffer severe disability The National Institute of Child Health
and Human Development NICHD recently reported an urgent need to develop neuroprotective
combination therapies to be used hours to days after the insult in combination with hypothermia This
project will test the efficacy of hypothermia plus a novel immunomodulatory compound Preimplantation
Factor PIF to develop a more effective combination treatment to prevent brain injury