Synthetic PreImplantation Factor (sPIF) plus hypothermia to treat neonatal brain injury

ABSTRACT Perinatal hypoxic-ischemic encephalopathy (HIE) is one of the most serious birth complications in infants. Hypoxic ischemia affects 30.6 cases per 1000 live births. The majority (43.5%) have mild HIE, and 34.8 and 21.7% experience moderate to severe HIE. The acute phase of HIE is caused by reduced blood flow and a deficit in oxygen and glucose in the brain, resulting in neonatal neurologic sequelae (seizures, coma, and hypotonia), and involves multiple organs (kidney, liver, heart, and intestines). However, approximately 25% of survivors suffer significant long-term disability including impaired mental and motor development, cerebral palsy, epilepsy, respiratory difficulties, depressed tone/reflexes, cortical blindness, sensorineural hearing loss, and death. Hypothermia has been used to reduce mortality and developmental complications in term infants with HIE, but it is effective in only 50% of cases, for unclear reasons. Thus, currently, no prophylactic drug or inter- vention is available to prevent HIE in all cases. The National Institute of Child Health and Human Development reported an urgent need to develop neuroprotective combination therapies to be used hours to days after the insult in combination with hypothermia. Several 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, suggesting an urgent need for new adjuvant therapies to counteract HIE. We recently awarded a phase 1 study (STTR) to test the efficacy of moderate hypothermia plus an immunomodulatory compound, synthetic PreImplantation Factor (sPIF), in a rat model of HIE. We proposed to examine a short-term dose-ranging study with sPIF plus hypothermia to determine which dose is most effective, as well as to perform a longer-term comparison of the selected sPIF dose plus hypothermia combination and compare the results to hypothermia alone. As proposed, we performed sPIF dose (1 mg/kg) both for acute and longer-term effects with and without moderate hypothermia. Our studies on histology and neurobehavioral test with sPIF 1 mg/kg plus hypothermia are promising (Please see Significance and Research Design sections for progress report). Due to a limited time window during the pandemic, we were unable to complete the dose- ranging study with sPIF plus hypothermia. Accordingly, in this phase II study, we will first complete, 1) a dose-response, 2) additional behavioral and cognitive function tests, and 3) functional MRI. We will then use the same murine model and injury system to determine 4) the frequency and duration of sPIF exposure, in the presence and absence of hypothermia. We will then determine 5) the basis of neuroprotection against HII and 6) prepare materials for submission to the FDA for a type C meeting. BioIncept received Fast-Track FDA designation for sPIF and a safety trial in patients with autoimmune hepatitis was completed successfully.