Development of a Neonatal Abstinence Syndrome Therapy

Project Summary Neonatal Abstinence SyndromeNAShas skyrocketed in recent years as a result of the opioid epidemic plaguing this countrySincethe number of babies affected by NAS has increased nearlyfoldEveryminutes a baby is born suffering from opioid withdrawaloften prematurely with developmental problems and potential long term adverse effects including cognitive impairmentApproximatelyof pregnant women abuseor more substanceswith nearlyof teenage pregnancies affectedIn additionmedically supervised maintenance therapy with methadone or buprenorphine of pregnant womencases per yearalso causes NAS and the need for hospitalization under emergency care with only palliative treatments availableTo prevent NAS altogetheran effective therapy applied to the pregnant mother could be an opioid antagonist that does not enter the motherandapos s braini edoes not affect opioid maintenancebut does penetrate the placenta and enters the fetal brain because of its immature blood brain barrierBBBThis approach has the potential not only to suppress NAS symptoms after birthbut also to prevent developmental abnormalities and premature birth as a result of opioid exposureThe risks and costs associated with developing new therapies for pregnant women make it unlikely that any traditional pharmaceutical or biotechnology company will embrace NAS as a therapeutic indicationWe have developed a potent peripherally selective neutral antagonist of the mu opioid receptornaltrexolBNwith good oral bioavailability in animal modelsBN is the main metabolite of naltrexonewhich has been administered to pregnant women to block opioid abusewithout obvious adverse effects to the newbornnaltrexone readily enters the adult brainImportantlyin a mouse modelBN crosses the placenta and is able to enter the fetal brain at high levelsbut is relatively excluded from entering the maternal brainas shown in humansWe have also demonstrated thatBN prevents opioid dependence with high potency when co administered with morphine in mouse pupsin mice the BBB does not fully close until post natal dayThe goal of this proposed workusing a guinea pig modelis to determine whetherBN administered to the pregnant female has similar pharmacokinetic behavior displaying preferential access to the fetal brain over the maternal brain and is orally availablethe preferred route for pregnant womenPhase IAimIf results meet our expectationswe will test the ability ofBN to block opioid dependenceand subsequent NAS symptomsselectively in the fetus and develop an optimized dosage regimenas a proof of principlePhase IIAimIn additionwe will implement an IND enabling toxicology programPhase IIAimProject Summary | PageProject Narrative Opioid induced Neonatal Abstinence SyndromeNAShas become a public health crisis for societyandapos s most vulnerable members leading to developmental abnormalitiespremature birthsand prolonged hospitalization under emergency care with only palliative treatment availableCurrentlypregnant women per year are on medically supervised opioid maintenance therapyhoweverthis treatment also causes NASProposed is a new pharmacological therapy to selectively block opioid effects in the brain of the developing fetuswithout affecting opioid maintenance in the motherto minimize or prevent NASdelayed fetal developmentpremature birthand long term consequencesProject Narrative | Page