Disialyl oligosaccharides as Necrotizing Enterocolitis therapeutics

DESCRIPTION provided by applicant Necrotizing enterocolitis NEC one of the most common and devastating intestinal disorders in preterm infants affects nearly of all very low birth weight infants and leads to a severe and often fatal destruction in the infantandapos s intestin More than a quarter of the affected infants die from NEC and the survivors are often faced with long term neurological complications Therapies to meet the clinical needs for this special and highly vulnerable population are extremely limited In many cases information guiding drug therapy for infants is largely extrapolated from clinical trials in adults which may lead to ineffective therapies and potentially unpredictable adverse effects We use a different approach guided by clinical observations that breast fed infants are at a fold lower risk to develop NEC than formula fed infants It has been shown recently that a specific human milk oligosaccharide HMO called disialyllacto N tetraose DSLNT contributes to the beneficial effects of breastfeeding as it protects from NEC in preclinical intervention studies in rats and also correlates with NEC risk in clinical cohort studies in humans While DSLNT is uniquely found in human milk and difficult to synthesize we have recently reported that two related disialyl hexasaccharides that we synthesized showed promising effects in protecting neonatal rats from NEC in the preclinical model Due to its potential therapeutic applications it is criticl to obtain them in large amounts for pre clinical and clinical studies We propose to carry out the large scale synthesis of the two promising compounds and follow up with dose dependence studies in the preclinical rat model for developing potential therapeutics We also propose to synthesize four additional compounds around the similar chemical space and to assess their in vivo efficacy in the NEC rat model The project will help to identify optimal candidates for proceeding to pre clinical tests in Phase II stage of the project and has great translational potential to be used to treat or prevent NEC in preterm infants who suffer from this devastating disease PUBLIC HEALTH RELEVANCE Disialyl glycans will be synthesized via an efficient enzymatic method and tested for their potential therapeutic use in treating or preventing human necrotizing enterocolitis NEC a deadly disease affecting nearly of all premature very low birth weight infants