Necrotizing enterocolitis (NEC), one of the most common and devastating intestinal disorders in preterm infants, affects nearly 10% of all very low-birth-weight infants and leads to a severe and often fatal destruction in the infant'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 6-10-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.
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 10% of all premature very-low-birth weight infants.
| Yu, Hai; Yan, Xuebin; Autran, Chloe A et al. (2017) Enzymatic and Chemoenzymatic Syntheses of Disialyl Glycans and Their Necrotizing Enterocolitis Preventing Effects. J Org Chem 82:13152-13160 |
