Disialyl oligosaccharides as Necrotizing Enterocolitis therapeutics

 描述(申请人提供)：坏死性小肠结肠炎(NEC)是早产儿中最常见和最具破坏性的肠道疾病之一，影响所有极低出生体重婴儿的近10%，并导致婴儿的肠道严重破坏，往往是致命的。超过四分之一的受影响婴儿死于NEC，幸存者经常面临长期的神经并发症。满足这一特殊和高度脆弱人群的临床需求的治疗方法极其有限。在许多情况下，指导婴儿药物治疗的信息在很大程度上是从成人的临床试验中推断出来的，这可能会导致无效的治疗方法和潜在的不可预测的不良反应。我们使用了一种不同的方法，根据临床观察，母乳喂养的婴儿患NEC的风险比配方奶喂养的婴儿低6-10倍。最近有研究表明，在大鼠的临床前干预研究中，一种名为二唾液乳酸-N-四糖(DSLNT)的特定人乳寡糖(HMO)有助于母乳喂养的有益效果，它还与人类临床队列研究中的NEC风险相关。虽然DSLNT是在母乳中唯一发现的，很难合成，但我们最近报道了我们合成的两种相关的二唾液六糖在临床前模型中对新生大鼠的NEC具有良好的保护作用。由于其潜在的治疗应用，大量获取它们用于临床前和临床研究是至关重要的。我们建议进行这两个有希望的化合物的大规模合成，并在临床前大鼠模型中进行后续剂量依赖研究，以开发潜在的治疗药物。我们还建议在相似的化学空间周围合成另外四个化合物，并在NEC大鼠模型中评估它们的体内疗效。该项目将帮助确定在项目第二阶段进行临床前测试的最佳候选者，并具有极大的翻译潜力，可用于治疗或预防患有这种毁灭性疾病的早产儿的NEC。

 DESCRIPTION (provided by applicant): 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.