Development of a novel therapeutic for treatment of white matter injury in premature infants

项目摘要 在美国，十分之一的婴儿是早产的，有脑白质损伤(WMI)的风险。WMI是 导致早产儿神经预后不良的最常见的新生儿脑损伤包括 脑性瘫痪、智力残疾、癫痫和失明。目前，还没有治疗方案。 可用于WMI。开发用于新生儿的新疗法特别具有挑战性，因为 在这一极其脆弱的人群中，对安全的适当关切。因此，治疗开发必须 在临床前开发过程中处于最前列的安全性。此外，大多数新生儿的WMI是检测不到的 受伤后的几个月里。因此，理想的治疗策略将是足够安全的，可以实施 早产并发症后属于高危类别的婴儿。 Tellus治疗公司发现了一种存在于人类母乳中的新的髓鞘化合物，具有潜在的 治疗新生儿WMI的可能性大，安全性高。我们有强有力的初步数据表明， 复方在体外和体内诱导少突胶质细胞发育，挽救围产期WMI小鼠模型， 刺激在围产期败血症中存活的小鼠的髓鞘形成和预防运动障碍。系统地交付 这种化合物对早产儿来说是复杂的疏水性和这一群体的能力 服用药物或口服食物，以及早产儿耐受的限制液体量。在此阶段 I SBIR项目，我们正在寻求早产儿药物输送的创新方法， 确定用于IND研究的配方并将其作为原型的目标 为临床研究奠定基础。 为实现这一目标，目标1将致力于开发一种用于静脉注射的新型脂肪乳剂 Delivery和Aim 2将对新生儿进行药代动力学(PK)和中枢神经系统暴露分析 猪，目标是确定一种可用于第二阶段支持IND的研究的配方。

Project Summary One in ten babies are born premature in the United States and are at risk of white matter injury (WMI). WMI is the most common neonatal brain injury leading to poor neurologic outcomes in premature infants, including cerebral palsy, intellectual disability, epilepsy, and blindness. Currently, there are no treatment options available for WMI. Developing novel therapeutics for use in neonates is particularly challenging due to appropriate concerns for safety in this extremely vulnerable population. As such, therapeutic development must have safety in the forefront during preclinical development. In addition, most WMI in neonates is undetectable for months following the injury. Therefore, the ideal therapeutic strategy would be safe enough to administer to infants that fall into high-risk categories following complications of preterm birth. Tellus Therapeutics has identified a novel myelinating compound present in human breastmilk with potential to treat neonatal WMI and a high likelihood for safety. We have strong preliminary data indicating that this compound induces oligodendrogenesis in vitro and in vivo, and rescues perinatal WMI in a mouse model, stimulating myelination and preventing motor deficits in mice that survive perinatal sepsis. Systemic delivery of this compound to the premature infant is complicated by hydrophobicity and the inability of this population to take medication or food by mouth, and the restricted fluid volumes tolerated by premature infants. In this Phase I SBIR project, we are pursuing an innovative approach to drug delivery in preterm neonates, with the goal of identifying a formulation to be used in IND-enabling studies and to serve as a prototype upon which to base the formulation for clinical studies. Toward this goal, Aim 1 will be focused on developing a novel, lipid emulsion formulation for intravenous delivery and Aim 2 will perform pharmacokinetic (PK) and central nervous system exposure analyses in neonatal pigs with the goal of identifying a formulation that can be used in IND-enabling studies in Phase II.