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

开发一种治疗早产儿脑白质损伤的新疗法

• 批准号: 10269036
• 负责人: Jason E Kralic
• 金额: $ 38.41万
• 依托单位: TELLUS THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10269036
• 关键词: Adult; Advanced Development; Affect; Animals; Blindness; Blood; Blood specimen; Brain; Brain region; Categories; Cerebral Palsy; Cessation of life; Characteristics; Clinic; Clinical; Clinical Research; Continuous Infusion; Contracts; Custom; Data; Development; Drug Delivery Systems; Drug Kinetics; Electrospray Ionization; Emulsions; Environment; Epilepsy; Event; Family; Family suidae; Fatty acid glycerol esters; Food; Formulation; Goals; Healthcare Systems; Hour; Human; Human Milk; Hydrophobicity; In Vitro; Individual; Infant; Infusion procedures; Injury; Intellectual functioning disability; Intravenous; Intravenous infusion procedures; Lipids; Liquid Chromatography; Liquid substance; Live Birth; Modeling; Mus; Neonatal; Neonatal Brain Injury; Neonatal Intensive Care Units; Neuraxis; Neurological outcome; Newborn Infant; Oligodendroglia; Oral cavity; Outcome; Patients; Perinatal; Perinatal Infection; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Plasma; Population; Positioning Attribute; Premature Birth; Premature Infant; Problem Solving; Procedures; Production; Property; Risk; Safety; Serum; Small Business Innovation Research Grant; Solubility; Solvents; Special Population; System; Therapeutic; Therapeutic Uses; Time; Toxicity Tests; United States; Vulnerable Populations; Withdrawal; Work; base; brain tissue; chemical stability; cohort; cost; disability; drug development; effective therapy; falls; high risk; improved; in vivo; innovation; manufacturability; mortality; motor deficit; mouse model; myelination; neonate; nerve stem cell; novel; novel therapeutics; postnatal; preclinical development; premature; preterm newborn; prevent; prototype; standard of care; tandem mass spectrometry; therapeutic candidate; therapeutic development; white matter injury

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.

项目摘要 在美国，十分之一的婴儿早产，并有白色物质损伤的风险。WMI是 最常见的新生儿脑损伤导致早产儿神经功能结局不良，包括 脑瘫、智力残疾、癫痫和失明。目前，没有治疗方案 可供选择。开发用于新生儿的新疗法特别具有挑战性， 对这一极其脆弱的人群的安全给予适当的关注。因此，治疗开发必须 在临床前开发期间将安全性放在首位。此外，大多数新生儿中的β-内酰胺酶是检测不到的。 在受伤后的几个月里因此，理想的治疗策略将是足够安全的， 早产并发症后属于高危类别的婴儿。 Tellus Therapeutics已经发现了一种存在于人类母乳中的新型髓鞘化合物， 用于治疗新生儿腹泻，安全性高。我们有强有力的初步数据表明， 化合物在体外和体内诱导少突神经发生，并在小鼠模型中挽救围产期早产， 刺激髓鞘形成和预防围产期败血症存活小鼠的运动缺陷。的全身递送 这种化合物对早产儿的影响由于疏水性而变得复杂， 口服药物或食物，以及早产儿耐受的有限液体量。在这个阶段 在SBIR项目中，我们正在寻求一种创新的早产儿给药方法， 目标是确定一种配方，用于IND赋能研究，并作为原型， 为临床研究奠定基础。 为了实现这一目标，目标1将集中于开发一种新型的脂肪乳剂制剂，用于静脉注射。 分娩和Aim 2将在新生儿中进行药代动力学（PK）和中枢神经系统暴露分析 猪，目的是确定可用于II期IND使能研究的制剂。