Prevention of White Matter Injury in Premature Infants

早产儿脑白质损伤的预防

• 批准号: 10164837
• 负责人: SCOTT A. RIVKEES
• 金额: $ 70.06万
• 依托单位: MEDOSOME BIOTEC, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10164837
• 关键词: Address; Affect; Air; Animal Model; Area; Brain; Brain Injuries; Canis familiaris; Cell Differentiation process; Cell Proliferation; Cells; Cerebral Palsy; Child; Clinical Research; Data; Diazoxide; Diffuse; Disease; Etiology; Florida; Goals; Hypoxia; Impairment; Individual; Infant; Laboratories; Lead; Low Birth Weight Infant; Modeling; Morbidity - disease rate; Necrosis; Neuraxis; Oligodendroglia; Periventricular white matter injury; Pharmacologic Substance; Pharmacology; Phase; Play; Premature Infant; Prevention; Property; Public Health; Rattus; Research; Risk; Rivers; Role; Safety; Slice; Small Business Technology Transfer Research; Testing; Therapeutic; Therapeutic Agents; Therapeutic Uses; Toxicology; United States; Universities; White Matter Disease; Work; care costs; drug development; efficacy study; experience; high throughput screening; in vitro testing; in vivo; manufacturing process; mouse model; myelination; neonatal brain; neonatal mice; novel strategies; novel therapeutics; prevent; response; small molecule; white matter; white matter injury

ABSTRACT Up to 30% of low birth weight preterm infants manifest some form of periventricular white matter injury (PWMI) making it the most common form of brain injury affecting premature infants. PWMI is associated with significant morbidity, as affected individuals may have profound intellectual impairment and cerebral palsy. Highlighting the magnitude of PWMI, each year more than 400,000 infants are born prematurely in the United States. Of these infants, 150,000 are born at risk for PWMI, and about 25,000 children per year will develop PWMI. Thus, finding a prevention and treatment for PWMI is of major public health importance. Oligodendrocytes (OLs) are the myelinating cells of the central nervous system and play a critical role in white matter formation. It is believed that loss of Pre-oligodendrocytes (PreOLs), which are proliferative cells that develop into myelinating OLs, plays a major role in PWMI causation. Presently, there are few pharmacological approaches that specifically target PreOLs, resulting in increased proliferation of these cells and increased brain myelination. Medosome Biotec, LLC (MBT) and its research partners at the University of Florida believe a significant market exists to develop and commercialize a therapeutic treatment for white matter injury in premature infants and other brain myelination disorders. To address the shortcomings of current therapeutics, the team, led by Dr. Scott Rivkees (PI) at University of Florida, used high-throughput screening to identify compounds that to stimulate PreOL proliferation. These studies identified 4 compounds as having potential merit. In preliminary studies, we assessed myelination and toxicological properties of these compounds in brain slice and in vivo studies. These studies identified the compound K261- 0298 as the most potent stimulator of myelination. This compound was subsequently tested in short-term and long-term toxicology studies in neonatal mice and found to be non-toxic. This compound also stimulated myelination in neonatal mice. Building on our promising data, the proposed STTR fast-track application will first focus on testing this compound for efficacy in models of white matter injury in the Phase1 component. If protective, as anticipated, in the Phase 2 component, we will be to perform IND-enabling studies that will lead to an IND and clinical studies. To achieve these goals, our team will include Drs. Avery and McCardy, who direct the University of Florida Translational Drug Development Core; Charles River and ChemDiv Laboratories, which are CROs with extensive experience in the execution of pre-IND testing; and Pharmlex which has more than 10 years of experience in assisting a pharmaceutical companies in the United States and around the world to bring new therapeutics to the marketplace. This project presents an excellent opportunity to commercialize novel approaches for treating and preventing white matter injury in the tens of thousands of premature infants born and hospitalized each year. As such, we have the opportunity to develop new therapeutics for a huge unmet need.

摘要 高达30%的低出生体重早产儿表现出某种形式的脑室周围白质损伤 (PWMI)使其成为影响早产儿的最常见的脑损伤形式。PWMI与 严重的发病率，因为受影响的个人可能有严重的智力障碍和脑瘫。 突显PWMI规模的是，美国每年有超过40万名早产婴儿 各州。在这些婴儿中，有150,000名出生时有患PWMI的风险，每年将有大约25,000名儿童发育 PWMI。因此，寻找PWMI的预防和治疗方法具有重大的公共卫生意义。 少突胶质细胞是中枢神经系统的髓鞘细胞，在 白质形成。据认为，前少突胶质细胞(Preols)的丧失是指 发展为髓鞘样狼疮，在PWMI的病因中起主要作用。目前，几乎没有药理作用的药物 专门针对前OOL的方法，导致这些细胞的增殖增加和脑容量增加 髓鞘形成。 Medosome Biotec，LLC(MBT)及其佛罗里达大学的研究伙伴认为， 存在开发和商业化早产儿脑白质损伤治疗方法的市场 以及其他脑髓鞘形成障碍。为了解决目前治疗方法的不足，由Dr。 佛罗里达大学的Scott Rivkees(PI)使用高通量筛选来识别能够 刺激Preol增殖。这些研究确定了4种化合物具有潜在的价值。 在初步研究中，我们评估了这些化合物在大脑中的髓鞘形成和毒理学特性。 切片和活体研究。这些研究确定化合物K261-0298是最有效的刺激物 髓鞘形成。这种化合物随后在新生儿的短期和长期毒理学研究中进行了测试。 老鼠，并发现是无毒的。这种化合物还能刺激新生小鼠的髓鞘形成。建立在我们的 前景看好的数据，拟议的STTR快速通道应用程序将首先专注于测试这种化合物在 1期脑白质损伤模型。如果如预期的那样，在阶段2组件中进行保护， 我们将进行IND使能研究，这将导致IND和临床研究。 为了实现这些目标，我们的团队将包括佛罗里达大学的主任艾弗里博士和麦卡迪博士 转化性药物开发核心；Charles River和ChemDiv实验室，它们是CRO，拥有广泛的 有执行IND前测试的经验；以及有10年以上以下经验的Pharmlex 协助美国和世界各地的一家制药公司将新的疗法带到 市场。 这个项目提供了一个将治疗和治疗癌症的新方法商业化的绝佳机会。 预防每年出生和住院的数万早产儿的脑白质损伤。AS 这样，我们就有机会为巨大的未得到满足的需求开发新的疗法。