Prevention of White Matter Injury in Premature Infants

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色物质损伤 PWMI是影响早产儿的最常见的脑损伤形式。PWMI与 发病率很高，因为受影响的人可能有严重的智力障碍和脑瘫。 在美国，每年有40多万婴儿早产，这突出了PWMI的严重性。 States.在这些婴儿中，有15万人出生时有患PWMI的风险，每年约有25，000名儿童将患上PWMI。 PWMI。因此，寻找预防和治疗PWMI的方法具有重大的公共卫生意义。 少突胶质细胞（Oligodendrocytes，OL）是中枢神经系统的髓鞘形成细胞，在中枢神经系统中起关键作用。 形成白色物质。据信，前少突胶质细胞（PreOL）的损失是导致细胞凋亡的重要原因， 发展成髓鞘形成的OL，在PWMI病因中起主要作用。目前，几乎没有药理学 特异性靶向PreOL的方法，导致这些细胞的增殖增加， 髓鞘形成 Medosome Biotec，LLC（MBT）及其在佛罗里达大学的研究合作伙伴认为， 存在市场来开发和商业化早产儿白色物质损伤的治疗性治疗 和其他脑髓鞘形成障碍。为了解决目前治疗方法的缺点，由Dr。 佛罗里达大学的斯科特·里夫斯（PI）使用高通量筛选来鉴定化合物， 刺激PreOL增殖。这些研究确定了4种具有潜在价值的化合物。 在初步研究中，我们评估了这些化合物在脑中的髓鞘形成和毒理学性质， 切片和体内研究。这些研究确定化合物K261- 0298是最有效的刺激剂。 髓鞘形成该化合物随后在新生儿中进行了短期和长期毒理学研究。 小鼠，并发现无毒。该化合物还刺激了新生小鼠的髓鞘形成。充分发挥两国 有希望的数据，拟议的STTR快速通道应用将首先集中在测试这种化合物的疗效， 阶段1组件中的白色物质损伤模型。如果保护，如预期的那样，在第2阶段组件中， 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，我们的团队将包括艾弗里博士和麦卡迪博士，他们指导佛罗里达大学 转化药物开发核心; Charles River和ChemDiv实验室，它们是具有广泛 在执行IND前测试方面的经验;以及Pharmlex，其在以下方面拥有超过10年的经验： 帮助美国和世界各地的制药公司将新的治疗方法带到 市场。 该项目提供了一个极好的机会，使治疗和治疗癌症的新方法商业化， 预防每年出生和住院的数万名早产儿的白色物质损伤。作为 因此，我们有机会开发新的治疗方法，以满足巨大的未满足的需求。

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.