Discovery of Oligodendrocyte Stimulators

 描述(申请人提供)：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。在美国，每年有150,000名婴儿出生时就有患PWMI的风险，每年约有25,000名儿童会患上PWMI。在世界范围内，每年将有100万名婴儿出生时有患PWMI的风险，每年约有25万名儿童将患上PWMI。少突胶质细胞是中枢神经系统的髓鞘细胞，在白质形成中起着关键作用。据认为，肿瘤细胞的缺失和分化障碍 前少突胶质细胞是一种增殖性细胞，可发展为髓鞘少突胶质细胞，在PWMI的发病中起主要作用。目前，很少有针对前OLS的药理学方法，导致这些细胞的增殖和脑髓鞘形成的增加。为了解决这一缺陷，Scott Rivkees博士(佛罗里达大学)使用高通量筛选来识别会刺激Preol增殖的化合物。这些对25,000种化合物的初步研究确定二氮嗪是Preol增殖的刺激因素，并表明这种化合物促进了PWMI小鼠模型的髓鞘形成。然而，二氮卓在预防PWMI方面并不完全有效，这促使我们寻找其他可能比二氮卓更有效的化合物。Rivkees博士因此开发了610个二氮嗪小分子衍生物，并测试了它们刺激PreOL增殖的能力。这些研究确定了25种促进Preol增殖的化合物，其中4种(指定为先导化合物)明显强于二氮嗪。总部位于佛罗里达州的小型企业Medosome Biotec，LLC及其在佛罗里达大学的研究伙伴(Rivkees博士)假定，这些先导化合物有可能成为治疗髓鞘形成障碍的有效新疗法。在这些第一阶段的STTR研究中，该团队建议评估我们的先导化合物的毒性和髓鞘形成潜力。我们将：1.评估脑片中的髓鞘形成2.评估体内毒理学和髓鞘形成潜能这项工作的长期目标是开发和商业化治疗早产儿脑白质损伤和其他髓鞘形成障碍的新型治疗药物。这项STTR奖将把Medosome LLC的科学家和Rivkees博士(佛罗里达大学)联系在一起，Rivkees博士是白质损伤领域的领先专家。

 DESCRIPTION (provided by applicant): 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. In the US, 150,000 infants per year are born at risk for PWMI, and about 25,000 children per year will develop PWMI. World-wide, 1,000,000 infants will be born each year at risk for PWMI, and about 250,000 children per year will develop PWMI. 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 and impaired differentiation 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. To address this short coming, Dr. Scott Rivkees (University of Florida) used high-throughput screening to identify compounds that would stimulate PreOL proliferation. These initial studies of 25,000 compounds identified diazoxide as a stimulator of PreOL proliferation, and showed that this compound promotes myelination in a murine model of PWMI. However, diazoxide was not completely effective in preventing PWMI, leading us to look for other compounds that are potentially even more effective than diazoxide. Dr. Rivkees thus developed 610 small molecule derivatives of diazoxide that were tested for their ability stimulates the proliferation of PreOLs. These studies identified 25 compounds that stimulated PreOL proliferation, 4 of which (designated lead compounds) were significantly more potent than diazoxide. Medosome Biotec, LLC, a Florida-based small business, and its research partner at the University of Florida (Dr. Rivkees) postulate these lead compounds have the potential to be effective new therapeutics for disorders of myelination. In these Phase I STTR studies, the team proposes to assess the toxicity and myelination potential of our lead compounds. We will: 1. Evaluate myelination in brain slices 2. Assess in vivo toxicology and myelination potential The long-term goal of this work is to develop and commercialize novel therapeutic agents for the treatment of white matter injury in premature infants and other disorders of myelination. This STTR award will link scientists at Medosome LLC and Dr. Rivkees (University of Florida), who is a leading expert in the area of white matter injury.