Periventricular White Matter Injury Prevention

描述(申请人提供)：5%至20%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1-2的最常见的脑损伤形式。PWMI包括一系列的脑损伤，从弥漫性白质疾病到局灶性坏死2-4。PWMI与显著的发病率有关，因为受影响的个人可能有严重的智能障碍和脑瘫5-7。突显PWMI严重程度的是，美国每年有超过40万名婴儿早产8。在这些婴儿中，有15万出生时就有患PWMI的风险，每年约有2.5万名儿童会患上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。据估计，因PWMI而发展为脑性瘫痪的婴儿的一生护理费用超过每个婴儿150万美元。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，在白质形成中起着关键作用10-13。据认为，由于前少突胶质细胞(PreOdendrocell，PreOLs)的丢失，这些细胞是发展成髓鞘OLS的增殖性细胞，在PWMI的原因3中起主要作用。目前，我们还不知道针对前少突胶质细胞的药物治疗方法，导致这些细胞的增殖增加和脑髓鞘形成的增加。最近，我们使用高通量筛选来鉴定能够刺激Preol增殖的化合物(HITS)。事实证明，这些研究非常成功。我们确定二氮嗪是Preol增殖的刺激物，并表明该化合物促进了PWMI小鼠模型的髓鞘形成。二氮嗪通过激活KATP通道14-15起作用。我们还发现，其他KATP激动剂可以刺激Preol的增殖。我们还鉴定了OLS中的KATP通道成分。因此，我们假设二氮嗪将是一种潜在的治疗PWMI的新方法，并且我们已经发现了一种治疗PWMI的新方法。我们建议将我们对二氮嗪的研究扩展到临床前、概念验证研究中，包括细胞培养和动物研究。这些研究是在美国食品和药物管理局和中枢神经系统(CNS)药物化学专家的指导下进行的。更具体地说，我们将：1.评估二氮卓新生儿毒性。2.确定二氮嗪对OL期的特异性反应。3.在动物模型上评价对PWMI的保护作用。4.评估新生儿二氮卓治疗的远期疗效。5.确定替代二氮杂衍生物这些研究将集中于先导化合物二氮杂，原因有几个。首先，二氮嗪是美国食品和药物管理局(FDA)批准的一种仿制药，用于急性治疗高血压和15-16岁婴儿的高胰岛素血症。第二，二氮嗪目前是高胰岛素血症婴儿的首选治疗方法，与婴儿使用二氮卓有关的主要不良事件尚未报道17。第三，开发仿制药的新用法具有良好的临床和商业先例18-20。第四，毒理学研究表明，二氮嗪具有非常广泛的治疗指数，对新生啮齿动物的LD50值超过500毫克/公斤。与我们研究中使用的有效剂量10毫克/公斤相比，这个值非常有利。因此，我们将避免与新药开发相关的高昂成本和漫长的时间框架，将FDA批准的仿制药应用于新的临床应用。这项工作的长期目标是开发治疗早产儿PWMI的新型治疗剂。最终，这样的研究将导致重要的发现，对治疗和预防每年出生和住院的数万名早产儿的脑白质损伤具有重大的公共健康益处。 公共卫生相关性：这项工作的目标是评估二氮卓作为治疗早产儿脑白质损伤的治疗剂的有效性。我们预计，这些研究将导致开发新的方法来治疗和预防每年出生和住院的数万早产儿的脑白质损伤。

DESCRIPTION (provided by applicant): Five to twenty percent 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 1-2. PWMI includes a spectrum of brain injury ranging from diffuse white matter disease to focal necrosis 2-4. PWMI is associated with significant morbidity, as affected individuals may have profound intellectual impairment and cerebral palsy 5-7. Highlighting the magnitude of PWMI, each year in the United States more than 400,000 infants are born prematurely 8. Of these infants, 150,000 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. It is estimated the lifetime care costs for infants who develop cerebral palsy due to PWMI exceeds $1.5 million per infant9. 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 10-13. It is believed that due to loss of Pre-oligodendrocytes (PreOLs), which are proliferative cells that develop into myelinating OLs, plays a major role in PWMI causation 3. Presently, we are unaware of pharmacological approaches that specifically target PreOLs, resulting in increased proliferation of these cells and increased brain myelination. Recently, we used high-throughput screening to identify compounds ("hits") that would stimulate PreOL proliferation. These studies proved to be highly successful. We identified diazoxide as a stimulator of PreOL proliferation and showed that this compound promotes myelination in a murine model of PWMI. Diazoxide acts by activating KATP channels 14-15. We also found that other KATP activators stimulate PreOL proliferation. We also identified KATP channel component in OLs. We thus hypothesize that diazoxide will be a potential novel therapeutic for PWMI, and that we have discovered a novel therapy for PWMI. We propose to extend our study of diazoxide in preclinical, proof-of-concept studies involving cell culture and animal studies. These studies have been developed with direction form the US Food and Drug Administration and experts in central nervous system (CNS) medicinal chemistry. More specifically we will: 1. Assess diazoxide neonatal toxicity. 2. Define OL-stage specific responses to diazoxide. 3. Evaluate protection against PWMI in animal models. 4. Assess long-term effects of neonatal diazoxide therapy. 5. Identify alternative diazoxide-derivative compounds These studies will focus on the lead compound diazoxide for several reasons. First, diazoxide is a generic drug that is approved by the US Food and Drug Administration (FDA) for the acute treatment of hypertension and the treatment of hyperinsulinism in infants15-16. Second, diazoxide is currently the treatment of choice for infants with hyperinsulinism, and major adverse events related to diazoxide use in infants have not been reported 17. Third, there is favorable clinical and commercial precedent for developing new use indications for generic drugs18-20. Fourth, toxicology studies show that diazoxide has a very broad therapeutic index, with an LD50 value greater than 500 mg/kg in neonatal rodents. This value compares very favorably with the effective 10 mg/kg dose used in our studies. As such, we will avoid the high costs and the lengthy time frame associated with new drug development in applying FDA-approved, generic drugs for novel clinical applications. The long-term goal of this work is to develop novel therapeutic agent for the treatment of PWMI in premature infants. Ultimately, research such as this will lead to important discoveries with significant public health benefit for treating and preventing white matter injury in the tens of thousands of premature infants born and hospitalized each year. PUBLIC HEALTH RELEVANCE: The goal of this work is to assess the utility of diazoxide as a therapeutic agent for the treatment of white matter injuries in premature infants. We anticipate that these studies will lead to the development of novel approaches for treating and preventing white matter injury in the tens of thousands of premature infants born and hospitalized each year.