Periventricular White Matter Injury Prevention

描述（由申请人提供）：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的最常见的脑损伤形式1-2。PWMI包括一系列脑损伤，从弥漫性白质病变到局灶性坏死。PWMI与显著的发病率相关，因为受影响的个体可能有严重的智力损伤和脑瘫5-7。在美国，每年有超过40万婴儿早产，这凸显了早产婴儿的严重程度。在这些婴儿中，有15万名出生时就有罹患PWMI的风险，每年约有2.5万名儿童将罹患PWMI。在世界范围内，每年将有1,000,000名婴儿出生时面临患PWMI的风险，每年约有250,000名儿童将发展为PWMI。据估计，因PWMI而发展为脑瘫的婴儿的终生护理费用超过每个婴儿150万美元9。因此，找到预防和治疗PWMI的方法对公共卫生具有重要意义。少突胶质细胞（Oligodendrocytes, OLs）是中枢神经系统的髓鞘细胞，在白质形成中起关键作用10-13。据认为，由于Pre-oligodendrocytes （PreOLs）的缺失，Pre-oligodendrocytes是一种增殖细胞，可发育成髓鞘ol，在PWMI病因中起主要作用3。目前，我们还不知道专门针对preol的药理学方法，导致这些细胞增殖增加和脑髓鞘形成增加。最近，我们使用高通量筛选来鉴定会刺激PreOL增殖的化合物（“命中”）。这些研究证明是非常成功的。我们确定了二氮氧化物作为PreOL增殖的刺激剂，并表明该化合物促进小鼠PWMI模型中的髓鞘形成。二氮氧化合物通过激活KATP通道14-15起作用。我们还发现其他KATP激活剂刺激PreOL增殖。我们还在OLs中发现了KATP通道成分。因此，我们假设二氮氧化物将是一种潜在的新型治疗PWMI的药物，并且我们已经发现了一种新的治疗PWMI的方法。我们建议将我们的研究扩展到临床前，包括细胞培养和动物研究的概念验证研究中。这些研究是在美国食品和药物管理局和中枢神经系统药物化学专家的指导下进行的。更具体地说，我们将：评估二氮氧化合物的新生儿毒性。2. 定义ol期对二氮氧化合物的特异性反应。3. 评估动物模型对PWMI的保护作用。4. 评估新生儿二氮氧化合物治疗的长期效果。5. 鉴别可替代的二氮氧化物衍生物由于几个原因，这些研究将集中在先导化合物二氮氧化物上。首先，二氮氧化物是一种被美国食品和药物管理局（FDA）批准用于急性高血压和婴儿高胰岛素血症治疗的仿制药。其次，二氮氧化合物目前是高胰岛素血症婴儿的首选治疗方法，与婴儿使用二氮氧化合物相关的主要不良事件尚未报道17。第三，开发仿制药新适应症有良好的临床和商业先例18-20。第四，毒理学研究表明，二氮氧化物对新生啮齿动物的治疗指数非常广泛，LD50值大于500 mg/kg。这个值与我们研究中使用的10mg /kg有效剂量相比非常有利。因此，我们将避免在将fda批准的仿制药用于新的临床应用时，与新药开发相关的高成本和冗长的时间框架。本研究的长期目标是开发新的治疗早产儿PWMI的药物。最终，诸如此类的研究将带来重大的公共卫生发现，对治疗和预防每年成千上万出生和住院的早产儿的白质损伤有重大的公共卫生益处。

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.