Therapeutic agents to prevent developmental neuroimpairment after placental hormone loss

项目摘要/摘要 早产会导致妊娠的关键内分泌器官--胎盘过早丧失。胎盘内分泌 功能障碍或缺失可能会使成千上万的婴儿面临终身神经发育障碍的风险 年。我们已经开始定义胎盘激素对神经发育障碍的作用，例如 一种新的小鼠模型中的自闭症谱系障碍(Asd)。减少一种单一的胎盘激素， 别孕酮(Allo)在妊娠晚期会产生特定的长期神经发育缺陷，类似于 在早产和自闭症中出现的那些。ALLO是一种神经活性类固醇，由孕酮通过 妊娠晚期的胎盘。它通过变构激活GABA-A受体(GABAAR)作用于大脑； 它的丧失可能会改变对正常发育至关重要的GABA能环境。胎盘异位基因铅减少 与出生后小脑髓鞘形成和自闭症样行为的改变有关，与男性 表现出髓鞘形成增加，女性减少，只有男性表现出类似ASD的特征，包括社交 认知缺陷和重复行为增加。我们的小鼠模型和人类早产雄性小脑 显示髓鞘碱性蛋白(MBP)和其他髓鞘形成的蛋白质标记物增加，在小鼠中，这与 有类似ASD的行为。在妊娠晚期向CRE-Lox母鼠注射单剂Allo拯救了 雄性plKO小鼠小脑MBP异常和ASD样行为。这些发现支持我们总体上 改变男性后代小脑白质发育和ASD样行为的假说 暴露于减少胎盘的Allo可接受药物治疗。这些最初的救援实验 是有希望的，我们已经找到了一种有效的救援范例，但仍然存在关键的知识缺口， 必须解决的问题。在这里，我们将测试Allo和它的两个工程衍生品-Ganaxolone(GAN)，它 有更长的半衰期，和加博沙多(GAB)，它主要激活突触外而不是突触 GABAARs--在其他适应症的II/III期试验中，所有这些药物都显示出良好的人体安全性。我们会 比较外源性等位基因与其类似物挽救复杂神经行为效应的能力 胎盘激素丢失(目标1)，并确定围产期服用Allo或以下一种药物的时机的影响 其衍生物(目标2)对胎盘激素丢失后神经抢救程度的影响。这些特工将会是 在我们的新小鼠模型中，使用小脑MBP表达作为初始生物标记物和神经行为进行评估 以正常化为相关治疗目标。实现这些目标将提供新的机械论见解 研究GABA能药物的必要特性，以最好地挽救关键胎盘激素的损失，并服用 朝着开发预防或修复复杂神经发育的新疗法迈出了实际的一步 胎盘丢失的后遗症。

PROJECT SUMMARY/ABSTRACT Premature birth results in early loss of the key endocrine organ of pregnancy, the placenta. Placental endocrine dysfunction or loss may place many thousands of infants at risk of life-long neurodevelopmental impairment each year. We have begun to define the placental hormone contribution to neurodevelopmental disorders, such as autism spectrum disorders (ASD) in a novel mouse model. Reducing a single placental hormone, allopregnanolone (ALLO), in late gestation produces specific long-term neurodevelopmental deficits that mimic those seen in preterm birth and ASD. ALLO is a neuroactive steroid synthesized from progesterone by the placenta during late gestation. It acts on the brain through allosteric activation of GABA-A receptor (GABAAR); its loss can alter the GABAergic milieu that is critical for normal development. Decreased placental ALLO leads to alterations in postnatal cerebellar myelination and ASD-like behaviors in a sex-linked manner, with males showing increased myelination, females a decrease and only males exhibiting ASD-like features including social cognition deficits and increased repetitive behavior. Both our mouse model and human preterm male cerebellum showed increased Myelin Basic Protein (MBP) and other protein markers of myelination that, in mice, correlated with ASD-like behavior. A single ALLO dose injected into pregnant Cre-Lox dams in late gestation rescued the cerebellar MBP abnormalities and ASD-like behaviors in male plKO mice. These findings support our overall hypothesis that altered cerebellar white matter development and ASD-like behaviors seen in male offspring exposed to reduced placental ALLO is amenable to pharmacological treatment. These initial rescue experiments are promising and we have found a rescue paradigm that works, but there are still critical knowledge gaps that must be addressed. Here we will test ALLO and two of its engineered derivatives—ganaxolone (GAN), which has a longer half-life, and gaboxadol (GAB), which activates primarily extrasynaptic rather than synaptic GABAARs-- all of which have shown good human safety profiles in phase II/III trials for other indications. We will compare the ability of exogenous ALLO versus its analogues to rescue the complex neurobehavioral effects of placental hormone loss (Aim 1) and determine the effects of perinatal timing of administration of ALLO or one of its derivatives (Aim 2) on degree of neurological rescue after placental hormone loss. These agents will be assessed in our new mouse model using cerebellar MBP expression as an initial biomarker and neurobehavioral normalization as the relevant therapeutic goal. Accomplishing these aims will provide new mechanistic insights into the necessary properties of GABAergic agents that best rescue loss of a key placental hormone and take a practical step towards development of new treatments to prevent or repair the complex neurodevelopmental sequelae of placental loss.