Therapeutic agents to prevent developmental neuroimpairment after placental hormone loss

预防胎盘激素丢失后发育性神经损伤的治疗药物

基本信息

批准号：
10700989
负责人：
ANNA A PENN
金额：
$ 20.56万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-08 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10700989
关键词：
Abbreviations Acute Address Adverse effects Age Allopregnanolone Anatomy Area Behavior Behavioral Biological Markers Birth Brain Brain Injuries Cerebellum Clinical Complex Cre-LoxP Development Disease Dose Drug Delivery Systems Embryo Endocrine Endocrine Glands Engineering Enzymes Exhibits Exposure to FOS gene Female Functional disorder GABA Agents GABA-A Receptor Genes Goals Half-Life Hormones Human Impairment Infant Investigation Knowledge Link Modeling Mus Myelin Basic Proteins Nature Neurodevelopmental Deficit Neurodevelopmental Disorder Neurodevelopmental Impairment Neurologic Neurosciences Newborn Infant Outcome Pathway interactions Perinatal Pharmacological Treatment Pharmacotherapy Phase II/III Trial Placenta Placental Hormones Pregnancy Premature Birth Premature Infant Production Progesterone Property Receptor Activation Repair Complex Reporting Rest Risk Risk Factors Role Safety Synapses Testing Therapeutic Therapeutic Agents Therapeutic Effect Time Work analog autism spectrum disorder behavior test brain dysfunction cell type cellular targeting experimental study fetal ganaxolone high risk human male improved insight male molecular marker mouse model myelination neurobehavioral neuroprotection neurosteroids novel offspring postnatal pre-clinical pregnant prenatal prevent protein biomarkers protein expression public health relevance repetitive behavior response sex social cognition white matter

项目摘要

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.

项目概要/摘要早产会导致妊娠关键内分泌器官胎盘内分泌的早期丧失。功能障碍或丧失可能使成千上万的婴儿面临终生神经发育障碍的风险今年我们开始定义胎盘激素对神经发育障碍的影响，例如减少单一胎盘激素的新型小鼠模型中的自闭症谱系障碍（ASD），四氢孕酮 (ALLO) 在妊娠晚期会产生特定的长期神经发育缺陷，类似于 ALLO 是一种由黄体酮合成的神经活性类固醇。妊娠晚期的胎盘通过 GABA-A 受体 (GABAAR) 的变构激活作用于大脑；它的缺失会改变对正常发育至关重要的 GABA 环境，从而减少胎盘 ALLO 导联。与性别相关的出生后小脑髓鞘形成和自闭症谱系障碍样行为的改变，男性显示出髓鞘形成增加，女性减少，只有男性表现出类似自闭症谱系障碍的特征，包括社交我们的小鼠模型和人类早产男性小脑都存在认知缺陷和重复行为增加。显示髓鞘碱性蛋白 (MBP) 和其他髓鞘形成蛋白标记物增加，在小鼠中，这些标记物与妊娠晚期向怀孕的 Cre-Lox 母鼠注射单一 ALLO 剂量可挽救具有自闭症谱系障碍 (ASD) 样行为的小鼠。雄性 plKO 小鼠的小脑 MBP 异常和 ASD 样行为这些发现支持了我们的总体结果。改变男性后代小脑白质发育和自闭症谱系障碍行为的假设暴露于减少的胎盘 ALLO 可以进行药物治疗。是有希望的，我们已经找到了一种有效的救援模式，但仍然存在关键的知识差距在这里，我们将测试 ALLO 及其两种工程衍生物——加奈索酮 (GAN)。半衰期较长，而加波沙朵 (GAB) 主要激活突触外而非突触 GABAAR——所有这些都在其他适应症的 II/III 期试验中显示出良好的人体安全性。比较外源性 ALLO 与其类似物拯救复杂神经行为效应的能力胎盘激素损失（目标 1）并确定 ALLO 或其中之一的围产期给药时间的影响其衍生物（目标 2）对胎盘激素丢失后的神经救援程度有影响。在我们的新小鼠模型中使用小脑 MBP 表达作为初始生物标志物和神经行为进行评估正常化作为相关治疗目标的实现将提供新的机制见解。研究 GABA 能药物的必要特性，该药物能最好地挽救关键胎盘激素的损失，并采取开发新疗法以预防或修复复杂的神经发育的实际步骤胎盘丢失的后遗症。