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

• 批准号: 10510450
• 负责人: ANNA A PENN
• 金额: $ 24.68万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 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/10510450
• 关键词: Acute; Address; Adverse effects; Age; Allopregnanolone; Anatomy; Area; Behavior; Behavioral; Biological Markers; Birth; Birth Place; 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; Life; 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; 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

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.

项目总结/摘要 早产会导致早期失去怀孕的关键内分泌器官胎盘。胎盘内分泌 功能障碍或丧失可能使数千名婴儿面临终生神经发育障碍的风险 年我们已经开始确定胎盘激素对神经发育障碍的作用，如 自闭症谱系障碍（ASD）在一种新的小鼠模型。减少一种胎盘激素， 别孕烯醇酮（ALLO），在妊娠后期产生特定的长期神经发育缺陷， 早产和ASD中出现的症状。ALLO是一种由孕酮合成的神经活性类固醇， 妊娠晚期的胎盘。它通过GABA-A受体（GABAAR）的变构激活作用于大脑; 它的丧失可以改变对正常发育至关重要的GABA能环境。胎盘ALLO导联减少 出生后小脑髓鞘形成和ASD样行为的改变与性别相关， 显示髓鞘形成增加，女性减少，只有男性表现出ASD样特征，包括社会 认知缺陷和重复行为增加。我们的小鼠模型和人类早产男性小脑 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， 有自闭症的人在妊娠晚期，向妊娠Cre-Lox母鼠注射单次ALLO剂量， 小脑MBP异常和ASD样行为。这些发现支持了我们的总体观点。 在雄性后代中观察到小脑白色发育和ASD样行为改变的假说 暴露于减少的胎盘ALLO的患者适合于药物治疗。这些最初的拯救实验 是有希望的，我们已经找到了一个有效的救援模式，但仍然存在关键的知识差距， 必须加以解决。在这里，我们将测试ALLO及其两个工程衍生物-加奈索酮（GAN）， 具有较长的半衰期，加波沙朵（GAB）主要激活突触外而不是突触 GABAAR-所有这些都在II/III期试验中显示出良好的人体安全性。我们将 比较外源性ALLO与其类似物拯救复杂的神经行为效应的能力。 胎盘激素丢失（目的1），并确定ALLO或以下之一的围产期给药时间的影响 其衍生物（目的2）对胎盘激素丧失后神经救援程度的影响。这些特工将 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进行评估， 正常化作为相关的治疗目标。实现这些目标将提供新的机械见解 GABA能药物的必要特性，最好地挽救关键胎盘激素的损失， 为开发新的治疗方法以预防或修复复杂的神经发育障碍迈出了实际的一步。 胎盘丢失的后遗症