White Matter Pathology in Angelman Syndrome and Its Potential as an Outcome Measure in Clinical Trials

项目概要 白质 (WM) 通路缺陷在神经发育障碍中很常见，包括 Angelman 综合症（AS）。迄今为止进行的少数影像学研究表明，AS 个体的 WM 丧失 体积和可能延迟髓鞘形成。然而，这些异常的定义仍然不明确，使得 很难将它们与行为表型联系起来，因此很难确定它们的治疗价值 生物标志物。因此，一个未满足的主要需求是阐明其解剖学和病理生理学基础 AS 中 WM 发展异常，并测试预防或逆转 WM 缺陷是否会导致 核心行为领域的改善。我们对 AS 模型的初步光学和电子显微镜研究 小鼠表明，轴突生长受损会导致髓鞘形成延迟，并最终导致终生 轴突口径和 WM 体积的缺陷。我们的初步磁共振成像 (MRI) 结合 AS 儿童的弥散张量成像 (DTI) 数据表明 WM 体积和 表明髓鞘形成有类似的延迟。重要的是，我们发现运动系统中 WM 损伤的程度 与 AS 患者运动功能障碍的严重程度密切相关。在这里我们将利用实验 AS 模型小鼠的易驯化性以及我们通过 UNC Angelman 综合症获得 AS 个体的独特途径 诊所（美国第一家 AS 诊所）揭示 WM 缺陷的发展基础 作为。具体来说，我们将测试我们的数据驱动的中心假设，即 WM 通路异常和 相关的 AS 表型源于轴突径向生长的缺陷和相关的轴突生长延迟 髓鞘形成，可以通过恢复神经元中 UBE3A 的表达来预防。为了实现我们的 目标，我们的目标是 (1) 定义 AS 中 WM 缺陷的发育轨迹和潜在解剖学基础 模型小鼠，(2) 建立这些缺陷的神经影像学相关性并测试它们是 AS 儿童运动表型的生物标志物，以及 (3) 模拟早期与晚期治疗的疗效 干预以实现 AS 中 WM 发展和运动结果的正常化。通过我们的研究， 我们寻求为 AS 的治疗策略提供信息，并建立 WM 完整性作为 AS 的一种新的结果衡量标准 即将进行的 AS 临床试验。

PROJECT SUMMARY White matter (WM) pathway deficits are common in neurodevelopmental disorders, including Angelman syndrome (AS). The few imaging studies performed to date suggest that AS individuals have loss of WM volume and possibly delayed myelination. However, these abnormalities remain poorly defined, making it difficult to link them to behavioral phenotypes and, consequently, to establish their value as therapeutic biomarkers. Accordingly, a major unmet need is to elucidate the anatomical and pathophysiological basis of abnormal WM development in AS, and to test whether prevention or reversal of WM deficits leads to improvement in core behavioral domains. Our preliminary light and electron microscopy studies of AS model mice suggest that impairments in axon growth precipitate delays in myelination and culminate in lifelong deficits in axon caliber and WM volume. Our preliminary magnetic resonance imaging (MRI) coupled with diffusion tensor imaging (DTI) data from children with AS demonstrate a conserved deficit in WM volume and indicate a similar delay in myelination. Importantly, we find in motor systems that the degree of WM insult strongly correlates with the severity of motor dysfunction in AS patients. Here we will leverage the experimental tractability of AS model mice and our unique access to AS individuals through the UNC Angelman Syndrome Clinic (the first AS clinic established in the United States) to reveal the developmental basis of WM deficits in AS. Specifically, we will test our data-driven central hypothesis that WM pathway abnormalities and associated AS phenotypes arise from deficits in the radial growth of axons and associated delays in myelination, which can be prevented by reinstatement of UBE3A expression in neurons. To achieve our goals, we aim to (1) Define the developmental trajectory and underlying anatomical basis for WM deficits in AS model mice, (2) Establish neuroimaging correlates of these deficits and test the hypothesis that they are a biomarker for motor phenotypes in children with AS, and (3) Model the efficacy of early versus late therapeutic intervention toward the normalization of WM development and motor outcomes in AS. Through our research, we seek to inform treatment strategies for AS and to establish WM integrity as a novel outcome measure for upcoming AS clinical trials.