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

项目摘要 白色物质（WM）通路缺陷在神经发育障碍中很常见，包括Angelman 综合征（AS）。迄今为止进行的少数影像学研究表明，AS个体存在WM损失 体积和可能延迟的髓鞘形成。然而，这些异常仍然定义不清， 很难将它们与行为表型联系起来，因此，很难确定它们作为治疗药物的价值。 生物标志物。因此，一个主要的未满足的需要是阐明的解剖学和病理生理学基础， AS中WM的异常发展，并测试WM缺陷的预防或逆转是否会导致 核心行为领域的改善。我们对AS模型的光镜和电镜初步研究 小鼠提示轴突生长的损伤会导致髓鞘形成的延迟，并最终导致终生的 轴突口径和WM体积的缺陷。我们的初步磁共振成像（MRI）结合 来自AS儿童的扩散张量成像（DTI）数据显示WM体积存在保守缺陷， 表明髓鞘形成也有类似延迟。重要的是，我们发现在运动系统中，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模型小鼠的易处理性和我们通过Escherichangelman综合征对AS个体的独特访问 诊所（美国建立的第一家AS诊所），以揭示儿童WM缺陷的发展基础。 如.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， 相关的AS表型由轴突径向生长的缺陷和相关的生长延迟引起。 髓鞘形成，这可以通过恢复神经元中的UBE 3A表达来阻止。实现我们 本研究的目的是：（1）明确AS WM缺陷的发展轨迹和解剖学基础 模型小鼠，（2）建立这些缺陷的神经影像学相关性，并测试它们是一个神经系统缺陷的假设。 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 对AS中WM发展和运动结果的正常化进行干预。通过我们的研究， 我们寻求为AS的治疗策略提供信息，并将WM完整性作为一种新的结局指标， 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.