Novel therapeutic strategies for treatment of Angelman Syndrome

描述（由申请人提供）：Angelman综合征（AS）是一种遗传性神经系统疾病，表现为癫痫发作、共济失调、严重智力迟钝、几乎无法说话，并与其他认知障碍（如自闭症和Rett综合征）在遗传和生物化学上相关。本项目设计的最终目标是为未来人类AS干预措施的合理发展奠定基础。研究人员提出的证据表明，AS是一种潜在的可治疗的疾病。这种令人兴奋的可能性在实验上是可以测试的，这在很大程度上要归功于Ube3am-/p+小鼠模型的非凡实用性。他们开发了三种不同的治疗干预措施，以确定Ube3am-/p+小鼠模型表型是否可以通过干预(1)在遗传异常部位，(2)在功能障碍的下游生化部位，或(3)通过直接修改突触功能以产后方式恢复。由于有效治疗的可获得性通常是新生儿筛查小组纳入条件的标准，他们的目标是建立这些治疗策略的临床前可行性，确定治疗的时间限制，并确定未来人类治疗研究的最佳分子靶点。

DESCRIPTION (Provided by Applicant): Angelman syndrome (AS) is a genetic neurological disorder that presents with seizure, ataxia, severe mental retardation, virtual absence of speech, and is genetically and biochemically associated with other cognitive disorders, such as autism and Rett syndrome. This project is designed with the ultimate goal of establishing the basis for future rational development of human AS interventions. The investigators present evidence which indicates that AS is potentially a treatable disorder. This exciting possibility is experimentally testable due in large part to the extraordinary utility of the Ube3am-/p+ mouse model. They have developed three distinct therapeutic interventions to determine if the Ube3am-/p+ mouse model phenotype can be rescued in a postnatal fashion through intervention (1) at the site of genetic abnormality, (2) at the downstream biochemical site of dysfunction, or (3) by directly modifying synaptic function. Because the availability of an effective treatment is often a criterion for inclusion of a condition on a newborn screening panel, their goal is to establish the preclinical viability of these therapeutic strategies, determine the temporal constraints for treatment, and identify the optimal molecular targets for future human therapeutic research. PROJECT NARRATIVE: Angelman syndrome (AS) is a genetic neurological disorder occurring in one in 12,000 population. Independent living is not possible for adults with AS. The goals of this project are to establish the viability of three distinct therapeutic strategies to ameliorate the severe cognitive impairments exhibited by AS individuals.