Center for the Development of Phenotype-Based Treatments of Autism Spectrum Disorder

项目概要-总体 如果有一个问题，团结不同的和声乐社区的家庭受自闭症谱系 自闭症（ASD），尽管已经花费了数亿美元， 自闭症研究，有这么少的治疗选择，以减少残疾的亲人。 我们提出的基于表型的治疗发展中心的总体目标是 自闭症谱系障碍是为了发现ASD儿童群体的有效治疗目标， 严格定义的表型特征。很明显，有很多原因， ASD的轨迹。此外，ASD的一些最令人衰弱的方面是由于严重的共病， 焦虑、癫痫和智力残疾等病症。考虑到广泛的临床和 由于ASD的行为特征，单一治疗不太可能纠正所有这些问题。这项建议 是基于这样一个前提，即确定有临床意义的ASD亚型将有助于分析 病因学和更有效的治疗方法的发展。该中心的具体目标包括： 目标1：加强对ASD儿童，特别是智力残疾儿童的临床评估， 以更好地表征表现出临床显著焦虑的亚组。正确诊断和有效 治疗有望大大改善这些儿童的生活质量。 目的#2：进行一项为期16周的随机比较治疗试验， 焦虑症的行为干预 自闭症儿童 （BIACA），舍曲林和安慰剂在ASD青年中的应用。 目的#3：使用fMRI研究治疗疗效的神经预测因子，治疗诱导的 变化，以及目标1中定义的焦虑子类型的特征。 目的#4：对新招募的一组儿童进行行为、神经成像和电生理分析。 患有ASD的儿童（2-3岁半），大脑相对于身体尺寸不成比例地扩大。的 这一目标的主要目标是增加我们对认知功能和大脑系统的理解， 从而导致这些儿童的预后更差。这将使设计更有针对性 行为干预。虽然没有证据表明这些儿童获得标准教育的机会较少 行为疗法，已经很清楚，他们构成了一个ASD表型，受益较少， 标准干预。如何治疗这些儿童尚不清楚，该中心努力填补这一空白。 目标#5：从目标#4中研究的儿童子集中生成iPSC患者资源。 每个受试者的iPSC系将分化成神经祖细胞、少突胶质细胞和神经胶质细胞。 小胶质细胞，以确定灰色和白色物质的发展扩大的大脑的贡献。细胞 还将通过RNA测序研究品系，以确定基因网络和信号机制， 改变了这些研究可能为这种形式的ASD的药物治疗提供额外的靶点。

PROJECT SUMMARY – OVERALL If there is one issue that unites the diverse and vocal community of families affected by autism spectrum disorder (ASD), it is the frustration that despite the hundreds of millions of dollars that have been spent on autism research, there are so few treatment options available to decrease the disabilities of their loved ones. The overarching goal of our proposed Center for the Development of Phenotype-Based Treatments of Autism Spectrum Disorder is to discover targets for effective treatments in groups of children with ASD with rigorously defined phenotypic characteristics. It has become abundantly clear that there are many causes and trajectories of ASD. Moreover, some of the most debilitating aspects of ASD are due to the serious co-morbid conditions such as anxiety, seizures and intellectual disability. Considering the broad range of clinical and behavioral features of ASD, it is unlikely that a single treatment will correct all of these problems. This proposal is based on the premise that identifying clinically meaningful subtypes of ASD will facilitate the analysis of etiologies and the development of more effective therapeutics. The Specific Aims for the Center include: Aim #1: To use enhanced clinical evaluations of children with ASD, particularly those with intellectual disability, to better characterize the sub-group that exhibits clinically significant anxiety. Proper diagnosis and effective treatment holds the promise of a much-improved quality of life for these children. Aim #2: To conduct a 16-week randomized comparative treatment trial of Behavioral Intervention for Anxiety in Children with Autism (BIACA), sertraline, and pill placebo in youth with ASD. Aim #3: To use fMRI to investigate neural predictors of treatment efficacy, markers of treatment-induced change, and signatures of anxiety sub-types defined in Aim 1. Aim #4: To carry out behavioral, neuroimaging and electrophysiological analyses of a newly recruited group of children (2-3 1/2-years-old) with ASD and brains that are disproportionately enlarged relative to body size. The major goal of this aim is to increase our understanding of the cognitive functions and brain systems that are so impacted as to lead to a poorer prognosis for these children. This would inform the design of more targeted behavioral interventions. While there is no evidence that these children have less access to standard behavioral therapies, it has become clear that they constitute an ASD phenotype that benefits less from standard interventions. How to treat these children is not yet clear and the Center endeavors to fill this gap. Aim #5: To generate an iPSC patient resource from a subset of the children that are investigated in Aim #4. Lines of iPSCs for each subject will be differentiated into neural progenitor cells, oligodendrocytes and microglial cells to identify gray and white matter contributions to the development of enlarged brains. The cell lines will also be studied by RNA-sequencing to identify gene networks and signaling mechanisms that are altered. These studies may provide additional targets for pharmacological treatment of this form of ASD.