Piloting Treatment with Insulin-Like Growth Factor-1 in Phelan-McDermid Syndrome

描述（由申请人提供）：自闭症谱系障碍（ASD）现在可以被认为具有多种不同的遗传风险基因，一个例子是SHANK 3缺陷，其特征在于全面发育迟缓，运动技能缺陷，言语延迟或缺失，以及ASD。根据机构间自闭症协调委员会2011年战略计划，需要利用遗传发现进行转化研究，以开发动物模型，了解对大脑功能的影响，并发现开发新疗法的特定靶点。拟议的项目建立在以前的Shank 3模型系统中的电生理学研究的基础上，并依赖于破坏离子型谷氨酸信号传导和受损的长时程增强的临床前证据，这些证据被胰岛素样生长因子-1（IGF-1）逆转。该项目将专门试点IGF-1，这是一种商业上可用的化合物，已知可促进突触成熟和可塑性，并已被证明可逆转Rett综合征小鼠模型的表型和电生理缺陷。该项目旨在评估IGF-1治疗SHANK 3缺乏症的安全性，耐受性和可行性。我们使用广泛的行为评估电池评估32名SHANK 3缺陷儿童的初步结果已经确定了重要的方向，用于改进具有明确神经生物学基础的综合征核心特征的测量，该项目还将探索语言和社会注意力的新颖和客观评估的可行性。该项目的结果预计将提供证据表明，IGF-1是安全的，耐受性良好，并有效地针对SHANK 3缺陷的ASD的核心症状。根据脆性X综合征、Rett综合征和结节性硬化症的新兴治疗方法的发展途径，我们预计SHANK 3缺陷中的IGF-1有可能代表ASD单基因疾病治疗的下一个前沿，并可能更广泛地阐明与ASD治疗相关的途径。

DESCRIPTION (provided by applicant): Autism spectrum disorders (ASD) can now be conceived of as having multiple distinct genetic risk genes and one example is SHANK3 deficiency, characterized by global developmental delay, motor skills deficits, delayed or absent speech, and ASD. According to the Interagency Autism Coordinating Committee 2011 Strategic Plan, there is a need for translational research that takes advantage of genetic findings in order to develop animal models to understand the effects on brain function and discover specific targets for the development of novel therapeutics. The proposed project builds on previous electrophysiological studies in the Shank3-model system and relies on preclinical evidence of disrupted ionotropic glutamate signaling and impaired long term potentiation that is reversed with insulin-like growth factor-1 (IGF-1). This project will specifically pilot IGF-1, a commercialy available compound that is known to promote synaptic maturation and plasticity and has already been shown to reverse phenotypic and electrophysiological deficits in mouse models of Rett Syndrome. The project aims to assess the safety, tolerability, and feasibility of treatment with IGF-1 in SHANK3 deficiency. Preliminary results from our work evaluating 32 children with SHANK3 deficiency using a broad behavioral assessment battery has identified important directions for refining the measurement of core features of the syndrome with clear neurobiological underpinnings and this project will also explore the feasibility of novel and objective assessments of language and social attention. Results from this project are expected to provide evidence that IGF-1 is safe, well tolerated, and efficacious in targeting core symptoms of ASD in SHANK3 deficiency. Following the development pathway of emerging therapeutics in Fragile X syndrome, Rett syndrome, and tuberous sclerosis, we anticipate that IGF-1 in SHANK3 deficiency has the potential to represent the next forefront in the treatment of single gene disorders in ASD and may shed light on pathways relevant to the treatment of ASD more broadly.