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个不同的遗传风险基因，其中一个例子是SHANK3缺陷，其特征是整体发育迟缓，运动技能缺陷，语言延迟或缺失，以及ASD。根据跨部门自闭症协调委员会2011年战略计划，有必要进行转化研究，利用基因发现来开发动物模型，以了解对大脑功能的影响，并为开发新的治疗方法发现特定的目标。拟议的项目建立在先前shank3模型系统的电生理学研究的基础上，并依赖于临床前证据，证明嗜离子性谷氨酸信号被破坏，长期增强被胰岛素样生长因子-1 （IGF-1）逆转。该项目将专门试验IGF-1，这是一种商业化的化合物，已知可以促进突触成熟和可塑性，并且已经证明可以逆转Rett综合征小鼠模型的表型和电生理缺陷。该项目旨在评估用IGF-1治疗SHANK3缺陷的安全性、耐受性和可行性。我们使用广泛的行为评估系统对32名SHANK3缺陷儿童进行了评估，初步结果为完善具有明确神经生物学基础的该综合征核心特征的测量确定了重要方向，该项目还将探索对语言和社会注意力进行新颖客观评估的可行性。该项目的结果有望提供证据，证明IGF-1在SHANK3缺乏症患者的ASD核心症状中是安全、耐受性良好和有效的。根据脆性X综合征、Rett综合征和结节性硬化症新兴疗法的发展路径，我们预计SHANK3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，并可能更广泛地揭示与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.