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

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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.