eP002: Pilot study of insulin-like growth factor 1 on differing metabolic responders with Phelan-McDermid syndrome: Preliminary results


      Phelan-McDermid Syndrome (PMS) is a rare genetic neurodevelopmental disorder with variable clinical manifestations. These features can include intellectual disability, autism, developmental delays, and seizures. PMS can be caused by deletions within the 22q13 region or pathogenic variants of the SH3 and multiple ankyrin repeat domains 3 (SHANK3) gene, which plays an important role in the development, function, and maintenance of excitatory synapses. While there are currently no approved treatments for PMS, one potential therapy is insulin-like growth factor-1 (IGF-1). IGF-1 is a protein that supports the development of mature synapses and regulates cellular function via several regulatory pathways. IGF-1 has been used to promote growth in children with short stature due to IGF-1 deficiency or growth hormone (GH) deficiency, but only for a limited amount of time. Animal models of PMS have shown the rescue of neurological and behavioral functions following treatment with IGF-1. We aim to explore the impact of IGF-1 treatment on the metabolic response to a large panel of metabolites and effectors to determine if IGF-1 can rescue the abnormal metabolic pathways present in individuals with PMS.


      Previous experiments employing the Biolog Phenotype Mammalian Microarrays (PM-Ms) assessed the metabolic profile of lymphoblastoid cell lines (LCLs) from individuals with PMS: results from these experiments were analyzed to identify five subjects who were high metabolizers of IGF-1 and five that were low metabolizers. The Biolog data for those ten people were evaluated across all eight PM-M Biolog plates to determine which plates had the greatest differences when compared to a group of 50 controls.


      Ten abnormal metabolic responders were identified from a PMS cohort of 54 individuals. Five controls were randomly selected from a cohort of 50 people. Four Biolog PM-M plates were identified as plates of interest with the effectors being carbon energy sources, hormones, growth factors and cytokines (PM-M1, and PM-M6 to M8). The LCLs of these ten subjects with PMS showing abnormal metabolic response to IGF-1 will be utilized in our pilot study aimed at addressing the efficacy of IGF-1 treatment with the potential to identify ideal candidates for the treatment.


      The 15 selected LCLs will be used to determine the effect IGF-1 has on the differing metabolic profile of the high, low, and average responders.