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Metabolic Approach for the Development and Validation of Candidate Treatments for Phelan-McDermid Syndrome

Biochemical/Metabolic and Therapeutics
  • Primary Categories:
    • Other Therapies
  • Secondary Categories:
    • Other Therapies
Introduction:
Phelan-McDermid Syndrome (PMS) is characterized by intellectual disability, autistic features, developmental delays, and neonatal hypotonia. Extensive clinical and genetic variability in PMS has hampered treatment development. Several clinical trials have employed insulin-like growth factor 1 (IGF-1) and human growth hormone (hGH) to alleviate neurological symptoms in PMS and other disorders. We propose to employ the metabolic response of cells from individuals with PMS to candidate compounds to assess the therapeutical potential of these chemicals and identify individuals who will likely have the best treatment outcome. Our preliminary studies characterized the metabolic response to IGF-1 and hGH, stratified the PMS population based on the individual’s metabolic profile, and corrected metabolic abnormalities. We applied the same approach to other compounds used for clinical trials in PMS. 

Our study aims to (1) analyze the metabolic response of cells from individuals with PMS to candidate treatments and (2) stratify the PMS population into individuals who will potentially respond better or worse to the selected compounds. 

Methods:
First, we divided the PMS cohort into the top 25% high and 25% low responders based on their individual metabolic responses to insulin, lithium, and zinc. Then, each of the five high and five low responders' cell lines were treated with the candidate compounds at 1ng, 10ng, and 100ng. The same five control cell lines from our previous study will be used to compare the treated patient cell lines to. 

Results:
As seen in our previous study, there was a noticeable overlap among the subgroups stratified by their metabolic responses: 9 of the 12 low responders were similar across the three compounds, and 5 of the 12 high responders were similar across the three compounds. From this, we narrowed the treatment group to include 4 cell lines that were the same across the low-responder group and 1 unique cell line that was different for each compound. The high responder group included 3 cell lines that were the same across the 3 compounds and two unique cell lines for each of the 3 compounds selected. Experiments on the cell lines are currently ongoing. 

Conclusion:
This pilot project proposes a translational approach based on metabolic profiling that may address some of the clinical variability in PMS. The stratification of individuals with PMS into subgroups based on responses to candidate treatments allows for future investigations into pathogenic mechanisms, explores the response to candidate drugs within patient cells, and eventually allows for better pre-clinical selection of candidate subjects for clinical trials to optimize the beneficial activities of the therapeutic compounds and minimize their adverse effects. 

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