Novel Findings in Phelan-Mcdermid Syndrome and Their Translation into Therapeutics

Background: Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder characterized by intellectual disability, hypotonia, delayed or absent speech, and autistic features. Within the chromosomal region implicated in PMS, SHANK3 has been identified as the critical gene whose haploinsufficiency causes the neurological and behavioral symptoms.

Objectives: We investigate all aspects of the PMS pathophysiology through an integrated approach that includes patient assessments, genetics and genomics, design and characterization of cell and animal models, and drug screening. Basic scientists work closely with clinicians and clinician scientists with the ultimate goal of translation of research findings into improved therapeutics.

Methods: The genetics of PMS is investigated with tools that can identify a wide spectrum of mutations, from single-nucleotide variants to copy number variants. We also characterize, molecularly and phenotypically, cell models for PMS, including neural progenitor cells (NPCs) differentiated from iPSC cells isolated from patients with PMS and control individuals, and control NPCs silenced for SHANK3. We use various mouse and rat lines as models to study the changes in gene expression, cell and circuit physiology and behaviors due to Shank3 reduction or loss. All these models are also used for drug testing. We carry out deep phenotyping of patients and have begun both a multi-site study of PMS, and a longitudinal study in PMS.

Results: The integration of genetic and clinical findings is extending the mutational landscape for PMS and is revealing genotype-phenotype relationships in PMS. Three iPSC-derived NPCs lines have been derived from PMS patients and respective controls, and we expect a total of 12 to be completed by the end of next year. These cells, as well as iPSC-derived NPCs silenced for SHANK3, will be subjected to deep characterization, including RNAseq and phenotyping of cellular readouts.  The generation and characterization of the Shank3 mouse and rat models demonstrated the deleterious effect of Shank3-deficiency on social behavior, synaptic plasticity, and seizures.  IGF-1 treatments in the Shank3-mouse model showed significant beneficial effects on motor performance and synaptic plasticity deficits and oxytocin treatment in the Shank3-rat model reversed the synaptic plasticity and the social behavior deficits. Pilot clinical trials of IGF-1 in PMS show safety and some preliminary evidence of efficacy. Larger trials are underway.

Conclusions: Our studies are uncovering the pathways and brain circuits altered in the PMS and are revealing the beneficial effects of IGF-1 and oxytocin in PMS models. We see preliminary evidence of efficacy of IGF-1 in patients with PMS.