Human Pluripotent Stem Cell-derived Cortical Neurons for High Throughput Medication Screening in Autism: A Proof of Concept Study in SHANK3 Haploinsufficiency Syndrome

Overview

Journal EBioMedicine

Specialty Biomedical Engineering

Date 2016 Jun 23

PMID 27333044

Citations 46

Authors

Helene Darville

Aurelie Poulet

Frederique Rodet-Amsellem

Laure Chatrousse

Julie Pernelle

Claire Boissart

Delphine Heron

Caroline Nava

Anselme Perrier

Margot Jarrige

Francis Coge

Mark J Millan

Thomas Bourgeron

Marc Peschanski

Richard Delorme

Alexandra Benchoua

Affiliations

Soon will be listed here.

Abstract

Autism spectrum disorders affect millions of individuals worldwide, but their heterogeneity complicates therapeutic intervention that is essentially symptomatic. A versatile yet relevant model to rationally screen among hundreds of therapeutic options would help improving clinical practice. Here we investigated whether neurons differentiated from pluripotent stem cells can provide such a tool using SHANK3 haploinsufficiency as a proof of principle. A library of compounds was screened for potential to increase SHANK3 mRNA content in neurons differentiated from control human embryonic stem cells. Using induced pluripotent stem cell technology, active compounds were then evaluated for efficacy in correcting dysfunctional networks of neurons differentiated from individuals with deleterious point mutations of SHANK3. Among 202 compounds tested, lithium and valproic acid showed the best efficacy at corrected SHANK3 haploinsufficiency associated phenotypes in cellulo. Lithium pharmacotherapy was subsequently provided to one patient and, after one year, an encouraging decrease in autism severity was observed. This demonstrated that pluripotent stem cell-derived neurons provide a novel cellular paradigm exploitable in the search for specific disease-modifying treatments.

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