title: Human Pluripotent Stem Cell-derived Cortical Neurons for High Throughput Medication Screening in Autism: A Proof of Concept Study in SHANK3 Haploinsufficiency Syndrome.
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.
authors.affiliation: CECS, I-STEM, AFM, 91030 Evry Cedex, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Darville
authors.affiliation: CECS, I-STEM, AFM, 91030 Evry Cedex, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Poulet
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Robert Debré Hospital, Department of Child and Adolescent Psychiatry, Paris, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Rodet-Amsellem
authors.affiliation: CECS, I-STEM, AFM, 91030 Evry Cedex, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Chatrousse
authors.affiliation: INSERM UMR 861 I-STEM AFM, 91030 Evry Cedex, France; UEVE UMR 861 I-STEM AFM, 91030 Evry Cedex, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Pernelle
authors.affiliation: CECS, I-STEM, AFM, 91030 Evry Cedex, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Boissart
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Department of Genetic and Cytogenetic, Pitié-Salpêtrière Hospital, 75013 Paris, France; Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Inserm U 1127, CNRS UMR 7225, ICM, F-75013 Paris, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Héron
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Department of Genetic and Cytogenetic, Pitié-Salpêtrière Hospital, 75013 Paris, France; Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Inserm U 1127, CNRS UMR 7225, ICM, F-75013 Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Nava
authors.affiliation: INSERM UMR 861 I-STEM AFM, 91030 Evry Cedex, France; UEVE UMR 861 I-STEM AFM, 91030 Evry Cedex, France.
authors.forename: Anselme
authors.initials: A
authors.lastname: Perrier
authors.affiliation: INSERM UMR 861 I-STEM AFM, 91030 Evry Cedex, France; UEVE UMR 861 I-STEM AFM, 91030 Evry Cedex, France.
authors.forename: Margot
authors.initials: M
authors.lastname: Jarrige
authors.affiliation: IDR Servier, Croissy sur Seine, France.
authors.forename: Francis
authors.initials: F
authors.lastname: Cogé
authors.affiliation: IDR Servier, Croissy sur Seine, France.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Millan
authors.affiliation: Institut Pasteur, Human Genetics and Cognitive Functions Unit, Paris, France; CNRS UMR 3571: Genes, synapses and cognition, Institut Pasteur, Paris, France; University Denis Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bourgeron
authors.affiliation: INSERM UMR 861 I-STEM AFM, 91030 Evry Cedex, France; UEVE UMR 861 I-STEM AFM, 91030 Evry Cedex, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Peschanski
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Robert Debré Hospital, Department of Child and Adolescent Psychiatry, Paris, France; Institut Pasteur, Human Genetics and Cognitive Functions Unit, Paris, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Delorme
authors.affiliation: CECS, I-STEM, AFM, 91030 Evry Cedex, France. Electronic address: abenchoua@istem.fr.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Benchoua
mesh_terms: D000067877:Autism Spectrum Disorder / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D057895:Haploinsufficiency / Q000187:drug effects; D000066449:Human Embryonic Stem Cells; D006801:Humans; D008094:Lithium / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010641:Phenotype; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012720:Severity of Illness Index; D059467:Transcriptome / Q000187:drug effects; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C492357:SHANK3 protein, human; D014635:Valproic Acid; D008094:Lithium
keywords: Autism; Drug repurposing; High throughput screening; Lithium; SHANK3; Valproate