title: Large-scale screening using familial dysautonomia induced pluripotent stem cells identifies compounds that rescue IKBKAP expression.
abstract: Patient-specific induced pluripotent stem cells (iPSCs) represent a novel system for modeling human genetic disease and could provide a source of cells for large-scale drug-discovery screens. Here we demonstrate the feasibility of performing a primary screen in neural crest precursors derived from iPSCs that were generated from individuals with familial dysautonomia (FD), a rare, fatal genetic disorder affecting neural crest lineages. We tested 6,912 small-molecule compounds and characterized eight that rescued expression of IKBKAP, the gene responsible for FD. One of the hits, SKF-86466, was found to induce IKBKAP transcription through modulation of intracellular cAMP levels and PKA-dependent CREB phosphorylation. SKF-86466 also rescued IKAP protein expression and the disease-specific loss of autonomic neuronal marker expression. Our data implicate alpha-2 adrenergic receptor activity in regulating IKBKAP expression and demonstrate that small-molecule discovery using an iPSC-based disease model can identify candidate drugs for potential therapeutic intervention.
authors.affiliation: Center for Stem Cell Biology, Sloan-Kettering Institute for Cancer Research, New York, New York, USA. glee48@jhmi.edu
authors.forename: Gabsang
authors.initials: G
authors.lastname: Lee
authors.forename: Christina N
authors.initials: CN
authors.lastname: Ramirez
authors.forename: Hyesoo
authors.initials: H
authors.lastname: Kim
authors.forename: Nadja
authors.initials: N
authors.lastname: Zeltner
authors.forename: Becky
authors.initials: B
authors.lastname: Liu
authors.forename: Constantin
authors.initials: C
authors.lastname: Radu
authors.forename: Bhavneet
authors.initials: B
authors.lastname: Bhinder
authors.forename: Yong Jun
authors.initials: YJ
authors.lastname: Kim
authors.forename: In Young
authors.initials: IY
authors.lastname: Choi
authors.forename: Bipasha
authors.initials: B
authors.lastname: Mukherjee-Clavin
authors.forename: Hakim
authors.initials: H
authors.lastname: Djaballah
authors.forename: Lorenz
authors.initials: L
authors.lastname: Studer
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology; D001709:Biotechnology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D004402:Dysautonomia, Familial / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D057166:High-Throughput Screening Assays; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009432:Neural Crest / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017354:Point Mutation; D035602:Transcriptional Elongation Factors
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D002352:Carrier Proteins; C114720:Elp1 protein, human; D050505:Mutant Proteins; D035602:Transcriptional Elongation Factors