Large-scale screening using familial dysautonomia induced pluripotent stem cells identifies compounds that rescue IKBKAP expression

Nat Biotechnol. 2012 Dec;30(12):1244-8. doi: 10.1038/nbt.2435. Epub 2012 Nov 25.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-2 Receptor Antagonists / pharmacology
  • Biotechnology
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism*
  • Cells, Cultured
  • Drug Evaluation, Preclinical
  • Dysautonomia, Familial / drug therapy*
  • Dysautonomia, Familial / genetics
  • Dysautonomia, Familial / metabolism*
  • Dysautonomia, Familial / pathology
  • Gene Expression / drug effects
  • High-Throughput Screening Assays
  • Humans
  • Induced Pluripotent Stem Cells / drug effects*
  • Induced Pluripotent Stem Cells / metabolism*
  • Induced Pluripotent Stem Cells / pathology
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Neural Crest / drug effects
  • Neural Crest / metabolism
  • Neural Crest / pathology
  • Point Mutation
  • Transcriptional Elongation Factors

Substances

  • Adrenergic alpha-2 Receptor Antagonists
  • Carrier Proteins
  • Elp1 protein, human
  • Mutant Proteins
  • Transcriptional Elongation Factors