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

Gabsang Lee, Christina N. Ramirez, Hyesoo Kim, Nadja Zeltner, Becky Liu, Constantin Radu, Bhavneet Bhinder, Yong Jun Kim, In Young Choi, Bipasha Mukherjee-Clavin, Hakim Djaballah, Lorenz Studer

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1244-1248
Number of pages5
JournalNature biotechnology
Volume30
Issue number12
DOIs
StatePublished - Dec 2012

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Applied Microbiology and Biotechnology
  • Molecular Medicine
  • Biomedical Engineering

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    Lee, G., Ramirez, C. N., Kim, H., Zeltner, N., Liu, B., Radu, C., Bhinder, B., Kim, Y. J., Choi, I. Y., Mukherjee-Clavin, B., Djaballah, H., & Studer, L. (2012). Large-scale screening using familial dysautonomia induced pluripotent stem cells identifies compounds that rescue IKBKAP expression. Nature biotechnology, 30(12), 1244-1248. https://doi.org/10.1038/nbt.2435