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


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.

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Figure 1: HTS assay development.
Figure 2: Results of 6,912-compound screen in FD-NCs.
Figure 3: Functional studies on the mechanism of SKF action.


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We would like to thank members of the Studer lab for valuable discussions on the manuscript and the members of the HTS Core Facility for their help during the course of this study. We also thank J. Hendrikx and P. Anderson for technical help in flow cytometry assays. Work in the Studer lab was supported by grants from NYSTEM (L.S.) and Druckenmiller Fellowship from New York Stem Cell Foundation (G.L.). Robertson Investigator Award from New York Stem Cell Foundation (G.L.) and Maryland Stem Cell Research Funding (G.L.) supported experiments in the Lee lab. Work of the HTS Core Facility was supported by W.H. Goodwin and A. Goodwin and the Commonwealth Foundation for Cancer Research, the Experimental Therapeutics Center at MSKCC, the W.R. Hearst Fund in Experimental Therapeutics, the L.S. Wells Foundation, and by grant 5 P30 CA008748-44 from National Institutes of Health National Cancer Institute.

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Authors and Affiliations



G.L.: conception and study design, maintenance/differentiation/isolation/expansion of FD-hiPSCs and FD-NCs, data analysis, cellular/molecular assays for validation/confirmation, data assembly, analysis and interpretation, and writing manuscript; C.N.R.: study design, development of assay, performing screening, data analysis and writing of manuscript; C.R.: performing screening; B.B.: HTS data analysis; H.K., N.Z., B.L., Y.J.K., I.Y.C. and B.M.C.: cellular/molecular assays for validation/confirmation; H.D.: study design, data analysis, interpretation of HTS data and writing manuscript; L.S.: conception and study design, data analysis and interpretation, and writing manuscript.

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Correspondence to Gabsang Lee or Lorenz Studer.

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The authors declare no competing financial interests.

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Lee, G., Ramirez, C., Kim, H. et al. Large-scale screening using familial dysautonomia induced pluripotent stem cells identifies compounds that rescue IKBKAP expression. Nat Biotechnol 30, 1244–1248 (2012).

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