Large-scale screening using familial dysautonomia induced pluripotent stem cells identifies compounds that rescue IKBKAP expression.
Large-scale screening using familial dysautonomia induced pluripotent stem cells identifies compounds that rescue IKBKAP expression.
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DOI：
10.1038/nbt.2435
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发表时间：
2012-12
影响因子：
46.9
通讯作者：
中科院分区：
文献类型：
--
作者：
Patient-specific induced pluripotent stem cells (iPSCs) represent a novel system for modeling human genetic disease and could develop into a key drug discovery platform. We recently reported disease-specific phenotypes in iPSCs from familial dysautonomia (FD) patients. FD is a rare but fatal genetic disorder affecting neural crest lineages. Here we demonstrate the feasibility of performing a primary screen in FD-iPSC derived neural crest precursors. Out of 6,912 compounds tested we characterized 8 hits that rescue expression of IKBKAP, the gene responsible for FD. One of those hits, SKF-86466, is shown to induce IKBKAP transcription via modulation of intracellular cAMP levels and PKA dependent CREB phosphorylation. SKF-86466 also rescues IKAP protein expression and the disease-specific loss of autonomic neuron marker expression. Our data implicate alpha-2 adrenergic receptor activity in regulating IKBKAP expression and demonstrate that small molecule discovery in an iPSC-based disease model can identify candidate drugs for potential therapeutic intervention.
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影响因子：
64.8
作者：
Itzhaki, Ilanit;Maizels, Leonid;Gepstein, Lior
通讯作者：
Gepstein, Lior
影响因子：
14.8
作者：
Lee, Gabsang;Chambers, Stuart M.;Studer, Lorenz
通讯作者：
Studer, Lorenz
影响因子：
4.4
作者：
Hims, Matthew M.;Shetty, Ranjit S.;Slaugenhaupt, Susan A.
通讯作者：
Slaugenhaupt, Susan A.
影响因子：
3.6
作者：
Trendelenburg, AU;Wahl, CA;Starke, K
通讯作者：
Starke, K
DOI：
10.1073/pnas.0904825106
发表时间：
2009-08-04
影响因子：
11.1
作者：
Papapetrou, Eirini P.;Tomishima, Mark J.;Sadelain, Michel
通讯作者：
Sadelain, Michel