Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs

Gabsang Lee, Eirini P. Papapetrou, Hyesoo Kim, Stuart M. Chambers, Mark J. Tomishima, Christopher A. Fasano, Yosif M. Ganat, Jayanthi Menon, Fumiko Shimizu, Agnes Viale, Viviane Tabar, Michel Sadelain, Lorenz Studer

Research output: Contribution to journalArticle

Abstract

The isolation of human induced pluripotent stem cells (iPSCs) offers a new strategy for modelling human disease. Recent studies have reported the derivation and differentiation of disease-specific human iPSCs. However, a key challenge in the field is the demonstration of disease-related phenotypes and the ability to model pathogenesis and treatment of disease in iPSCs. Familial dysautonomia (FD) is a rare but fatal peripheral neuropathy, caused by a point mutation in the IKBKAP gene involved in transcriptional elongation. The disease is characterized by the depletion of autonomic and sensory neurons. The specificity to the peripheral nervous system and the mechanism of neuron loss in FD are poorly understood owing to the lack of an appropriate model system. Here we report the derivation of patient-specific FD-iPSCs and the directed differentiation into cells of all three germ layers including peripheral neurons. Gene expression analysis in purified FD-iPSC-derived lineages demonstrates tissue-specific mis-splicing of IKBKAP in vitro. Patient-specific neural crest precursors express particularly low levels of normal IKBKAP transcript, suggesting a mechanism for disease specificity. FD pathogenesis is further characterized by transcriptome analysis and cell-based assays revealing marked defects in neurogenic differentiation and migration behaviour. Furthermore, we use FD-iPSCs for validating the potency of candidate drugs in reversing aberrant splicing and ameliorating neuronal differentiation and migration. Our study illustrates the promise of iPSC technology for gaining new insights into human disease pathogenesis and treatment.

Original languageEnglish (US)
Pages (from-to)402-406
Number of pages5
JournalNature
Volume461
Issue number7262
DOIs
StatePublished - Sep 17 2009
Externally publishedYes

Fingerprint

Familial Dysautonomia
Induced Pluripotent Stem Cells
Therapeutics
Neurons
Germ Layers
Aptitude
Neural Crest
Peripheral Nervous System
Gene Expression Profiling
Peripheral Nervous System Diseases
Cell Lineage
Sensory Receptor Cells
Point Mutation
Cell Differentiation
Technology
Phenotype
Gene Expression

ASJC Scopus subject areas

  • General

Cite this

Lee, G., Papapetrou, E. P., Kim, H., Chambers, S. M., Tomishima, M. J., Fasano, C. A., ... Studer, L. (2009). Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. Nature, 461(7262), 402-406. https://doi.org/10.1038/nature08320

Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. / Lee, Gabsang; Papapetrou, Eirini P.; Kim, Hyesoo; Chambers, Stuart M.; Tomishima, Mark J.; Fasano, Christopher A.; Ganat, Yosif M.; Menon, Jayanthi; Shimizu, Fumiko; Viale, Agnes; Tabar, Viviane; Sadelain, Michel; Studer, Lorenz.

In: Nature, Vol. 461, No. 7262, 17.09.2009, p. 402-406.

Research output: Contribution to journalArticle

Lee, G, Papapetrou, EP, Kim, H, Chambers, SM, Tomishima, MJ, Fasano, CA, Ganat, YM, Menon, J, Shimizu, F, Viale, A, Tabar, V, Sadelain, M & Studer, L 2009, 'Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs', Nature, vol. 461, no. 7262, pp. 402-406. https://doi.org/10.1038/nature08320
Lee G, Papapetrou EP, Kim H, Chambers SM, Tomishima MJ, Fasano CA et al. Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. Nature. 2009 Sep 17;461(7262):402-406. https://doi.org/10.1038/nature08320
Lee, Gabsang ; Papapetrou, Eirini P. ; Kim, Hyesoo ; Chambers, Stuart M. ; Tomishima, Mark J. ; Fasano, Christopher A. ; Ganat, Yosif M. ; Menon, Jayanthi ; Shimizu, Fumiko ; Viale, Agnes ; Tabar, Viviane ; Sadelain, Michel ; Studer, Lorenz. / Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. In: Nature. 2009 ; Vol. 461, No. 7262. pp. 402-406.
@article{9c3fd431a1964307b3eaea0ec1d82b4e,
title = "Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs",
abstract = "The isolation of human induced pluripotent stem cells (iPSCs) offers a new strategy for modelling human disease. Recent studies have reported the derivation and differentiation of disease-specific human iPSCs. However, a key challenge in the field is the demonstration of disease-related phenotypes and the ability to model pathogenesis and treatment of disease in iPSCs. Familial dysautonomia (FD) is a rare but fatal peripheral neuropathy, caused by a point mutation in the IKBKAP gene involved in transcriptional elongation. The disease is characterized by the depletion of autonomic and sensory neurons. The specificity to the peripheral nervous system and the mechanism of neuron loss in FD are poorly understood owing to the lack of an appropriate model system. Here we report the derivation of patient-specific FD-iPSCs and the directed differentiation into cells of all three germ layers including peripheral neurons. Gene expression analysis in purified FD-iPSC-derived lineages demonstrates tissue-specific mis-splicing of IKBKAP in vitro. Patient-specific neural crest precursors express particularly low levels of normal IKBKAP transcript, suggesting a mechanism for disease specificity. FD pathogenesis is further characterized by transcriptome analysis and cell-based assays revealing marked defects in neurogenic differentiation and migration behaviour. Furthermore, we use FD-iPSCs for validating the potency of candidate drugs in reversing aberrant splicing and ameliorating neuronal differentiation and migration. Our study illustrates the promise of iPSC technology for gaining new insights into human disease pathogenesis and treatment.",
author = "Gabsang Lee and Papapetrou, {Eirini P.} and Hyesoo Kim and Chambers, {Stuart M.} and Tomishima, {Mark J.} and Fasano, {Christopher A.} and Ganat, {Yosif M.} and Jayanthi Menon and Fumiko Shimizu and Agnes Viale and Viviane Tabar and Michel Sadelain and Lorenz Studer",
year = "2009",
month = "9",
day = "17",
doi = "10.1038/nature08320",
language = "English (US)",
volume = "461",
pages = "402--406",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7262",

}

TY - JOUR

T1 - Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs

AU - Lee, Gabsang

AU - Papapetrou, Eirini P.

AU - Kim, Hyesoo

AU - Chambers, Stuart M.

AU - Tomishima, Mark J.

AU - Fasano, Christopher A.

AU - Ganat, Yosif M.

AU - Menon, Jayanthi

AU - Shimizu, Fumiko

AU - Viale, Agnes

AU - Tabar, Viviane

AU - Sadelain, Michel

AU - Studer, Lorenz

PY - 2009/9/17

Y1 - 2009/9/17

N2 - The isolation of human induced pluripotent stem cells (iPSCs) offers a new strategy for modelling human disease. Recent studies have reported the derivation and differentiation of disease-specific human iPSCs. However, a key challenge in the field is the demonstration of disease-related phenotypes and the ability to model pathogenesis and treatment of disease in iPSCs. Familial dysautonomia (FD) is a rare but fatal peripheral neuropathy, caused by a point mutation in the IKBKAP gene involved in transcriptional elongation. The disease is characterized by the depletion of autonomic and sensory neurons. The specificity to the peripheral nervous system and the mechanism of neuron loss in FD are poorly understood owing to the lack of an appropriate model system. Here we report the derivation of patient-specific FD-iPSCs and the directed differentiation into cells of all three germ layers including peripheral neurons. Gene expression analysis in purified FD-iPSC-derived lineages demonstrates tissue-specific mis-splicing of IKBKAP in vitro. Patient-specific neural crest precursors express particularly low levels of normal IKBKAP transcript, suggesting a mechanism for disease specificity. FD pathogenesis is further characterized by transcriptome analysis and cell-based assays revealing marked defects in neurogenic differentiation and migration behaviour. Furthermore, we use FD-iPSCs for validating the potency of candidate drugs in reversing aberrant splicing and ameliorating neuronal differentiation and migration. Our study illustrates the promise of iPSC technology for gaining new insights into human disease pathogenesis and treatment.

AB - The isolation of human induced pluripotent stem cells (iPSCs) offers a new strategy for modelling human disease. Recent studies have reported the derivation and differentiation of disease-specific human iPSCs. However, a key challenge in the field is the demonstration of disease-related phenotypes and the ability to model pathogenesis and treatment of disease in iPSCs. Familial dysautonomia (FD) is a rare but fatal peripheral neuropathy, caused by a point mutation in the IKBKAP gene involved in transcriptional elongation. The disease is characterized by the depletion of autonomic and sensory neurons. The specificity to the peripheral nervous system and the mechanism of neuron loss in FD are poorly understood owing to the lack of an appropriate model system. Here we report the derivation of patient-specific FD-iPSCs and the directed differentiation into cells of all three germ layers including peripheral neurons. Gene expression analysis in purified FD-iPSC-derived lineages demonstrates tissue-specific mis-splicing of IKBKAP in vitro. Patient-specific neural crest precursors express particularly low levels of normal IKBKAP transcript, suggesting a mechanism for disease specificity. FD pathogenesis is further characterized by transcriptome analysis and cell-based assays revealing marked defects in neurogenic differentiation and migration behaviour. Furthermore, we use FD-iPSCs for validating the potency of candidate drugs in reversing aberrant splicing and ameliorating neuronal differentiation and migration. Our study illustrates the promise of iPSC technology for gaining new insights into human disease pathogenesis and treatment.

UR - http://www.scopus.com/inward/record.url?scp=70349301819&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70349301819&partnerID=8YFLogxK

U2 - 10.1038/nature08320

DO - 10.1038/nature08320

M3 - Article

VL - 461

SP - 402

EP - 406

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7262

ER -