SMRT compounds abrogate cellular phenotypes of ataxia telangiectasia in neural derivatives of patient-specific hiPSCs

Peiyee Lee; Nathan T. Martin; Kotoka Nakamura; Soheila Azghadi; Mandana Amiri; Uri Ben-David; Susan Perlman; Richard A. Gatti; Hailiang Hu; William E. Lowry

doi:10.1038/ncomms2824

SMRT compounds abrogate cellular phenotypes of ataxia telangiectasia in neural derivatives of patient-specific hiPSCs

Peiyee Lee, Nathan T. Martin, Kotoka Nakamura, Soheila Azghadi, Mandana Amiri, Uri Ben-David, Susan Perlman, Richard A. Gatti, Hailiang Hu, William E. Lowry

Research output: Contribution to journal › Article › peer-review

Abstract

Ataxia telangiectasia is a devastating neurodegenerative disease caused primarily by loss of function mutations in ATM, a hierarchical DNA repair gene and tumour suppressor. So far, murine models of ataxia telangiectasia have failed to accurately recapitulate many aspects of the disease, most notably, the progressive cerebellar ataxia. Here we present a model of human ataxia telangiectasia using induced pluripotent stem cells, and show that small molecule read-through compounds, designed to induce read-through of mRNA around premature termination codons, restore ATM activity and improve the response to DNA damage. This platform allows for efficient screening of novel compounds, identification of target and off-target effects, and preclinical testing on relevant cell types for the pathogenic dissection and treatment of ataxia telangiectasia.

Original language	English
Article number	1824
Journal	Nature Communications
Volume	4
DOIs	https://doi.org/10.1038/ncomms2824
State	Published - 2013
Externally published	Yes

All Science Journal Classification (ASJC) codes

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ncomms2824

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@article{9973fce98a604ea8b4e7c69698bc9b85,

title = "SMRT compounds abrogate cellular phenotypes of ataxia telangiectasia in neural derivatives of patient-specific hiPSCs",

abstract = "Ataxia telangiectasia is a devastating neurodegenerative disease caused primarily by loss of function mutations in ATM, a hierarchical DNA repair gene and tumour suppressor. So far, murine models of ataxia telangiectasia have failed to accurately recapitulate many aspects of the disease, most notably, the progressive cerebellar ataxia. Here we present a model of human ataxia telangiectasia using induced pluripotent stem cells, and show that small molecule read-through compounds, designed to induce read-through of mRNA around premature termination codons, restore ATM activity and improve the response to DNA damage. This platform allows for efficient screening of novel compounds, identification of target and off-target effects, and preclinical testing on relevant cell types for the pathogenic dissection and treatment of ataxia telangiectasia.",

author = "Peiyee Lee and Martin, {Nathan T.} and Kotoka Nakamura and Soheila Azghadi and Mandana Amiri and Uri Ben-David and Susan Perlman and Gatti, {Richard A.} and Hailiang Hu and Lowry, {William E.}",

note = "Funding Information: P.L., N.T.M., K.N., S.A., M.A., U.B.-D. and H.H. performed and helped design experiments. P.L., N.T.M., R.A.G., H.H. and W.E.L. interpreted experiments and wrote the manuscript. For correspondence regarding small molecule compounds, contact H.H.; regarding cell culture or reprogramming, contact W.E.L., R.A.G. and W.E.L. provided financial support for the experiments. W.E.L. holds the Maria Rowena Ross Chair in Cell Biology. P.L. was funded by a training grant from CIRM (TG2-01169). R.A.G. holds the Rebecca Smith Chair in Molecular Pathology and Laboratory Medicine. This work was supported by grants from: CIRM no. RT2-01920, NIH R01NS052528, APRAT and A-T Ease Foundation to R.A.G.",

year = "2013",

doi = "10.1038/ncomms2824",

language = "الإنجليزيّة",

volume = "4",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

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TY - JOUR

T1 - SMRT compounds abrogate cellular phenotypes of ataxia telangiectasia in neural derivatives of patient-specific hiPSCs

AU - Lee, Peiyee

AU - Martin, Nathan T.

AU - Nakamura, Kotoka

AU - Azghadi, Soheila

AU - Amiri, Mandana

AU - Ben-David, Uri

AU - Perlman, Susan

AU - Gatti, Richard A.

AU - Hu, Hailiang

AU - Lowry, William E.

N1 - Funding Information: P.L., N.T.M., K.N., S.A., M.A., U.B.-D. and H.H. performed and helped design experiments. P.L., N.T.M., R.A.G., H.H. and W.E.L. interpreted experiments and wrote the manuscript. For correspondence regarding small molecule compounds, contact H.H.; regarding cell culture or reprogramming, contact W.E.L., R.A.G. and W.E.L. provided financial support for the experiments. W.E.L. holds the Maria Rowena Ross Chair in Cell Biology. P.L. was funded by a training grant from CIRM (TG2-01169). R.A.G. holds the Rebecca Smith Chair in Molecular Pathology and Laboratory Medicine. This work was supported by grants from: CIRM no. RT2-01920, NIH R01NS052528, APRAT and A-T Ease Foundation to R.A.G.

PY - 2013

Y1 - 2013

N2 - Ataxia telangiectasia is a devastating neurodegenerative disease caused primarily by loss of function mutations in ATM, a hierarchical DNA repair gene and tumour suppressor. So far, murine models of ataxia telangiectasia have failed to accurately recapitulate many aspects of the disease, most notably, the progressive cerebellar ataxia. Here we present a model of human ataxia telangiectasia using induced pluripotent stem cells, and show that small molecule read-through compounds, designed to induce read-through of mRNA around premature termination codons, restore ATM activity and improve the response to DNA damage. This platform allows for efficient screening of novel compounds, identification of target and off-target effects, and preclinical testing on relevant cell types for the pathogenic dissection and treatment of ataxia telangiectasia.

AB - Ataxia telangiectasia is a devastating neurodegenerative disease caused primarily by loss of function mutations in ATM, a hierarchical DNA repair gene and tumour suppressor. So far, murine models of ataxia telangiectasia have failed to accurately recapitulate many aspects of the disease, most notably, the progressive cerebellar ataxia. Here we present a model of human ataxia telangiectasia using induced pluripotent stem cells, and show that small molecule read-through compounds, designed to induce read-through of mRNA around premature termination codons, restore ATM activity and improve the response to DNA damage. This platform allows for efficient screening of novel compounds, identification of target and off-target effects, and preclinical testing on relevant cell types for the pathogenic dissection and treatment of ataxia telangiectasia.

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U2 - 10.1038/ncomms2824

DO - 10.1038/ncomms2824

M3 - مقالة

SN - 2041-1723

VL - 4

JO - Nature Communications

JF - Nature Communications

M1 - 1824

ER -

SMRT compounds abrogate cellular phenotypes of ataxia telangiectasia in neural derivatives of patient-specific hiPSCs

Abstract

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