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

Author

Listed:
  • Peiyee Lee

    (Eli and Edythe Broad Center for Regenerative Medicine, UCLA
    UCLA, 621 Charles E. Young Drive South, Los Angeles, California 90095, USA)

  • Nathan T. Martin

    (David Geffen UCLA School of Medicine)

  • Kotoka Nakamura

    (David Geffen UCLA School of Medicine)

  • Soheila Azghadi

    (Eli and Edythe Broad Center for Regenerative Medicine, UCLA)

  • Mandana Amiri

    (David Geffen UCLA School of Medicine)

  • Uri Ben-David

    (Institute of Life Sciences, The Hebrew University of Jeruselum)

  • Susan Perlman

    (David Geffen School of Medicine)

  • Richard A. Gatti

    (David Geffen UCLA School of Medicine
    Molecular Biology Institute, UCLA
    David Geffen UCLA School of Medicine)

  • Hailiang Hu

    (David Geffen UCLA School of Medicine)

  • William E. Lowry

    (Eli and Edythe Broad Center for Regenerative Medicine, UCLA
    UCLA, 621 Charles E. Young Drive South, Los Angeles, California 90095, USA
    Molecular Biology Institute, UCLA)

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.

Suggested Citation

  • Peiyee Lee & Nathan T. Martin & Kotoka Nakamura & Soheila Azghadi & Mandana Amiri & Uri Ben-David & Susan Perlman & Richard A. Gatti & Hailiang Hu & William E. Lowry, 2013. "SMRT compounds abrogate cellular phenotypes of ataxia telangiectasia in neural derivatives of patient-specific hiPSCs," Nature Communications, Nature, vol. 4(1), pages 1-8, June.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms2824
    DOI: 10.1038/ncomms2824
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