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.
authors: Eli and Edythe Broad Center for Regenerative Medicine, UCLA, Los Angeles, California 90095, USA.
authors: Peiyee
authors: P
authors: Lee
authors: Nathan T
authors: NT
authors: Martin
authors: Kotoka
authors: K
authors: Nakamura
authors: Soheila
authors: S
authors: Azghadi
authors: Mandana
authors: M
authors: Amiri
authors: Uri
authors: U
authors: Ben-David
authors: Susan
authors: S
authors: Perlman
authors: Richard A
authors: RA
authors: Gatti
authors: Hailiang
authors: H
authors: Hu
authors: William E
authors: WE
authors: Lowry
mesh_terms: D001260:Ataxia Telangiectasia / Q000473:pathology*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D002460:Cell Line; D065150:Cellular Reprogramming / Q000187:drug effects / Q000235:genetics; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D011839:Radiation, Ionizing; D054852:Small Molecule Libraries / Q000494:pharmacology*
chemical_list: C468783:H2AX protein, human; D006657:Histones; D054852:Small Molecule Libraries; D064007:Ataxia Telangiectasia Mutated Proteins
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