Eli and Edythe Broad Center for Regenerative Medicine, UCLA, Los Angeles, California 90095, USA.
Nat Commun. 2013;4:1824. doi: 10.1038/ncomms2824.
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.
毛细血管扩张性共济失调症是一种破坏性的神经退行性疾病，主要由 ATM 功能丧失突变引起，ATM 是一个层次分明的 DNA 修复基因和肿瘤抑制基因。到目前为止，毛细血管扩张性共济失调症的小鼠模型未能准确再现该疾病的许多方面，尤其是进行性小脑共济失调。在这里，我们使用诱导多能干细胞建立了一种人类毛细血管扩张性共济失调症模型，并表明，设计用于诱导 mRNA 绕过提前终止密码子通读的小分子通读化合物可恢复 ATM 活性并改善对 DNA 损伤的反应。该平台允许对新型化合物进行高效筛选，确定靶标和脱靶效应，并在相关细胞类型上进行临床前测试，以进行毛细血管扩张性共济失调症的发病机制研究和治疗。
