Spinal muscular atrophy (SMA) is caused by mutation or deletion of the survival motor neuron 1 (SMN1) gene, resulting in low levels of functional SMN protein. We have reported recently the identification of small molecules (coumarins, iso-coumarins and pyrido-pyrimidinones) that modify the alternative splicing of SMN2, a paralogous gene to SMN1, restoring the survival motor neuron (SMN) protein level in mouse models of SMA. Herein, we report our efforts to identify a novel chemotype as one strategy to potentially circumvent safety concerns from earlier derivatives such as in vitro phototoxicity and in vitro mutagenicity associated with compounds 1 and 2 or the in vivo retinal findings observed in a long-term chronic tox study with 3 at high exposures only. Optimized representative compounds modify the alternative splicing of SMN2, increase the production of full length SMN2 mRNA, and therefore levels of full length SMN protein upon oral administration in two mouse models of SMA.

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一种新型的生存运动神经元2拼接修饰剂治疗脊髓性肌萎缩症的发现

脊髓性肌萎缩症（SMA）是由存活运动神经元1（SMN1）基因的突变或缺失引起的，导致功能性SMN蛋白水平较低。我们最近报道了鉴定小分子（香豆素，异香豆素和吡啶基嘧啶酮）的修饰，这些分子修饰了SMN1的同源基因SMN2的选择性剪接，从而恢复了SMA小鼠模型中的存活运动神经元（SMN）蛋白水平。在本文中，我们报告了我们的努力，旨在确定一种新的化学型，作为一种可能的策略，可以避免较早的衍生物产生的安全性问题，例如与化合物1和2相关的体外光毒性和体外诱变性或在长期慢性毒物研究中仅在3次高暴露下观察到的体内视网膜发现。优化的代表性化合物修饰了SMN2的可变剪接，增加了SMN2全长mRNA的产生，因此在两种SMA小鼠模型中口服时，增加了SMN2蛋白的水平。