Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease
Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease
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DOI：
10.1056/nejmoa1813279
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发表时间：
2019-10-24
影响因子：
158.5
通讯作者：
Yu, T. W.
中科院分区：
文献类型：
--
作者：
Kim, J.;Hu, C.;Yu, T. W.
基因组测序通常对于罕见疾病的诊断至关重要，但其中许多疾病缺乏具体的治疗方法。我们描述了一种罕见的致命性神经退行性疾病的分子诊断如何导致 milasen 的合理设计、测试和制造，这是一种针对特定患者量身定制的剪接调节反义寡核苷酸药物。在患者细胞系中进行的概念验证实验成为在首次接触患者后一年内启动 milasen“N-of-1”研究的基础。没有严重的不良事件，治疗与癫痫发作的客观减少有关（通过脑电图和家长报告确定）。这项研究为快速开发患者定制治疗提供了可能的模板。 （由米拉奇迹基金会和其他人资助。）一名患有神经元蜡样质脂褐质沉着症的儿童被发现携带基因 MFSD8 (CLN7) 功能丧失突变。基因诊断一年后，这名儿童开始接受寡核苷酸药物治疗，该药物旨在纠正由其中一个突变引起的异常前信使 RNA 剪接。
Genome sequencing is often pivotal in the diagnosis of rare diseases, but many of these conditions lack specific treatments. We describe how molecular diagnosis of a rare, fatal neurodegenerative condition led to the rational design, testing, and manufacture of milasen, a splice-modulating antisense oligonucleotide drug tailored to a particular patient. Proof-of-concept experiments in cell lines from the patient served as the basis for launching an "N-of-1" study of milasen within 1 year after first contact with the patient. There were no serious adverse events, and treatment was associated with objective reduction in seizures (determined by electroencephalography and parental reporting). This study offers a possible template for the rapid development of patient-customized treatments. (Funded by Mila's Miracle Foundation and others.)A child with a neuronal ceroid lipofuscinosis was found to carry loss-of-function mutations in the gene MFSD8 (CLN7). A year after genetic diagnosis, the child began treatment with an oligonucleotide drug that was designed to correct the aberrant pre-messenger RNA splicing caused by one of these mutations.