Fernandes Stephanie A, Douglas Andrew G L, Varela Miguel A, Wood Matthew J A, Aoki Yoshitsugu
Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK ; Institute of Biosciences, University of Sao Paulo, Rua do Matao, 05508-090 Sao Paulo, SP, Brazil.
Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK.
J Nucleic Acids. 2013;2013:208245. doi: 10.1155/2013/208245. Epub 2013 Nov 17.
Amyotrophic lateral sclerosis (ALS) is a progressive and lethal disease of motor neuron degeneration, leading to paralysis of voluntary muscles and death by respiratory failure within five years of onset. Frontotemporal dementia (FTD) is characterised by degeneration of frontal and temporal lobes, leading to changes in personality, behaviour, and language, culminating in death within 5-10 years. Both of these diseases form a clinical, pathological, and genetic continuum of diseases, and this link has become clearer recently with the discovery of a hexanucleotide repeat expansion in the C9orf72 gene that causes the FTD/ALS spectrum, that is, c9FTD/ALS. Two basic mechanisms have been proposed as being potentially responsible for c9FTD/ALS: loss-of-function of the protein encoded by this gene (associated with aberrant DNA methylation) and gain of function through the formation of RNA foci or protein aggregates. These diseases currently lack any cure or effective treatment. Antisense oligonucleotides (ASOs) are modified nucleic acids that are able to silence targeted mRNAs or perform splice modulation, and the fact that they have proved efficient in repeat expansion diseases including myotonic dystrophy type 1 makes them ideal candidates for c9FTD/ALS therapy. Here, we discuss potential mechanisms and challenges for developing oligonucleotide-based therapy for c9FTD/ALS.
肌萎缩侧索硬化症（ALS）是一种进行性致命的运动神经元变性疾病，会导致随意肌麻痹，并在发病后五年内死于呼吸衰竭。额颞叶痴呆（FTD）的特征是额叶和颞叶变性，导致人格、行为和语言发生变化，最终在5至10年内死亡。这两种疾病在临床、病理和遗传方面构成了一个疾病连续体，最近随着在C9orf72基因中发现导致FTD/ALS谱系（即c9FTD/ALS）的六核苷酸重复扩增，这种联系变得更加清晰。已经提出了两种可能导致c9FTD/ALS的基本机制：该基因编码的蛋白质功能丧失（与异常DNA甲基化有关）以及通过形成RNA病灶或蛋白质聚集体获得功能。这些疾病目前缺乏任何治愈方法或有效治疗手段。反义寡核苷酸（ASO）是经过修饰的核酸，能够使靶向mRNA沉默或进行剪接调节，并且它们已被证明在包括1型强直性肌营养不良在内的重复扩增疾病中有效，这使得它们成为c9FTD/ALS治疗的理想候选药物。在此，我们讨论开发基于寡核苷酸的c9FTD/ALS治疗方法的潜在机制和挑战。
