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使用外显子跳跃三环 DNA 寡聚物对肌肉萎缩症的小鼠模型进行功能矫正。

Functional correction in mouse models of muscular dystrophy using exon-skipping tricyclo-DNA oligomers.

机构信息

Université de Versailles St-Quentin, INSERM U1179, LIA BAHN CSM, Montigny-le-Bretonneux, France.

MRC Functional Genomics Unit, University of Oxford, Oxford, UK.

出版信息

Nat Med. 2015 Mar;21(3):270-5. doi: 10.1038/nm.3765. Epub 2015 Feb 2.

Abstract

Antisense oligonucleotides (AONs) hold promise for therapeutic correction of many genetic diseases via exon skipping, and the first AON-based drugs have entered clinical trials for neuromuscular disorders. However, despite advances in AON chemistry and design, systemic use of AONs is limited because of poor tissue uptake, and recent clinical reports confirm that sufficient therapeutic efficacy has not yet been achieved. Here we present a new class of AONs made of tricyclo-DNA (tcDNA), which displays unique pharmacological properties and unprecedented uptake by many tissues after systemic administration. We demonstrate these properties in two mouse models of Duchenne muscular dystrophy (DMD), a neurogenetic disease typically caused by frame-shifting deletions or nonsense mutations in the gene encoding dystrophin and characterized by progressive muscle weakness, cardiomyopathy, respiratory failure and neurocognitive impairment. Although current naked AONs do not enter the heart or cross the blood-brain barrier to any substantial extent, we show that systemic delivery of tcDNA-AONs promotes a high degree of rescue of dystrophin expression in skeletal muscles, the heart and, to a lesser extent, the brain. Our results demonstrate for the first time a physiological improvement of cardio-respiratory functions and a correction of behavioral features in DMD model mice. This makes tcDNA-AON chemistry particularly attractive as a potential future therapy for patients with DMD and other neuromuscular disorders or with other diseases that are eligible for exon-skipping approaches requiring whole-body treatment.

摘要

反义寡核苷酸(AONs)通过外显子跳跃有望成为治疗许多遗传疾病的方法,第一批基于 AON 的药物已进入神经肌肉疾病的临床试验。然而,尽管 AON 化学和设计取得了进展,但由于组织摄取不良,全身使用 AON 的应用受到限制,最近的临床报告证实尚未达到足够的治疗效果。在这里,我们提出了一类由三环 DNA(tcDNA)组成的新型 AON,其在全身给药后具有独特的药理特性和前所未有的多种组织摄取能力。我们在两种杜氏肌营养不良症(DMD)的小鼠模型中证明了这些特性,DMD 是一种神经肌肉疾病,通常由编码肌营养不良蛋白的基因发生移码缺失或无义突变引起,其特征是进行性肌肉无力、心肌病、呼吸衰竭和神经认知障碍。尽管目前的裸露 AON 不能进入心脏或大量穿过血脑屏障,但我们表明,tcDNA-AON 的全身给药可促进肌营养不良蛋白在骨骼肌、心脏(在较小程度上是大脑)中的表达得到高度挽救。我们的结果首次证明了在 DMD 模型小鼠中心肺功能的生理改善和行为特征的纠正。这使得 tcDNA-AON 化学特别有吸引力,可作为治疗 DMD 及其他神经肌肉疾病或其他适合外显子跳跃方法的患者的潜在未来疗法,这些方法需要全身治疗。

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