Antisense nucleic acid splice correction therapy for Duchenne muscular dystrophy and related disorders

杜氏肌营养不良症及相关疾病的反义核酸剪接校正疗法

• 批准号: G0900887/1
• 负责人: Matthew Wood
• 金额: $ 191.22万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0900887%2F1
• 关键词: Antisense; nucleic; acid; splice; correction

Degenerative diseases cause increasing medical and social burdens in aging Western societies. Few of these diseases are treatable and therefore it is vital that new types of therapies are developed. In this research we will study Duchenne muscular dystrophy (DMD), a common, X-linked inherited, degenerative disease of muscle caused by lack of the protein dystrophin, and that is uniformly fatal and currently untreatable, typically leading to the deaths of affected boys in their 20s. We will investigate a new type of gene therapy for DMD, which has already shown promise in two preliminary clinical trials in DMD patients. The therapy, called exon skipping, uses small DNA patches known as antisense oligonucleotides (AOs) to correct the effects of mutations in the dystrophin gene, thereby producing new dystrophin protein of near-normal function and correcting the harmful effects of the disease. The recent clinical trials tested the application of this method in single muscles and therefore one of the major challenges in taking this therapy forward is to develop the means to deliver the AOs effectively to all muscle groups and also to the heart, given that all are affected by the disease. We have recently discovered that attaching small protein fragments known as peptides to the AO allows greatly improved delivery of the AO compounds to multiple muscle groups and heart. In this research we now also plan to test protein fragments that potentially allow the AO to be targeted specifically to muscle and /or heart, initially studying a recently discovered prototype compound known as B-MSP-PMO. We plan to test its long-term effectiveness in two mouse models of DMD, one mild and one severe, and also to attempt to understand better how this compound is targeted to muscle and to what extent it is likely to be safe to use. We also plan to evaluate improved versions of this AO as we are currently working to discover improved peptides that may target the AO to muscle and or heart with even greater efficiency. We will also investigate further recent exciting findings where we have discovered that the delivery of such drugs can be enhanced further by administering them together with a range of sugars. This work will therefore significantly advance the prospects for a disease-modifying therapy for DMD and also for other diseases where exon skipping or AO delivery would be a valuable therapy.

在西方老龄化社会中，退行性疾病造成越来越多的医疗和社会负担。这些疾病中很少有可治疗的，因此开发新的治疗方法至关重要。在这项研究中，我们将研究杜氏肌营养不良症（DMD），这是一种常见的X连锁遗传性肌肉退行性疾病，由缺乏蛋白质肌营养不良蛋白引起，并且是致命的，目前无法治疗，通常导致20多岁受影响的男孩死亡。我们将研究一种新型的DMD基因疗法，该疗法已经在DMD患者的两项初步临床试验中显示出希望。这种称为外显子跳跃的疗法使用称为反义寡核苷酸（AO）的小DNA补丁来纠正肌营养不良蛋白基因突变的影响，从而产生功能接近正常的新肌营养不良蛋白，并纠正疾病的有害影响。最近的临床试验测试了这种方法在单个肌肉中的应用，因此，将这种疗法向前推进的主要挑战之一是开发有效地将AO递送到所有肌肉群以及心脏的方法，因为所有肌肉群都受到疾病的影响。我们最近发现，将称为肽的小蛋白质片段连接到AO上可以大大改善AO化合物向多个肌肉群和心脏的递送。在这项研究中，我们现在还计划测试可能允许AO特异性靶向肌肉和/或心脏的蛋白质片段，最初研究最近发现的原型化合物B-MSP-PMO。我们计划在两种DMD小鼠模型中测试其长期有效性，一种是轻度，一种是重度，并试图更好地了解这种化合物是如何靶向肌肉的，以及在多大程度上使用它可能是安全的。我们还计划评估这种AO的改进版本，因为我们目前正在努力发现改进的肽，这些肽可能以更高的效率将AO靶向肌肉和/或心脏。我们还将进一步研究最近令人兴奋的发现，我们发现这些药物的递送可以通过将它们与一系列糖一起施用来进一步增强。因此，这项工作将显着推进DMD的疾病修饰疗法的前景，以及外显子跳跃或AO递送将是有价值的疗法的其他疾病的前景。