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

在老龄化的西方社会，退化性疾病造成了越来越多的医疗和社会负担。这些疾病中没有几种是可以治疗的，因此开发新类型的治疗方法至关重要。在这项研究中，我们将研究Duchenne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，由缺乏营养不良蛋白引起，通常是致命的，目前无法治疗，通常会导致受影响的男孩在20多岁时死亡。我们将研究一种治疗DMD的新型基因疗法，该疗法已经在两项针对DMD患者的初步临床试验中显示出了希望。这种名为外显子跳跃的疗法使用被称为反义寡核苷酸(AOS)的小DNA斑块来纠正dystrophin基因突变的影响，从而产生功能接近正常的新的dystrophin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块肌肉中的应用，因此，鉴于所有肌肉都受到这种疾病的影响，发展这种疗法的主要挑战之一是开发将AO有效地输送到所有肌肉组和心脏的方法。我们最近发现，将被称为多肽的小蛋白片段附着到AO上，可以极大地改善AO化合物向多个肌肉群和心脏的输送。在这项研究中，我们现在还计划测试有可能使AO专门针对肌肉和/或心脏的蛋白质片段，最初研究的是最近发现的被称为B-MSP-PMO的原型化合物。我们计划在两种DMD小鼠模型上测试其长期有效性，一种是轻度的，另一种是重度的，并试图更好地了解这种化合物是如何针对肌肉的，以及它在多大程度上可能是安全的。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多肽，可能会以更高的效率靶向AO的肌肉和/或心脏。我们还将进一步调查最近令人兴奋的发现，我们发现这些药物可以通过与一系列糖类一起给药来进一步促进药物的传递。因此，这项工作将大大推进DMD和其他疾病的疾病修正疗法的前景，在这些疾病中，外显子跳过或AO传递将是一种有价值的治疗方法。

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.