Antisense Oligonucleotide Therapy for Neuromuscular Disease

神经肌肉疾病包括通常影响肌肉（包括心肌）和大脑的主要遗传性病症的不同群组，导致这些组织的进行性变性并最终导致非常显著的发病率和死亡率。这些疾病以杜氏肌营养不良症（DMD）为例，杜氏肌营养不良症（DMD）是一种影响约3500个新生男孩中的1个的一致致命的遗传性肌肉疾病，其由于肌营养不良蛋白基因的缺陷而产生，所述缺陷消除了肌营养不良蛋白蛋白的产生，肌营养不良蛋白是正常肌肉和心脏功能的关键蛋白质。结果，DMD患者发展出缓慢进行性肌肉变性和无力，导致12岁左右的肌肉萎缩，并最终导致由于呼吸或心肌衰竭而过早死亡，此时男孩通常在二十多岁。20年前，1993年诺贝尔生理学或医学奖授予罗伯茨和夏普，以表彰他们对所谓的“分裂基因”和RNA剪接的里程碑式发现-我们现在认为这是人类细胞内几乎所有人类基因表达所必需的基本过程。这种科学认识的范式转变导致了这样一种想法，即开发针对RNA并调节其加工的药物可能能够治疗严重的神经肌肉疾病，包括DMD，脊髓性肌萎缩症（SMA）和肌萎缩性侧索硬化症（ALS）-所有影响成人和儿童的破坏性退行性疾病，并代表巨大的未满足的医疗需求。近年来，虽然已经开发了许多用于治疗DMD的实验性疗法，但使用反义寡核苷酸（AON）靶向RNA的方法-所谓的外显子跳跃-可能是所有疗法中最先进和最有希望的。在过去的十年中，伍德实验室和其他人的世界领先的工作已经证实了这些AON药物对人类健康产生重大影响的潜力，特别是对于DMD。然而，目前主要的科学挑战仍有待克服，以便我们能够充分利用这种治疗方法的潜力。这些挑战包括：这些大的AON药物向肌肉、心脏和脑的关键组织的递送非常差;这些药物在肌肉中的活性非常低，在心脏和脑中的活性可以忽略不计;以及我们对药物活性和在预防或逆转疾病进展方面的期望临床结果之间的联系的有限理解。该领域现在已经足够成熟，可以进入下一个层次的理解，旨在阐明这些基本科学问题的答案，这将导致更有效和更广泛地利用靶向RNA治疗神经肌肉疾病。我们的研究将建立关于肌肉，心脏和大脑中有效RNA靶向的决定因素，其局限性和消除严重，危及生命的神经肌肉疾病的潜力的基本科学知识。它还将揭示关于大脑的基本知识，使我们能够了解在大脑和脊髓内靶向RNA的科学基础，以治疗严重的成人神经系统疾病。这反过来将充分利用靶向RNA的潜力来改善人类健康。

Neuromuscular diseases comprise a diverse group of mainly inherited conditions that typically affect muscles (including the heart muscle) and the brain, resulting in progressive degeneration of these tissues and leading ultimately to very significant morbidity and mortality. These diseases are exemplified by the disorder Duchenne muscular dystrophy (DMD) which is a uniformly fatal inherited muscle disease affecting ~1 in 3500 newborn boys, that arises due to defects in the dystrophin gene which abolish production of the dystrophin protein, a crucial protein for normal muscle and heart function. As a result DMD patients develop a slowly progressive muscle degeneration and weakness that results in loss of ambulation around 12 years of age and leading eventually to premature death due to respiratory or heart muscle failure when boys are typically in their twenties. Twenty years ago, the 1993 Nobel Prize in Physiology or Medicine was awarded to Roberts and Sharp for their landmark discovery of so-called 'split genes' and RNA splicing - what we now recognise as the essential process within human cells necessary for the expression of virtually all human genes. This paradigm-shift in scientific understanding led to the idea that developing medicines to target RNA and modulate its processing might be able to treat the severe neuromuscular diseases including DMD, spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) - all devastating degenerative disorders affecting adults and children and representing great unmet medical need. In recent years while a number of experimental therapies have been developed for treating DMD, the approach of targeting RNA using antisense oligonucleotides (AONs) - so-called exon skipping - is perhaps the most advanced and most promising of all. In the last decade, the world-leading work of the Wood Laboratory and others has confirmed the potential of these AON medicines to make a major impact human health, especially for DMD. However at present major scientific challenges remain to be overcome in order that we can exploit the full potential of this therapeutic method. These challenges include; the very poor delivery of these large AON drugs to the crucial tissues of muscle, heart and brain; the very low activity of these drugs in muscle and the negligible activity in heart and brain; and our limited understanding of the links between drug activity and the desired clinical outcome in terms of preventing or reversing the progression of disease. The field is now sufficiently mature to move to the next level of understanding aimed at elucidating answers to these fundamental scientific questions which will lead to the more effective and widespread exploitation of targeting RNA to treat neuromuscular diseases. Our research will establish essential scientific knowledge on the determinants of effective RNA targeting in muscle, heart and brain, its limitations and potential to abrogate severe, life-threatening neuromuscular disease. It will also reveal fundamental knowledge on the brain, allowing us to understand the scientific basis on which targeting RNA within the brain and spinal cord might be seriously advanced to treat severe, adult neurological disease. This in turn will harness the full potential of targeting RNA for improvement of human health.