Antisense Oligonucleotide Therapy for Neuromuscular Disease

神经肌肉疾病包括一组主要是遗传性的疾病，通常影响肌肉(包括心肌)和大脑，导致这些组织的进行性退化，最终导致非常严重的发病率和死亡率。这些疾病以Duchenne肌营养不良症(DMD)为例，Duchenne肌营养不良症是一种致命的遗传性肌肉疾病，每3500名新生儿中就有1人受到影响，原因是dystrophin基因缺陷导致dystrophin蛋白的产生取消，dystrophin蛋白是正常肌肉和心脏功能的关键蛋白质。结果，DMD患者发展为缓慢进行性的肌肉退化和虚弱，导致12岁左右失去行走能力，并最终导致因呼吸或心脏肌肉衰竭而过早死亡，而男孩通常在20多岁。二十年前，1993年诺贝尔生理学或医学奖授予罗伯茨和夏普，以表彰他们里程碑式的发现，即所谓的“分裂基因”和RNA剪接--我们现在认识到，这是人类细胞内必不可少的过程，几乎是所有人类基因表达所必需的。科学认识的这种范式转变导致了这样的想法，即开发针对RNA并调节其加工的药物可能能够治疗包括DMD、脊髓性肌萎缩症(SMA)和肌萎缩侧索硬化症(ALS)在内的严重神经肌肉疾病-所有这些毁灭性的退行性疾病都会影响成人和儿童，并代表着巨大的未得到满足的医疗需求。近年来，虽然已经开发了许多治疗DMD的实验疗法，但使用反义寡核苷酸(AON)靶向RNA的方法-所谓的外显子跳过-可能是所有方法中最先进和最有前途的。在过去的十年中，伍德实验室和其他机构的世界领先工作证实了这些怡安药物对人类健康，特别是对DMD产生重大影响的潜力。然而，目前仍有重大的科学挑战有待克服，以便我们能够充分发挥这种治疗方法的潜力。这些挑战包括：这些大型AON药物对肌肉、心脏和大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，在心脏和大脑中的活性可以忽略不计；我们对药物活性与预防或逆转疾病进展方面的预期临床结果之间的联系的了解有限。该领域现在已经足够成熟，可以进入下一层次的理解，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来治疗神经肌肉疾病。我们的研究将建立关于在肌肉、心脏和大脑中有效的RNA靶向的决定因素、其局限性和根除严重的、危及生命的神经肌肉疾病的潜力的基本科学知识。它还将揭示大脑的基本知识，使我们能够了解在大脑和脊髓内靶向RNA可能被严重推进以治疗严重的成人神经疾病的科学基础。这反过来将充分利用靶向RNA改善人类健康的潜力。

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.