MDUK Oxford Neuromuscular Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, U.K.
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX 3TA, U.K.
Biochem Soc Trans. 2020 Jun 30;48(3):813-821. doi: 10.1042/BST20190282.
Genetic approaches for the diagnosis and treatment of inherited muscle diseases have advanced rapidly in recent years. Many of the advances have occurred in the treatment of Duchenne muscular dystrophy (DMD), a muscle wasting disease where affected boys are typically wheelchair bound by age 12 years and generally die in their twenties from respiratory failure or cardiomyopathy. Dystrophin is a 421 kD protein which links F-actin to the extracellular matrix via the dystrophin-associated protein complex (DAPC) at the muscle membrane. In the absence of dystrophin, the DAPC is lost, making the muscle membrane more susceptible to contraction-induced injury. The identification of the gene causing DMD in 1986 resulted in improved diagnosis of the disease and the identification of hotspots for mutation. There is currently no effective treatment. However, there are several promising genetic therapeutic approaches at the preclinical stage or in clinical trials including read-through of stop codons, exon skipping, delivery of dystrophin minigenes and the modulation of expression of the dystrophin related protein, utrophin. In spite of significant progress, the problem of targeting all muscles, including diaphragm and heart at sufficiently high levels, remains a challenge. Any therapy also needs to consider the immune response and some treatments are mutation specific and therefore limited to a subgroup of patients. This short review provides a summary of the current status of DMD therapy with a particular focus on those genetic strategies that have been taken to the clinic.
近年来，用于遗传性肌肉疾病诊断和治疗的遗传方法取得了快速进展。许多进展都发生在杜氏肌营养不良症（DMD）的治疗中，这是一种肌肉消耗疾病，受影响的男孩通常在 12 岁时就需要坐轮椅，并且通常由于呼吸衰竭或心肌病在二十多岁时死亡。肌营养不良蛋白是一种 421kD 的蛋白质，通过肌膜上的肌营养不良蛋白相关蛋白复合物（DAPC）将 F-肌动蛋白与细胞外基质连接。在没有肌营养不良蛋白的情况下，DAPC 会丢失，使肌肉膜更容易受到收缩引起的损伤。1986 年，导致 DMD 的基因的鉴定导致了疾病的诊断得到改善，并确定了突变的热点。目前尚无有效的治疗方法。然而，有几种有前途的基因治疗方法处于临床前阶段或临床试验中，包括终止密码子通读、外显子跳跃、肌营养不良蛋白微基因的传递和肌营养不良蛋白相关蛋白 utrophin 的表达调控。尽管取得了重大进展，但仍存在一个挑战，即如何将药物靶向所有肌肉，包括膈肌和心脏，并达到足够高的水平。任何治疗方法还需要考虑免疫反应，并且一些治疗方法是针对特定突变的，因此仅限于一小部分患者。本文综述了 DMD 治疗的现状，特别关注已进入临床的基因治疗策略。
