Pharmacological therapeutics targeting the secondary defects and downstream pathology of Duchenne muscular dystrophy.
Pharmacological therapeutics targeting the secondary defects and downstream pathology of Duchenne muscular dystrophy.
复制标题
DOI：
10.1080/21678707.2016.1240613
复制
发表时间：
2016
影响因子：
0.8
通讯作者：
Kunkel LM
中科院分区：
文献类型：
--
作者：
Spinazzola JM;Kunkel LM
自从1986年肌营养不良蛋白基因被发现以来，杜氏肌营养不良症（DMD）的治疗方法还没有被发现。目前，有许多基于基因的疗法正在开发中，旨在恢复和/或修复原发性缺陷。然而，越来越多的了解的病理生理后果的肌营养不良蛋白的情况下，揭示了几个有前途的下游靶点的治疗发展。在这篇综述中，我们讨论了DMD治疗的各种策略，针对下游的后果，肌营养不良蛋白的缺乏，包括肌肉质量损失，炎症，纤维化，钙超载，氧化应激和缺血。每种方法的原理和药物在临床前和临床研究中的疗效进行了讨论。在过去的30年里，有效的DMD药物治疗仅限于皮质类固醇，这与许多负面副作用有关。我们对肌营养不良蛋白缺乏导致DMD病理学的后果的了解揭示了几个潜在的治疗靶点。这些方法中的一些可能具有单独或与基于遗传的方法组合改善或减缓疾病进展的潜力。这些药物治疗对DMD患者的适用性，无论其基因突变如何，以及即使对晚期患者的潜在益处，都值得继续研究。
Since the identification of the dystrophin gene in 1986, a cure for Duchenne muscular dystrophy (DMD) has yet to be discovered. Presently, there are a number of genetic-based therapies in development aimed at restoration and/or repair of the primary defect. However, growing understanding of the pathophysiological consequences of dystrophin absence has revealed several promising downstream targets for the development of therapeutics. In this review, we discuss various strategies for DMD therapy targeting downstream consequences of dystrophin absence including loss of muscle mass, inflammation, fibrosis, calcium overload, oxidative stress, and ischemia. The rationale of each approach and the efficacy of drugs in preclinical and clinical studies are discussed. For the last 30 years, effective DMD drug therapy has been limited to corticosteroids, which are associated with a number of negative side effects. Our knowledge of the consequences of dystrophin absence that contribute to DMD pathology has revealed several potential therapeutic targets. Some of these approaches may have potential to improve or slow disease progression independently or in combination with genetic-based approaches. The applicability of these pharmacological therapies to DMD patients irrespective of their genetic mutation, as well as the potential benefits even for advanced stage patients warrants their continued investigation.