Micro-dystrophin and follistatin co-delivery restores muscle function in aged DMD model.
Micro-dystrophin and follistatin co-delivery restores muscle function in aged DMD model.
复制标题
DOI：
10.1093/hmg/ddt342
复制
发表时间：
2013-12
影响因子：
3.5
通讯作者：
L. Rodino-Klapac;P. Janssen;K. Shontz;Benjamin D. Canan;C. Montgomery;D. Griffin;K. Heller;K. Heller-K.
中科院分区：
文献类型：
--
作者：
L. Rodino-Klapac;P. Janssen;K. Shontz;Benjamin D. Canan;C. Montgomery;D. Griffin;K. Heller;K. Heller-K.
药理学策略在毁灭性的肌肉消耗性疾病杜氏肌营养不良症（DMD）中提供了适度的改善。临床前基因治疗研究在mdx小鼠模型中显示出了希望;然而，在疾病发作后进行的研究未能完全纠正肌肉力量或防止收缩引起的损伤。在这里，我们研究了治疗效果与显着的疾病病理老年营养不良小鼠肌肉生理学相结合的两种有前途的疗法：微肌营养不良蛋白基因替代和肌肉增强卵泡抑素，一种有效的肌肉生长抑制素抑制剂。用微肌养蛋白和卵泡抑素单独治疗mdx小鼠表现出显著的改善，但不足以完全恢复肌肉力量和对野生型水平的损伤的反应。引人注目的是，当组合时，微肌养蛋白/卵泡抑素治疗恢复了力的产生，并赋予老年mdx小鼠对收缩诱导的损伤的抵抗力。微型肌营养不良蛋白的临床前研究未能证明mdx小鼠中观察到的生理缺陷的完全纠正。重要的是，增加了一个肌肉增强策略，与微肌营养不良蛋白基因治疗相结合的卵泡抑素的交付完全恢复抵抗离心收缩引起的损伤和改善的力量。离心收缩引起的损伤是与DMD患者中发生的运动引起的损伤相关的临床前参数，并且在此，我们证明了微肌营养不良蛋白/卵泡抑素组合疗法的治疗潜力的令人信服的证据。
Pharmacologic strategies have provided modest improvement in the devastating muscle-wasting disease, Duchenne muscular dystrophy (DMD). Pre-clinical gene therapy studies have shown promise in the mdx mouse model; however, studies conducted after disease onset fall short of fully correcting muscle strength or protecting against contraction-induced injury. Here we examine the treatment effect on muscle physiology in aged dystrophic mice with significant disease pathology by combining two promising therapies: micro-dystrophin gene replacement and muscle enhancement with follistatin, a potent myostatin inhibitor. Individual treatments with micro-dystrophin and follistatin demonstrated marked improvement in mdx mice but were insufficient to fully restore muscle strength and response to injury to wild-type levels. Strikingly, when combined, micro-dystrophin/follistatin treatment restored force generation and conferred resistance to contraction-induced injury in aged mdx mice. Pre-clinical studies with miniature dystrophins have failed to demonstrate full correction of the physiological defects seen in mdx mice. Importantly, the addition of a muscle enhancement strategy with delivery of follistatin in combination with micro-dystrophin gene therapy completely restored resistance to eccentric contraction-induced injury and improved force. Eccentric contraction-induced injury is a pre-clinical parameter relevant to the exercise induced injury that occurs in DMD patients, and herein, we demonstrate compelling evidence for the therapeutic potential of micro-dystrophin/follistatin combinatorial therapy.