Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Hum Gene Ther. 2011 Dec;22(12):1499-509. doi: 10.1089/hum.2011.102. Epub 2011 Aug 30.
Duchenne muscular dystrophy (DMD) is a lethal, X-linked recessive disease affecting 1 in 3,500 newborn boys for which there is no effective treatment or cure. One novel strategy that has therapeutic potential for DMD is inhibition of myostatin, a negative regulator of skeletal muscle mass that may also promote fibrosis. Therefore, our goal in this study was to evaluate systemic myostatin inhibition in the golden retriever model of DMD (GRMD). GRMD canines underwent liver-directed gene transfer of a self-complementary adeno-associated virus type 8 vector designed to express a secreted dominant-negative myostatin peptide (n = 4) and were compared with age-matched, untreated GRMD controls (n = 3). Dogs were followed with serial magnetic resonance imaging (MRI) for 13 months to assess cross-sectional area and volume of skeletal muscle, then euthanized so that tissue could be harvested for morphological and histological analysis. We found that systemic myostatin inhibition resulted in increased muscle mass in GRMD dogs as assessed by MRI and confirmed at tissue harvest. We also found that hypertrophy of type IIA fibers was largely responsible for the increased muscle mass and that reductions in serum creatine kinase and muscle fibrosis were associated with long-term myostatin inhibition in GRMD. This is the first report describing the effects of long-term, systemic myostatin inhibition in a large-animal model of DMD, and we believe that the simple and effective nature of our liver-directed gene-transfer strategy makes it an ideal candidate for evaluation as a novel therapeutic approach for DMD patients.
杜氏肌营养不良症（DMD）是一种致命的 X 连锁隐性疾病，每 3500 名新生男婴中就有 1 名受到影响，目前尚无有效的治疗或治愈方法。一种具有治疗 DMD 潜力的新策略是抑制肌肉生长抑制素，肌肉生长抑制素是一种骨骼肌质量的负调节剂，也可能促进纤维化。因此，我们在这项研究中的目标是评估 DMD 金毛猎犬模型中的系统性肌肉生长抑制素抑制作用（GRMD）。GRMD 犬接受了肝脏定向基因转移的自互补腺相关病毒 8 载体，该载体旨在表达一种分泌型显性负性肌肉生长抑制素肽（n = 4），并与年龄匹配的未经治疗的 GRMD 对照犬（n = 3）进行了比较。狗接受了 13 个月的连续磁共振成像（MRI）检查，以评估骨骼肌的横截面积和体积，然后安乐死以收获组织进行形态学和组织学分析。我们发现，系统性肌肉生长抑制素抑制导致 GRMD 犬的肌肉质量增加，这可以通过 MRI 评估，并在组织收获时得到证实。我们还发现，IIA 型纤维的肥大在很大程度上是导致肌肉质量增加的原因，而血清肌酸激酶和肌肉纤维化的减少与 GRMD 中的长期肌肉生长抑制素抑制有关。这是首次描述在 DMD 大动物模型中进行长期系统性肌肉生长抑制素抑制的效果，我们相信我们的肝脏定向基因转移策略的简单有效性质使其成为评估 DMD 患者新型治疗方法的理想候选者。
