Recent clinical studies of single gene replacement therapy for neuromuscular disorders have shown they can slow or stop disease progression, but such therapies have had little impact on reversing muscle disease that was already present. To reverse disease in patients with muscular dystrophy, new muscle mass and strength must be rebuilt at the same time that gene replacement prevents subsequent disease. Here, we show that treatment of FKRP mice with a dual gene therapy packaged into a single adeno-associated virus (AAV) vector can build muscle strength and mass that exceed levels found in wild-type mice and can induce normal ambulation endurance in a 1-h walk test. Dual therapy also showed more even increases in muscle mass and amplified muscle expression of both genes relative to either single gene therapy alone. These data suggest that treatment with single AAV-bearing dual gene therapies can overcome loss of ambulation by improving muscle strength at the same time it prevents subsequent muscle damage. This design platform could be used to create therapies for other forms of muscular dystrophy that may improve patient outcomes.

中文翻译：

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FKRP/FST 双重基因疗法使 LGMDR9 小鼠的行走正常化、增加力量、减少病理并放大基因表达


最近针对神经肌肉疾病的单基因替代疗法的临床研究表明，它们可以减缓或阻止疾病进展，但此类疗法对逆转已经存在的肌肉疾病影响甚微。为了逆转肌营养不良症患者的疾病，必须重建新的肌肉质量和力量，同时进行基因替换以预防后续疾病。在这里，我们表明，用包装到单个腺相关病毒（AAV）载体中的双基因疗法治疗 FKRP 小鼠可以增强肌肉力量和质量，超过野生型小鼠的水平，并且可以在 1 个月内诱导正常的行走耐力。 -h 步行测试。相对于单独的单基因疗法，双重疗法还显示出肌肉质量的更均匀增加以及两种基因的肌肉表达的增强。这些数据表明，使用单一携带 AAV 的双基因疗法可以通过提高肌肉力量来克服行走能力的丧失，同时防止随后的肌肉损伤。该设计平台可用于创建针对其他形式的肌营养不良症的疗法，从而改善患者的治疗效果。