Abstract：
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 FKRPP448L mice with a dual FKRP/FST 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 FKRP/FST 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 FKRP/FST 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.
摘要：
最近对单基因替代疗法治疗神经肌肉疾病的临床研究表明，它们可以减缓或阻止疾病进展，但是这种疗法对逆转已经存在的肌肉疾病几乎没有影响。为了逆转肌营养不良患者的疾病，新的肌肉质量和力量必须在基因替代防止后续疾病的同时重建。这里,我们表明,FKRPP448L小鼠用包装在单个AAV载体中的双重FKRP/FST基因治疗治疗,可以建立超过野生型小鼠的肌肉力量和质量,并且可以在一小时步行试验中诱导正常的步行耐力.双重FKRP/FST疗法还显示出相对于单独的任一单一基因疗法,两个基因的肌肉质量和扩增的肌肉表达更均匀的增加。这些数据表明,用携带FKRP/FST双重基因疗法的单一AAV治疗可以通过改善肌肉力量同时防止随后的肌肉损伤来克服步行损失。该设计平台可用于创建其他形式的肌营养不良症的疗法，以改善患者的预后。
