PDF(Pubmed)
Abstract：
Micro-dystrophin gene replacement therapies for Duchenne muscular dystrophy (DMD) are currently in clinical trials, but have not been thoroughly investigated for their efficacy on cardiomyopathy progression to heart failure. We previously validated Fiona/dystrophin-utrophin-deficient (dko) mice as a DMD cardiomyopathy model that progresses to reduced ejection fraction indicative of heart failure. Adeno-associated viral (AAV) vector delivery of an early generation micro-dystrophin prevented cardiac pathology and functional decline through 1 year of age in this new model. We now show that gene therapy using a micro-dystrophin optimized for skeletal muscle efficacy (AAV-μDys5), and which is currently in a clinical trial, is able to fully prevent cardiac pathology and cardiac strain abnormalities and maintain normal (>45%) ejection fraction through 18 months of age in Fiona/dko mice. Early treatment with AAV-μDys5 prevents inflammation and fibrosis in Fiona/dko hearts. Collagen in cardiac fibrotic scars becomes more tightly packed from 12 to 18 months in Fiona/dko mice, but the area of fibrosis containing tenascin C does not change. Increased tight collagen correlates with unexpected improvements in Fiona/dko whole-heart function that maintain impaired cardiac strain and strain rate. This study supports micro-dystrophin gene therapy as a promising intervention for preventing DMD cardiomyopathy progression.
摘要：
针对Duchenne型肌营养不良症（DMD）的微肌营养不良蛋白基因替代疗法目前正在临床试验中，但尚未对其对心肌病进展为心力衰竭的疗效进行彻底研究。我们先前验证了Fiona/肌养蛋白-肌养蛋白缺陷(dko)小鼠作为DMD心肌病模型,其进展到指示心力衰竭的降低的射血分数。在这种新模型中，早期微肌营养不良蛋白的腺相关病毒（AAV）载体递送可预防1岁以下的心脏病理学和功能下降。我们现在表明，使用针对骨骼肌功效优化的微肌营养不良蛋白（AAV-μDys5）进行基因治疗，目前正在进行临床试验，在Fiona/dko小鼠中，能够完全预防心脏病理学和心脏劳损异常，并在18个月大之前保持正常（>45％）的射血分数。用AAV-μDys5的早期治疗可预防Fiona/dko心脏的炎症和纤维化。在Fiona/dko小鼠中，从12到18个月，心脏纤维化疤痕中的胶原蛋白变得更紧密。但含有生腱蛋白C的纤维化面积没有变化。紧密胶原蛋白的增加与Fiona/dko整个心脏功能的意外改善相关，从而维持受损的心脏劳损和劳损率。这项研究支持微肌营养不良蛋白基因治疗作为预防DMD心肌病进展的有希望的干预措施。
