Phenotypic improvement of dystrophic muscles by rAAV/microdystrophin vectors is augmented by Igf1 codelivery
Phenotypic improvement of dystrophic muscles by rAAV/microdystrophin vectors is augmented by Igf1 codelivery
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DOI：
10.1016/j.ymthe.2005.04.001
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发表时间：
2005-09-01
影响因子：
12.4
通讯作者：
Chamberlain, JS
中科院分区：
文献类型：
--
作者：
Abmayr, S;Gregorevic, P;Chamberlain, JS
在杜氏肌营养不良症（DMD）中，肌营养不良蛋白的缺失导致肌膜不稳定，并增强肌纤维对收缩诱导的损伤的易感性。各种病毒载体已被用于将微型和微型肌营养不良蛋白表达盒递送至肌营养不良蛋白缺陷型mdx小鼠的肌肉，显著增加肌肉的形态和功能特性。然而，向成年mdx小鼠递送抗肌萎缩蛋白并没有完全挽救营养不良表型。在这里，我们研究了一种新的策略，涉及双重基因转移的重组腺相关病毒载体表达微肌营养不良蛋白（rAAV-mu Dys）或肌肉特异性同种型的Igf-1（rAAV-mlgf-1）。注射mdx肌肉与rAAV-mu Dys减少肌纤维变性和营业额，并增加其对机械损伤的抵抗力，但不增加肌肉质量或力的产生。用rAAV-mlgf-1注射mdx肌肉导致肌肉质量增加，但不能提供针对机械损伤的保护或阻止肌纤维变性，导致载体随时间的损失。相比之下，rAAV-mu Dys和rAAV-mlgf-1载体的共注射导致肌肉质量和强度增加，肌纤维变性减少，并且针对收缩诱导的损伤的保护增加。这些结果表明，双基因组合策略可以提高DMD基因治疗的疗效。
The absence of dystrophin in Duchenne muscular dystrophy (DMD) leads to sarcolemmal instability and enhances the susceptibility of muscle fibers to contraction-induced injury. Various viral vectors have been used to deliver mini- and microdystrophin expression cassettes to muscles of dystrophindeficient mdx mice, significantly increasing both the morphological and the functional properties of the muscles. However, dystrophin delivery to adult mdx mice has not yielded a complete rescue of the dystrophic phenotype. Here we investigated a novel strategy involving dual gene transfer of recombinant adeno-associated viral vectors expressing either microdystrophin (rAAV- mu Dys) or a muscle-specific isoform of Igf-1 (rAAV-mlgf-1). Injection of mdx muscles with rAAV-mu Dys reduced myofiber degeneration and turnover and increased their resistance to mechanical injury, but did not increase muscle mass or force generation. Injection of mdx muscles with rAAV-mlgf-1 led to increased muscle mass, but did not provide protection against mechanical injury or halt myofiber degeneration, leading to loss of the vector over time. In contrast, co-injection of the rAAV-mu Dys and rAAV-mlgf-1 vectors resulted in increased muscle mass and strength, reduced myofiber degeneration, and increased protection against contraction-induced injury. These results suggest that a dual-gene, combinatorial strategy could enhance the efficacy of gene therapy of DMD.