Systemic correction of the muscle disorder glycogen storage disease type II after hepatic targeting of a modified adenovirus vector encoding human acid-α-glucosidase
Systemic correction of the muscle disorder glycogen storage disease type II after hepatic targeting of a modified adenovirus vector encoding human acid-α-glucosidase
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DOI：
10.1073/pnas.96.16.8861
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发表时间：
1999-08-03
影响因子：
11.1
通讯作者：
Chen, YT
中科院分区：
文献类型：
--
作者：
Amalfitano, A;McVie-Wylie, AJ;Chen, YT
该报告表明，基因治疗载体的单次静脉给药可能导致人类遗传性肌肉疾病小鼠模型中所有受影响肌肉的矫正。这些结果是通过利用修饰的基于腺病毒的载体系统和受体介导的酶的溶酶体靶向的积极属性来实现的。所治疗的肌肉疾病，糖原累积病II型，是表现为进行性肌病的溶酶体累积病，继发于受影响个体的骨骼肌和/或心肌中的大量糖原累积，我们证明，单次静脉注射编码人酸性α-葡萄糖苷酶（GAA）的修饰Ad载体，导致高水平的前体GAA酶原的有效肝转导和分泌到治疗动物的血浆中。随后，证实了GAA敲除小鼠的骨骼肌和心肌中酶酶原的全身分布和摄取。结果，证明了各种肌肉组织中糖原累积的全身性减少（和校正）。该模型可以潜在地扩展到包括其他溶酶体酶疾病的治疗。从肌肉疾病的系统性基因治疗中吸取的教训也应该对其他肌肉疾病，如肌营养不良症产生影响。
This report demonstrates that a single intravenous administration of a gene therapy vector can potentially result in the correction of all affected muscles in a mouse model of a human genetic muscle disease. These results were achieved by capitalizing both on the positive attributes of modified adenovirus-based vectoring systems and receptor-mediated lysosomal targeting of enzymes. The muscle disease treated, glycogen storage disease type II, is a lysosomal storage disorder that manifests as a progressive myopathy, secondary to massive glycogen accumulations in the skeletal and/or cardiac muscles of affected individuals, We demonstrated that a single intravenous administration of a modified Ad vector encoding human acid alpha-glucosidase (GAA) resulted in efficient hepatic transduction and secretion of high levels of the precursor GAA proenzyme into the plasma of treated animals. Subsequently, systemic distribution and uptake of the proenzyme into the skeletal and cardiac muscles of the GAA-knockout mouse was confirmed. As a result, systemic decreases (and correction) of the glycogen accumulations in a variety of muscle tissues was demonstrated. This model can potentially be expanded to include the treatment of other lysosomal enzyme disorders. Lessons learned from systemic genetic therapy of muscle disorders also should have implications for other muscle diseases, such as the muscular dystrophies.