Mah C, Cresawn K O, Fraites T J, Pacak C A, Lewis M A, Zolotukhin I, Byrne B J
Powell Gene Therapy Center, University of Florida College of Medicine, Gainesville, FL 32610-0296, USA.
Gene Ther. 2005 Sep;12(18):1405-9. doi: 10.1038/sj.gt.3302550.
Glycogen storage disease type II (GSDII) is caused by a lack of functional lysosomal acid alpha-glucosidase (GAA). Affected individuals store glycogen in lysosomes beginning during gestation, ultimately resulting in fatal hypertrophic cardiomyopathy and respiratory failure. We have assessed the utility of recombinant adeno-associated virus (rAAV) vectors to restore GAA activity in vivo in a mouse model of GSDII (Gaa(-/-)). A single systemic administration of a rAAV serotype 1 (rAAV1) vector to neonate animals resulted in restored cardiac GAA activity to 6.4 times the normal level (mean=641+/-190% of normal (Gaa(+/+)) levels with concomitant glycogen clearance) at 11 months postinjection. Greater than 20% of normal levels of GAA activity were also observed in the diaphragm and quadriceps muscles. Furthermore, functional correction of the soleus skeletal muscle was also observed compared to age-matched untreated Gaa(-/-) control animals. These results demonstrate that rAAV1 vectors can mediate sustained therapeutic levels of correction of both skeletal and cardiac muscles in a model of fatal cardiomyopathy and muscular dystrophy.
II型糖原贮积病（GSDII）是由功能性溶酶体酸性α-葡萄糖苷酶（GAA）缺乏引起的。受影响个体从妊娠期间开始在溶酶体中储存糖原，最终导致致命的肥厚性心肌病和呼吸衰竭。我们评估了重组腺相关病毒（rAAV）载体在GSDII小鼠模型（Gaa(-/-)）体内恢复GAA活性的效用。对新生动物单次全身给予rAAV血清型1（rAAV1）载体，在注射后11个月时，心脏GAA活性恢复至正常水平的6.4倍（平均为正常（Gaa(+/+)）水平的641±190%），同时糖原清除。在膈肌和股四头肌中也观察到GAA活性高于正常水平的20%。此外，与年龄匹配的未治疗Gaa(-/-)对照动物相比，比目鱼肌骨骼肌的功能也得到了纠正。这些结果表明，rAAV1载体可以在致命性心肌病和肌肉萎缩症模型中介导骨骼肌和心肌的持续治疗水平的纠正。
