Pompe disease is caused by the deficiency of lysosomal acid α-glucosidase (GAA). It is expected that gene therapy to replace GAA with adeno-associated virus (AAV) vectors will be less effective early in life because of the rapid loss of vector genomes. AAV2/8-LSPhGAA (3 × 1010 vector genomes [vg]/mouse) was administered to infant (2-week-old) or adult (2-month-old) GAA knockout mice. AAV vector transduction in adult mice significantly corrected GAA deficiency in the heart (p < 0.0001), diaphragm (p < 0.01), and quadriceps (p < 0.001) for >50 weeks. However, in infant mice, the same treatment only partially corrected GAA deficiency in the heart (p < 0.05), diaphragm (p < 0.05), and quadriceps (p < 0.05). The clearance of glycogen was much more efficient in adult mice compared with infant mice. Improved wire hang test latency was observed for treated adults (p < 0.05), but not for infant mice. Abnormal ventilation was corrected in both infant and adult mice. Vector-treated female mice demonstrated functional improvement, despite a lower degree of biochemical correction compared with male mice. The relative vector dose for infants was approximately 3-fold higher than adults, when normalized to body weight at the time of vector administration. Given these data, the dose requirement to achieve similar efficacy will be higher for the treatment of young patients.

中文翻译：

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比较婴儿和成年小鼠揭示的庞贝病肝贮藏基因疗法的年龄效应。

庞贝病是由溶酶体酸α-葡萄糖苷酶（GAA）缺乏引起的。可以预期，由于载体基因组的快速丧失，用腺相关病毒（AAV）载体替代GAA的基因疗法在生命早期将不太有效。将AAV2 / 8-LSPhGAA（3×1010个载体基因组[vg] /小鼠）施用于婴儿（2周龄）或成年（2月龄）GAA基因敲除小鼠。成年小鼠的AAV载体转导可显着纠正心脏（p <0.0001）、,肌（p <0.01）和股四头肌（p <0.001）超过50周的GAA缺乏症。但是，在婴儿小鼠中，相同的治疗只能部分纠正心脏（p <0.05），diaphragm肌（p <0.05）和股四头肌（p <0.05）的GAA缺乏症。与婴儿小鼠相比，成年小鼠的糖原清除效率更高。观察到治疗后的成年鼠的电线悬挂测试潜伏期延长（p <0.05），而婴儿小鼠则没有。纠正了婴儿和成年小鼠的异常通气。用载体处理的雌性小鼠表现出功能改善，尽管与雄性小鼠相比生化校正程度较低。当以载体给药时的体重标准化时，婴儿的相对载体剂量比成人高约3倍。鉴于这些数据，对于年轻患者的治疗，达到类似功效的剂量要求将更高。当以载体给药时的体重标准化时，婴儿的相对载体剂量比成人高约3倍。鉴于这些数据，对于年轻患者的治疗，达到类似功效的剂量要求将更高。当以载体给药时的体重标准化时，婴儿的相对载体剂量比成人高约3倍。鉴于这些数据，对于年轻患者的治疗，达到类似功效的剂量要求将更高。