Efficacy of gene therapy for a prototypical lysosomal storage disease (GSD-II) is critically dependent on vector dose, transgene promoter, and the tissues targeted for vector transduction
Efficacy of gene therapy for a prototypical lysosomal storage disease (GSD-II) is critically dependent on vector dose, transgene promoter, and the tissues targeted for vector transduction
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DOI：
10.1006/mthe.2002.0563
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发表时间：
2002-04-01
影响因子：
12.4
通讯作者：
Amalfitano, A
中科院分区：
文献类型：
--
作者：
Ding, EY;Hu, HM;Amalfitano, A
溶酶体贮积病是基因治疗方法的一个有趣的靶标，因为用编码溶酶体酶的转基因转导“贮库”器官之后可以是酶分泌、全身分布、下游摄取和溶酶体靶向到非转导组织中。当考虑糖原累积病II型（GSD-II）的基因治疗方法时，这些益处是至关重要的。GSD-II是由溶酶体内酸性α-葡糖苷酶（GAA）活性缺乏引起的典型溶酶体贮积症。缺乏GAA可导致近端肢体肌病以及呼吸和心力衰竭，每种都分别由于骨骼肌或心脏组织中的异常糖原积累。在将肝脏转化为“储库”器官后，我们发现静脉注射[E1-，聚合酶-]AdGAA载体允许肝脏分泌超过至少20倍剂量范围的GAA。我们注意到，非常低的血浆GAA水平（来自肝脏分泌的GAA）可以允许肌肉组织（骨骼或心脏）摄取GAA，但在这些相同组织中发生糖原“交叉校正”之前，需要显著更高的血浆GAA水平。我们还证明了肝脏特异性增强子/启动子延长了GAA转基因从基于持久性[E1-，聚合酶-]腺病毒的载体基因组的表达至少180天，并显著减少了在该动物模型中引起的中和抗GAA抗体的量。最后，我们证明了骨骼肌也可以作为GAA分泌的“储库”器官，允许GAA的分泌及其被未感染的远端组织摄取，尽管后一种方法没有实现非注射肌肉中的糖原减少。
Lysosomal storage diseases are an intriguing target for gene therapy approaches, as transduction of a "depot" organ with a transgene encoding a lysosomal enzyme can be followed by secretion, systemic distribution, downstream uptake, and lysosomal targeting of the enzyme into non-transduced tissues. These benefits are of utmost importance when considering gene therapy approaches for glycogen storage disease type-II (GSD-II). GSD-II is a prototypical lysosomal storage disorder caused by lack of intralysosomal acid alpha-glucosidase (GAA) activity. Lack of GAA can result in a proximal limb myopathy and respiratory and cardiac failure, each due to abnormal glycogen accumulation in the skeletal muscles or cardiac tissues, respectively. After converting the liver into a "depot" organ, we found that intravenous injection of the [E1-,polymerase-]AdGAA vector allowed for hepatic secretion of GAA over an at least 20-fold dosage range. We noted that very low plasma GAA levels (derived from hepatic secretion of GAA) can allow for GAA uptake by muscle tissues (skeletal or cardiac), but significantly higher plasma GAA levels are required before glycogen "cross-correction" can occur in these same tissues. We also demonstrated that liver-specific enhancer/promoters prolonged GAA transgene expression from persistent [E1-,polymerase-] adenovirus based vector genomes for at least 180 days, and significantly diminished the amounts of neutralizing anti-GAA antibodies elicited in this animal model. Finally, we demonstrated that skeletal muscles can also serve as a "depot" organ for GAA secretion, allowing for secretion of GAA and its uptake by noninfected distal tissues, although glycogen reductions in non-injected muscles were not achieved by the latter approach.