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Hydrostatic isolated limb perfusion with adeno-associated virus vectors enhances correction of skeletal muscle in Pompe disease

Gene Therapy volume 17, pages 1500–1505 (2010)Cite this article

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Abstract

Glycogen storage disease type II (Pompe disease; MIM 232300) stems from the inherited deficiency of acid-α-glucosidase (GAA; acid maltase; EC 3.2.1.20), which primarily involves cardiac and skeletal muscles. We hypothesized that hydrostatic isolated limb perfusion (ILP) administration of an adeno-associated virus (AAV) vector containing a muscle-specific promoter could achieve relatively higher transgene expression in the hindlimb muscles of GAA-knockout (GAA-KO) mice, in comparison with intravenous (IV) administration. ILP administration of AAV2/8 vectors encoding alkaline phosphatase or human GAA-transduced skeletal muscles of the hindlimb widely, despite the relatively low number of vector particles administered (1 × 1011), and IV administration of an equivalent vector dose failed to transduce skeletal muscle detectably. Similarly, ILP administration of fewer vector particles of the AAV2/9 vector encoding human GAA (3 × 1010) transduced skeletal muscles of the hindlimb widely and significantly reduced glycogen content to, in comparison with IV administration. The only advantage for IV administration was moderately high-level transduction of cardiac muscle, which demonstrated compellingly that ILP administration sequestered vector particles within the perfused limb. Reduction of glycogen storage in the extensor digitorum longus demonstrated the potential advantage of ILP-mediated delivery of AAV vectors in Pompe disease, because type II myofibers are resistant to enzyme replacement therapy. Thus, ILP will enhance AAV transduction of multiple skeletal muscles while reducing the required dosages in terms of vector particle numbers.

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Acknowledgements

This work was supported by NIH Grant R01 HL081122 from the National Heart, Lung and Blood Institute. BS was supported by the Muscular Dystrophy Association. GAA-KO mice were provided courtesy of Dr Nina Raben at the National Institutes of Health (Bethesda, MD, USA). The AAV8 and AAV9 packaging plasmids were provided courtesy of Dr James M Wilson at the University of Pennsylvania (Philadelphia, PA, USA).

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  1. Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA

    B Sun, S Li, A Bird & D D Koeberl

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  1. B Sun
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Correspondence to D D Koeberl.

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Sun, B., Li, S., Bird, A. et al. Hydrostatic isolated limb perfusion with adeno-associated virus vectors enhances correction of skeletal muscle in Pompe disease. Gene Ther 17, 1500–1505 (2010). https://doi.org/10.1038/gt.2010.109

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