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

Sun, B

Li, S

Bird, A

Koeberl, DD

England

2017-03-01T14:20:26Z

2017-03-01T14:20:26Z

2010-12

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.

https://www.ncbi.nlm.nih.gov/pubmed/20686508

gt2010109

1476-5462

https://hdl.handle.net/10161/13714

eng

Springer Science and Business Media LLC

Gene Ther

10.1038/gt.2010.109

Animals

Dependovirus

Disease Models, Animal

Genetic Therapy

Genetic Vectors

Glycogen Storage Disease Type II

HEK293 Cells

Hindlimb

Humans

Infusions, Intravenous

Mice

Mice, Inbred C57BL

Mice, Knockout

Muscle, Skeletal

Perfusion

Promoter Regions, Genetic

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

Journal article

Sun, B|0000-0002-2191-0025

Koeberl, DD|0000-0003-4513-2464

https://www.ncbi.nlm.nih.gov/pubmed/20686508

1500

1505

12

Basic Science Departments

Clinical Science Departments

Duke

Molecular Genetics and Microbiology

Pediatrics

Pediatrics, Medical Genetics

School of Medicine

Published

17