Human Molecular Genetics, 2002, Vol. 11, No. 14 1637-1645
© 2002 Oxford University Press
Muscle as a putative producer of acid 
-glucosidase for glycogenosis type II gene therapy
1Département de Génétique, Développement et Pathologie Moléculaire, Institut Cochin, INSERM U567, Paris, France, 2Université Paris V, Paris, France, 3INSERM U153, Hopital de la Salpétrière, Paris, France, 4Dipartimento di Scienze Biochimiche e Biotecnologie Molecolar, University of Perugia, Italy, 5Généthon III, CNRS URA 1923, Evry, France and 6NIH, Bethesda, MD, USA
Received March 1, 2002; Accepted April 29, 2002
Glycogenosis type II (GSD II) is a lysosomal disorder affecting skeletal and cardiac muscle. In the infantile form of the disease, patients display cardiac impairment, which is fatal before 2 years of life. Patients with juvenile or adult forms can present diaphragm involvement leading to respiratory failure. The enzymatic defect in GSD II results from mutations in the acid 
-glucosidase (GAA) gene, which encodes a 76 kDa protein involved in intralysosomal glycogen hydrolysis. We previously reported the use of an adenovirus vector expressing GAA (AdGAA) for the transduction of myoblasts and myotubes cultures from GSD II patients. Transduced cells secreted GAA in the medium, and GAA was internalized by receptor-mediated capture, allowing glycogen hydrolysis in untransduced cells. In this study, using a GSD II mouse model, we evaluated the feasibility of GSD II gene therapy using muscle as a secretary organ. Adenovirus vector encoding AdGAA was injected in the gastrocnemius of neonates. We detected a strong expression of GAA in the injected muscle, secretion into plasma, and uptake by peripheral skeletal muscle and the heart. Moreover, glycogen content was decreased in these tissues. Electron microscopy demonstrated the disappearance of destruction foci, normally present in untreated mice. We thus demonstrate for the first time that muscle can be considered as a safe and easily accessible organ for GSD II gene therapy.
* To whom correspondence should be addressed at: Département de Génétique, Développement et Pathologie Moléculaire, Institut Cochin, INSERM U567, 24 rue du faubourg Saint-Jacques, 75014 Paris, France. Tel: +33 1 44412401; Email: emt{at}cochin.inserm.fr
Present address: INSERM U505, Institut des Cordeliers, Paris, France.
Present address: Institut de Génétique Moléculaire de Montpellier, CNRS UMR 5535, Montpellier, France.
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