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Non-viral, integrin-mediated gene transfer into fibroblasts from patients with lysosomal storage diseases

Journal of Gene Medicine, ISSN: 1099-498X, Vol: 3, Issue: 5, Page: 488-497
2001
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Article Description

Background Non-viral vectors consisting of Lipofectin/integrin-targeting peptide/DNA (LID) complexes have great potential for gene therapy, as they are safe, simple, and able to package large DNA molecules. In this study, these vectors were evaluated in vitro for the therapy of lysosomal storage disorders. Methods Non-viral vectors were designed to deliver therapeutic genes by integrin-mediated uptake into fibroblasts from patients with the lysosomal storage disorders fucosidosis and Fabry disease, which result from deficiencies of α-L-fucosidase and α-galactosidase A, respectively. The vectors consisted of a complex (LID) of Lipofectin and a peptide containing an integrin-targeting domain and a poly-lysine domain to which was bound plasmid DNA, containing α-L-fucosidase (LID-α-Fuc) or α-galactosidase A (LID-α-Gal). Results Patients' fibroblasts transfected with LID-α-Fuc and LID-α-Gal produced the corresponding enzyme at levels which were 10-40% of the total activity in cultures of normal fibroblasts. However, 95-98% of this activity was secreted. Transfection of endothelial cells, the main target cells in Fabry disease, with an LID-α-Gal produced a total α-galactosidase activity 65% higher than that in untransfected cultures after 6 days, 67% of the activity being secreted. Although transfection of fibroblasts with LID complexes also caused small changes in the distribution of endogenous lysosomal enzymes, it did not appear to affect the viability of the cells. Conclusions The integrin-mediated transfer of genes encoding lysosomal enzymes into cells results in the secretion of large amounts of normal enzyme that could be taken up by other cells. This could be a useful strategy for enzyme-replacement therapy. Copyright © 2001 John Wiley & Sons, Ltd.

Bibliographic Details

Elaine Joanna Estruch; Bryan G. Winchester; Stephen Lewis Hart; Christine Kinnon

Wiley

Biochemistry, Genetics and Molecular Biology; Pharmacology, Toxicology and Pharmaceutics; Medicine

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