Adenoviral gene transfer restores lysyl hydroxylase activity in type VI Ehlers-Danlos syndrome.

Abstract

Type VI Ehlers-Danlos syndrome is a disease characterized by disturbed lysine hydroxylation of collagen. The disease is caused by mutations in lysyl hydroxylase 1 gene and it affects several organs including the cardiovascular system, the joint and musculoskeletal system, and the skin. The skin of type VI Ehlers-Danlos syndrome patients is hyperelastic, scars easily, and heals slowly and poorly. We hypothesized that providing functional lysyl hydroxylase 1 gene to the fibroblasts in and around wounds in these patients would improve healing. In this study we tested the feasibility of transfer of the lysyl hydroxylase 1 gene into fibroblasts derived from rats and a type VI Ehlers-Danlos syndrome patient (in vitro) and into rat skin (in vivo). We first cloned human lysyl hydroxylase 1 cDNA into a recombinant adenoviral vector (Ad5RSV-LH). Transfection of human type VI Ehlers-Danlos syndrome fibroblasts (about 20% of normal lysyl hydroxylase 1 activity) with the vector increased lysyl hydroxylase 1 activity in these cells to near or greater levels than that of wild type, unaffected fibroblasts. The adenoviral vector successfully transfected rat fibroblasts producing both beta-galactosidase and lysyl hydroxylase 1 gene activity. We next expanded our studies to a rodent model. Intradermal injections of the vector to the abdominal skin of rats produced lysyl hydroxylase 1 mRNA and elevated lysyl hydroxylase 1 activity, in vivo. These data suggest the feasibility of gene replacement therapy to modify skin wound healing in type VI Ehlers-Danlos syndrome patients.

• Authors: T Rauma, S Kumpumäki, R Anderson, B L Davidson, H Ruotsalainen, R Myllylä, T Hautala
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 116 Issue 4 Pg. 602-5 (Apr 2001) ISSN: 0022-202X [Print] United States
• PMID: 11286629 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• RNA, Messenger
• Hydroxylysine
• Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase
• Galactosidases

Topics

• Adenoviridae (genetics)
• Ehlers-Danlos Syndrome (classification, enzymology, pathology)
• Fibroblasts (enzymology)
• Galactosidases (genetics)
• Gene Transfer Techniques
• Humans
• Hydroxylysine (metabolism)
• Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase (genetics, metabolism)
• RNA, Messenger (metabolism)
• Skin (enzymology, metabolism, pathology, physiopathology)