title: A preliminary in vitro study into the use of IL-1Ra gene therapy for the inhibition of intervertebral disc degeneration.
abstract: Conventional therapies for low back pain (LBP) are purely symptomatic and do not target the cause of LBP, which in approximately 40% of cases is caused by degeneration of the intervertebral disc (DIVD). Targeting therapies to inhibit the process of degeneration would be a potentially valuable treatment for LBP. There is increasing evidence for a role for IL-1 in DIVD. A natural inhibitor of IL-1 exists, IL-1Ra, which would be an ideal molecular target for inhibiting IL-1-mediated effects involved in DIVD and LBP. In this study, the feasibility of ex vivo gene transfer of IL-1Ra to the IVD was investigated. Monolayer and alginate cultures of normal and degenerate human intervertebral disc (IVD) cells were infected with an adenoviral vector carrying the IL-1Ra gene (Ad-IL-1Ra) and protein production measured using an enzyme-linked immunosorbent assay. The ability of these infected cells to inhibit the effects of IL-1 was also investigated. In addition, normal and degenerate IVD cells infected with Ad-IL-1Ra were injected into degenerate disc tissue explants and IL-1Ra production in these discs was assessed. This demonstrated that both nucleus pulposus and annulus fibrosus cells infected with Ad-IL-1Ra produced elevated levels of IL-1Ra for prolonged time periods, and these infected cells were resistant to IL-1. When the infected cells were injected into disc explants, IL-1Ra protein expression was increased which was maintained for 2 weeks of investigation. This in vitro study has shown that the use of ex vivo gene transfer to degenerate disc tissue is a feasible therapy for the inhibition of IL-1-mediated events during disc degeneration.
authors.affiliation: Division of Laboratory and Regenerative Medicine, School of Medicine, University of Manchester, Manchester, UK.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Le Maitre
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Freemont
authors.forename: Judith A
authors.initials: JA
authors.lastname: Hoyland
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002478:Cells, Cultured; D017364:Collagenases / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000494:pharmacology; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000378:metabolism; D007403:Intervertebral Disc / Q000473:pathology*; D053509:Matrix Metalloproteinase 13; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D008856:Microscopy, Fluorescence; D012795:Sialoglycoproteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D013122:Spinal Diseases / Q000473:pathology* / Q000628:therapy*; D013997:Time Factors; D014161:Transduction, Genetic / Q000379:methods
chemical_list: C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D012795:Sialoglycoproteins; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D019278:Matrix Metalloproteinase 3