A preliminary in vitro study into the use of IL-1Ra gene therapy for the inhibition of intervertebral disc degeneration.
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.
Le Maitre
Christine L
CL
Division of Laboratory and Regenerative Medicine, School of Medicine, University of Manchester, Manchester, UK.
Freemont
Anthony J
AJ
Hoyland
Judith A
JA
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
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