MANCHESTER, United Kingdom—Observational data have shown interleukin-1 (IL-1) as a key factor in intervertebral disc (IVD) degeneration. Christine L. Le Maitre, MD, and colleagues from the University of Manchester in the UK show for the first time that IL-1 can induce expression of collagen-degrading enzymes even in otherwise healthy discs and that IL-1 receptor antagonist (IL-1ra) can block this process, whether delivered by injection into the disc or by gene therapy. The study is reported in Arthritis Research & Therapy.1

"Such an approach applied in vivo could form the basis either of a therapy for preventing matrix loss in early degeneration or in preparing the diseased IVD for tissue engineering or regenerative medicine strategies designed to restore a normal matrix," Dr. Le Maitre writes.

"Such an approach applied in vivo could form the basis either of a therapy for preventing matrix loss in early degeneration or in preparing the diseased IVD for tissue engineering or regenerative medicine strategies designed to restore a normal matrix."—Christine L. Le Maitre, MD.
The researchers used in situ zymographic localization of matrix degrading activity in tissue from normal as well as degenerate discs to study the effects of IL-1, IL-1ra, and inhibitors of matrix degrading enzymes. Samples included both surgical and cadaveric discs.

Using gene therapy, genetically engineered nucleus pulposus cells were delivered to adenoviral constructs as either a marker green fluorescent protein (control) or as IL-1ra.

The investigators report direct evidence that metal-dependent proteases (MDP) are the major enzymes involved in matrix degradation in the nucleus pulposus and that serine/cysteine proteases plus MDP are important in the annulus. Furthermore, they found that matrix degradation correlates with MDP expression and that IL-1ra delivered by gene therapy can almost eliminate MDP expression for sustained periods.

"Breaking the autostimulation of IL-1 production could be the key to inhibiting progression of degeneration," they suggest, pointing out that IL-1 has greater expression in IVD that has been shown clinically to be the source of chronic low back pain.

The study is the first published evidence to show that gene therapy delivered into human IVD explants can change the process of degeneration, but it is unlikely to lead to human gene therapy trials anytime soon. Concerns about the death of a patient in a rheumatoid arthritis TNF-inhibitor gene therapy trial (the Targeted Genetics study) have not yet been resolved; the September 17 government panel's report investigating the death was blunt in its criticism of the trial design.2

References
1. Le Maitre CL, Hoyland JA, Freemont AJ. Interleukin-1 receptor antagonist delivered directly and by gene therapy inhibits matrix degradation in the intact degenerate human intervetebral disc: an in situ-zymographic and gene therapy study. Arthritis Res Ther. 2007;9R83. doi:10:1186/ar2282.
2. Wadman M. Poor trial design leaves gene therapy death a mystery. Nat Med. 2007;13:1124.