Advances in Gene Therapy for Intervertebral Disc Degeneration

Degeneration of the intervertebral disc (IVD) is believed to herald the beginning of many problems of the spinal column, such as low back pain, spinal stenosis, instability, disc herniations, and radiculopathy. Most treatments for these problems, such as fusion and disc replacement, are aimed at treating the problem after it already has begun. Currently, there are few approaches to prevent the problem, that is, to prevent the initiation of disc degeneration.

Interest in gene therapy among the medical community, including spinal medicine, has increased greatly over the past several decades. In spinal medicine, much research has been aimed at identifying the gene(s) responsible for IVD and developing methods that halt or reverse the degenerative process. Multiple genes have been implicated in the degeneration process, including genes for Types IX and XI collagen, various matrix metalloproteinases, and the vitamin D receptor (1-2). However, no single gene has been identified that accounts for the entire pathological degeneration scheme. The etiology of disc degeneration is believed to be multifactorial, and the genetic component as yet has not been entirely defined.

The goal of gene therapy is to restore protein production that is absent or deficient by introducing a functional gene into the target cell (3). The decline in IVD proteoglycan content of the disc that occurs with aging is due to an imbalance between the anabolic and catabolic pathways that normally maintain the disc matrix. Gene therapy research is approaching the question of disc degeneration from both of these directions: 1) augmenting the anabolic functions of the IVD cells, and/or 2) decreasing the catabolic processes that act on the extracellular matrix of the disc.

Both of these approaches utilize vectors, or carrier molecules, that transport the therapeutic gene to the disc target cells. The most commonly used vectors are adenoviruses, which harbor the ability to infect many cell types, including quiescent, non-dividing cells. They are also highly efficient for gene transfer. Other vectors include retroviruses, herpes simplex viruses, liposomes, and DNA-ligand complexes. Target cells incorporate the therapeutic genes from the vector and transcribe the exogenous gene, or transgene, into mRNA. The mRNA then is translated into the desirable protein product, e.g. transforming growth factor beta-1 (TGFB1).

Various genes have been used in both in vitro and in vivo studies, including TGFB1; bone morphogenetic proteins (BMP) -2, -7, and -12; LIM mineralization protein-1 (LMP1); transcription factor for Type II collagen (SOX9); and tissue inhibitor of metalloproteinase- 1 (TIMP1). In an in vitro model,Moon and colleagues transfected human IVD cells with the TGFB1 gene, which resulted in increased proteoglycan and collagen production 300 percent of control (4). Shimer et al (5) improved disc matrix integrity in an in vivo rat model using the gene for BMP-2. Other investigators also have demonstrated efficacy with other genes (6-9).

Disc degeneration is a process that occurs slowly over a long period of time. For gene therapy to be effective, its beneficial results (e.g. increasing the production of TGFB1) must be sustained. A second requirement of gene therapy is safety. Pre-clinical research performed to date has demonstrated gene therapy to be both efficacious and safe.

We are currently viewing the tip of the iceberg regarding our understanding of disc degeneration and its treatment by molecular manipulation. Further research is required to completely define the degenerative cascade and its genetic components and to refine gene transfer techniques. Clinical studies are necessary to validate gene therapy as a treatment modality for degenerative disc disease. We are now years, perhaps decades, away from being able to inject an IVD with a gene that will regenerate a degenerated disc or obstruct or prevent the degenerative process. Nevertheless, gene therapy research is advancing rapidly, and such a time will come.

 

General References
1. Noponen-Hietala N, Kyllonen E, Mannikko M, Ilkko E, Karppinen J, Ott J, Ala- Kokko L. Sequence variations in the collagen IX and XI genes are associated with degenerative lumbar spinal stenosis. Ann Rheum Dis. 2003;62(12):1208-1214.

2. Videman T, Leppavuori J, Kaprio J, Battie M, Gibbons L, Peltonen L, Koskenvuo M. Intragenic polymorphisms of the vitamin D receptor gene associated with intervertebral disc degeneration. Spine. 1998;23;2477-2485.

3. Kootstra NA, Verma IM. Gene therapy with viral vectors. Annu Rev Pharmacol Toxicol. 2003;43:413-439.

4. Moon, et al. Presented at the 27th Annual Meeting of the International Society for the Study of the Lumbar Spine; Adelaide, Australia, April 9-13, 2000.

5. Shimer AL, Chadderdon RC, Gilbertson LG, Kang JD. Gene therapy approaches for intervertebral disc degeneration. Spine. 2004;29(23):2770-2778.

6. Yoon, et al. Presented at the 29th Annual Meeting of the International Society for the Study of the Lumbar Spine; Cleveland, Ohio, May 14-18, 2002.

7. Yoon ST, Boden SD. Spine fusion by gene therapy. Gene Ther. 2004;11(4):360 -367.

8. Paul R, Haydon RC, Cheng H, Ishikawa A, Nenadovich N, Jiang W, et al. Potential use of SOX9 gene therapy for intervertebral degenerative disc disease. Spine. 2003;28(8):755-763.

9. Wallach CJ, Sobajima S, Watanabe Y, Kim JS, Georgescu HI, Robbins P, et al. Gene transfer of the catabolic inhibitor TIMP-1 increases measured proteoglycans in cells from degenerated human intervertebral discs. Spine. 2003;28(20):2331-2337.