Skip to main content

Advertisement

Log in

Gene therapy approach for disc degeneration and associated spinal disorders

  • Review
  • Published:
European Spine Journal Aims and scope Submit manuscript

Abstract

Disc degeneration is deeply associated with many spinal disorders and thus has a significant clinical impact on society. The currently available surgical treatment often necessitates removing a pathological disc and spinal fusion. However, it is also well known that these surgical treatments have many potential problems including invasion and cost. Therefore, biological approaches for regenerating these pathological discs have received much attention. Gene therapy is one of these biological approaches. Gene therapy involves the transfer of genes to cells so the recipient cells express these genes and thereby synthesize the RNA and protein they encode in a continuous fashion. One of the significant advantages of gene therapy is that we can expect a lasting duration of biological effect which is potentially beneficial for most disc degeneration associated disorders, as they are, by nature, chronic conditions. Originally, gene therapy was mediated by viral vectors, but recent technological progress has enabled us to opt for non-virus-mediated gene therapy for the disc. Furthermore, the development of the RNA interference technique has enabled us to down-regulate a specific gene expression in the disc opening the door for a new generation of intradiscal gene therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Aota Y, Kumano K, Hirabayashi S (1995) Postfusion instability at the adjacent segments after rigid pedicle screw fixation for degenerative lumbar spinal disorders. J Spinal Disord 8:464–473

    Article  PubMed  CAS  Google Scholar 

  2. Asazuma T, Yamugishi M, Sato M, Ichimura S, Fujikawa K, Crock HV (2004) Posterior spinal fusion for lumbar degenerative diseases using the Crock–Yamagishi (C–Y) spinal fixation system. J Spinal Disord Tech 17:174–177

    Article  PubMed  Google Scholar 

  3. Booth KC, Bridwell KH, Eisenberg BA, Baldus CR, Lenke LG (1999) Minimum 5-year results of degenerative spondylolisthesis treated with decompression and instrumented posterior fusion. Spine 24:1721–1727

    Article  PubMed  CAS  Google Scholar 

  4. Buckwalter JA (1995) Aging and degeneration of the human intervertebral disc. Spine 20:1307–1314

    PubMed  CAS  Google Scholar 

  5. Chung SA, Wei AQ, Connor DE, Webb GC, Molloy T, Pajic M, Diwan AD (2007) Nucleus pulposus cellular longevity by telomerase gene therapy. Spine 32:1188–1196

    Article  PubMed  Google Scholar 

  6. Cui M, Wan Y, Anderson DG, Shen FH, Leo BM, Laurencin CT, Balian G, Li X (2008) Mouse growth and differentiation factor-5 protein and DNA therapy potentiates intervertebral disc cell aggregation and chondrogenic gene expression. Spine J 8:287–295

    Article  PubMed  Google Scholar 

  7. Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T (2001) Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411:494–498

    Article  PubMed  CAS  Google Scholar 

  8. Etebar S, Cahill DW (1999) Risk factors for adjacent-segment failure following lumbar fixation with rigid instrumentation for degenerative instability. J Neurosurg Spine 90:163–169

    Article  CAS  Google Scholar 

  9. Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC (1998) Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391:806–811

    Article  PubMed  CAS  Google Scholar 

  10. Gertzbein SD, Betz R, Clements D, Errico T, Hammerberg K, Robbins S, Shepherd E, Weber A, Kerina M, Albin J, Wolk D, Ensor K (1996) Semirigid instrumentation in the management of lumbar spinal conditions combined with circumferential fusion. A multicenter study. Spine 21:1918–1925

    Article  PubMed  CAS  Google Scholar 

  11. Grunhagen T, Wilde G, Soukane DM, Shirazi-Adl SA, Urban JP (2006) Nutrient supply and intervertebral disc metabolism. J Bone Joint Surg 88-A:30–35

    Article  Google Scholar 

  12. Herweijer H, Wolff JA (2003) Progress and prospects: naked DNA gene transfer and therapy. Gene Ther 10:453–458

    Article  PubMed  CAS  Google Scholar 

  13. Hilibrand AS, Carlson GD, Palumbo MA, Jones PK, Bohlman HH (1999) Radiculopathy and myelopathy at segments adjacent to the site of a previous anterior cervical arthrodesis. J Bone Joint Surg 81-A:519–528

    Google Scholar 

  14. Hirsch C, Schajowicz F (1953) Studies on structural changes in the lumbar annulus fibrosus. Acta Orthop Scand 22:184–231

    PubMed  CAS  Google Scholar 

  15. Holm S, Maroudas A, Urban JP, Selstam G, Nachemson A (1981) Nutrition of the intervertebral disc: solute transport and metabolism. Connect Tissue Res 8:101–119

    Article  PubMed  CAS  Google Scholar 

  16. Hutvagner G, Zamore PD (2002) A microRNA in a multiple-turnover RNAi enzyme complex. Science 297:2056–2060

    Article  PubMed  CAS  Google Scholar 

  17. Kakutani K, Nishida K, Uno K, Takada T, Shimomura T, Maeno K, Kurosaka M, Doita M (2006) Prolonged down regulation of specific gene expression in nucleus pulposus cell mediated by RNA interference in vitro. J Orthop Res 24:1271–1278

    Article  PubMed  CAS  Google Scholar 

  18. Kostuik JP (1997) Intervertebral disc replacement. Experimental study. Clin Orthop 337:27–41

    Article  PubMed  Google Scholar 

  19. Lattermann C, Oxner WM, Xiao X, Li J, Gilbertson LG, Robbins PD, Kang JD (2005) The adeno associated viral vector as a strategy for intradiscal gene transfer in immune competent and pre-exposed rabbits. Spine 30:497–504

    Article  PubMed  Google Scholar 

  20. Lawrie A, Brisken AF, Francis SE, Tayler DI, Chamberlain J, Crossman DC, Cumberland DC, Newman CM (1999) Ultrasound enhances reporter gene expression after transfection of vascular cells in vitro. Circulation 99:2617–2620

    PubMed  CAS  Google Scholar 

  21. Lawrie A, Brisken AF, Francis SE, Cumberland DC, Crossman DC, Newman CM (2000) Microbubble-enhanced ultrasound for vascular gene delivery. Gene Ther 7:2023–2027

    Article  PubMed  CAS  Google Scholar 

  22. Lee CK (1988) Accelerated degeneration of the segment adjacent to a lumbar fusion. Spine 13:375–377

    Article  PubMed  CAS  Google Scholar 

  23. Le Maitre CL, Hoyland JA, Freemont AJ (2007) Interleukin–1 receptor antagonist delivered directly and by gene therapy inhibits matrix degradation in the intact degenerate human intervertebral disc: an in situ zymographic and gene therapy study. Arthritis Res Ther 9:R83. DOI 10.1186/ar2282

  24. Lemaire JP, Skalli W, Lavaste F, Templier A, Mendes F, Diop A, Sauty V, Laloux E (1997) Intervertebral disc prosthesis. Results and prospects for the year 2000. Clin Orthop 337:64–76

    Article  PubMed  Google Scholar 

  25. Liu X, Li K, Song J, Liang C, Wang X, Chen X (2006) Efficient and stable gene expression in rabbit intervertebral disc cells transduced with a recombinant baculovirus vector. Spine 31:732–735

    Article  PubMed  Google Scholar 

  26. Miyazaki T, Kobayashi S, Takeno K, Uchida K, Yayama T, Baba H (2007) Proteoglycan production of notochordal disc and non-notochordal disc. International Society for the Study of the Lumbar Spine, Hong Kong

  27. Moon SH, Gilbertson LG, Nishida K, Knaub M, Muzzonigro T, Robbins PD, Evans CH, Kang JD (2000) Human intervertebral disc cells are genetically modifiable by adenovirus-mediated gene transfer: implications for the clinical management of intervertebral disc disorders. Spine 25:2573–2579

    Article  PubMed  CAS  Google Scholar 

  28. Moon SH, Nishida K, Gilbertson L, Hall A, Robbins P, Kang JD (2001) Biologic response of human intervertebral disc cell to gene therapy cocktail. International Society for the Study of the Lumbar Spine, San Francisco

  29. Martinez J, Patkaniowska A, Urlaub H, Lührmann R, Tuschl T (2002) Single-stranded antisense siRNAs guide target RNA cleavage in RNAi. Cell 110:563–574

    Article  PubMed  CAS  Google Scholar 

  30. Nachemson A (1969) Intradiscal measurements of pH in patients with lumbar rhizopathies. Acta Orthop Scand 40:23–42

    Article  PubMed  CAS  Google Scholar 

  31. Newman CM, Lawrie A, Brisken AF, Cumberland DC (2001) Ultrasound gene therapy: on the road from concept to reality. Echocardiography 18:339–347

    Article  PubMed  CAS  Google Scholar 

  32. Nishida K, Kang JD, Suh JK, Robbins PD, Evans CH, Gilbertson LG (1998) Adenovirus-mediated gene transfer to nucleus pulposus cells. Implications for the treatment of intervertebral disc degeneration. Spine 23:2437–2442

    Article  PubMed  CAS  Google Scholar 

  33. Nishida K, Kang JD, Gilbertson LG, Moon SH, Suh JK, Vogt MT, Robbins PD, Evans CH (1999) Modulation of the biologic activity of the rabbit intervertebral disc by gene therapy: an in vivo study of adenovirus-mediated transfer of the human transforming growth factor beta 1 encoding gene. Spine 24:2419–2425

    Article  PubMed  CAS  Google Scholar 

  34. Nishida K, Gilbertson LG, Moon SH, Robbins PD, Evans CH, Kang JD (2000) Immune-privilege of the intervertebral disc: long-term transgene expression following direct adenovirus-mediated gene transfer. International Society for the Study of the Lumbar Spine, Adelaide

  35. Nishida K, Doita M, Takada T, Kakutani K, Miyamoto H, Shimomura T, Maeno K, Kurosaka M (2006) Sustained transgene expression in intervertebral disc cells in vivo mediated by microbubble-enhanced ultrasound gene therapy. Spine 31:1415–1419

    Article  PubMed  Google Scholar 

  36. Paul R, Haydon RC, Cheng H, Ishikawa A, Nenadovich N, Jiang W, Zhou L, Breyer B, Feng T, Gupta P, He TC, Phillips FM (2003) Potential use of Sox9 gene therapy for intervertebral degenerative disc disease. Spine 28:755–763

    Article  PubMed  Google Scholar 

  37. Schwarz DS, Hutvagner G, Haley B, Zamore PD (2002) Evidence that siRNAs function as guides, not primers, in the Drosophila and human RNAi pathways. Mol Cell 10:537–548

    Article  PubMed  CAS  Google Scholar 

  38. Suzuki T, Nishida K, Kakutani K, Doita M, Kaneyama S, Takada T, Kurosaka M (2008) Long term RNA interference in nucleus pulposus in vivo mediated by native unmodified short interference RNA. Orthopaedic Research Society, San Francisco

    Google Scholar 

  39. Thompson JP, Oegema TR Jr, Bradford DS (1991) Stimulation of mature canine intervertebral disc by growth factors. Spine 16:253–260

    Article  PubMed  CAS  Google Scholar 

  40. Tripathy SK, Black HB, Goldwasser E, Leiden JM (1996) Immune responses to transgene-encoded proteins limit the stability of gene expression after injection of replication-defective adenovirus vectors. Nat Med 2:545–550

    Article  PubMed  CAS  Google Scholar 

  41. Wallach CJ, Sobajima S, Watanabe Y, Kim JS, Georgescu HI, Robbins P, Gilbertson LG, Kang JD (2003) Gene transfer of the catabolic inhibitor TIMP–1 increases measured proteoglycans in cells from degenerated human intervertebral discs. Spine 28:2331–2337

    Article  PubMed  Google Scholar 

  42. Wallach CJ, Kim JS, Sobajima S, Lattermann C, Oxner WM, McFadden K, Robbins PD, Gilbertson LG, Kang JD (2006) Safety assessment of intradiscal gene transfer: a pilot study. Spine J 6:107–112

    Article  PubMed  Google Scholar 

  43. Wehling P, Schulitz KP, Robbins PD, Evans CH, Reinecke JA (1997) Transfer of genes to chondrocytic cells of the lumbar spine. Proposal for a treatment strategy of spinal disorders by local gene therapy. Spine 22:1092–1097

    Article  PubMed  CAS  Google Scholar 

  44. West JLIII, Ogilvie JW, Bradford DS (1991) Complications of the variable screw plate pedicle screw fixation. Spine 16:576–579

    Article  PubMed  Google Scholar 

Download references

Conflict of interest statement

None of the authors has any potential conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kotaro Nishida.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nishida, K., Suzuki, T., Kakutani, K. et al. Gene therapy approach for disc degeneration and associated spinal disorders. Eur Spine J 17 (Suppl 4), 459–466 (2008). https://doi.org/10.1007/s00586-008-0751-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00586-008-0751-5

Keywords

Navigation