Skip to main content

Gene Therapy Approaches for Disc Regeneration

  • Chapter
  • First Online:
The Intervertebral Disc

Abstract

One of the first articles describing the use of gene therapy was published in Science in 1972. In that paper, Friedmann and Roblin described how they induced mammalian cells to express bacterial and viral DNA, demonstrating the possibility that this method could later be used to promote therapies for treatment of human genetic diseases (Friedmann and Roblin 1972). Today, scientists are exploring the therapeutic use of gene therapy for the treatment of numerous pathological conditions including Parkinson disease (Yasuda et al. 2011), glioma (Lee et al. 2011), X-linked severe combined immunodeficiency (SCID-X) (Huston et al. 2011), diabetes (Rowzee et al. 2011), bone fractures (Sheyn et al. 2008; Kimelman-Bleich et al. 2011), and heart failure (Muona et al. 2012; Pleger et al. 2011). During the last two decades, efforts have been made to enhance the safety and efficiency of gene therapy. Despite numerous advances, the immune response, which led to the death of a patient in one clinical trial (Somia and Verma 2000), and insertional mutagenesis, which triggered the development of leukemia in several patients (Hacein-Bey-Abina et al. 2003; Cavazzana-Calvo et al. 2004), continue to pose a major barrier to the clinical use of gene therapy. Fortunately, improvements are constantly being made in protocols as well as in the safety features of some vectors, such as exogenous control of gene expression or the use of nonviral gene delivery methods (Herzog et al. 2010). Hundreds of clinical trials involving gene delivery are currently being conducted in the USA for the treatment of various diseases, ranging from cystic fibrosis to HIV (Flotte 2007).

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

Access this chapter

eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 129.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  • Aslan H, Zilberman Y, Arbeli V, Sheyn D, Matan Y, Liebergal M, Li J, Helm GA, Gazit D, Gazit Z (2006) Nucleofection-based ex vivo nonviral gene delivery to human stem cells as a platform for tissue regeneration. Tissue Eng 12(4):877–889

    Article  PubMed  CAS  Google Scholar 

  • Baffi MO, Slattery E, Sohn P, Moses HL, Chytil A, Serra R (2004) Conditional deletion of the TGF-beta type II receptor in Col2a expressing cells results in defects in the axial skeleton without alterations in chondrocyte differentiation or embryonic development of long bones. Dev Biol 276(1):124–142

    Article  PubMed  CAS  Google Scholar 

  • Bell DM, Leung KK, Wheatley SC, Ng LJ, Zhou S, Ling KW, Sham MH, Koopman P, Tam PP, Cheah KS (1997) SOX9 directly regulates the type-II collagen gene. Nat Genet 16(2):174–178

    Article  PubMed  CAS  Google Scholar 

  • Boden SD, Liu Y, Hair GA, Helms JA, Hu D, Racine M, Nanes MS, Titus L (1998) LMP-1, a LIM-domain protein, mediates BMP-6 effects on bone formation. Endocrinology 139(12):5125–5134

    Article  PubMed  CAS  Google Scholar 

  • Bron JL, Helder MN, Meisel HJ, Van Royen BJ, Smit TH (2009) Repair, regenerative and supportive therapies of the annulus fibrosus: achievements and challenges. Eur Spine J 18(3):301–313

    Article  PubMed  Google Scholar 

  • Bueno EM, Glowacki J (2009) Cell-free and cell-based approaches for bone regeneration. Nat Rev Rheumatol 5(12):685–697

    Article  PubMed  Google Scholar 

  • Cavazzana-Calvo M, Thrasher A, Mavilio F (2004) The future of gene therapy. Nature 427(6977):779–781

    Article  PubMed  CAS  Google Scholar 

  • 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(2):287–295

    Article  PubMed  Google Scholar 

  • Edelstein ML, Abedi MR, Wixon J (2007) Gene therapy clinical trials worldwide to 2007–an update. J Gene Med 9(10):833–842

    Article  PubMed  Google Scholar 

  • Elfervig MK, Minchew JT, Francke E, Tsuzaki M, Banes AJ (2001) IL-1beta sensitizes intervertebral disc annulus cells to fluid-induced shear stress. J Cell Biochem 82(2):290–298

    Article  PubMed  CAS  Google Scholar 

  • Feng G, Wan Y, Shen FH, Li X (2009) Nucleus pulposus explant culture model. J Orthop Res 27(6):814–819

    Article  PubMed  CAS  Google Scholar 

  • 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(6669):806–811

    Article  PubMed  CAS  Google Scholar 

  • Flotte TR (2007) Gene therapy: the first two decades and the current state-of-the-art. J Cell Physiol 213(2):301–305

    Article  PubMed  CAS  Google Scholar 

  • Friedmann T, Roblin R (1972) Gene therapy for human genetic disease? Science 175(25):949–955

    Article  PubMed  CAS  Google Scholar 

  • Glasson SS, Askew R, Sheppard B, Carito B, Blanchet T, Ma HL, Flannery CR, Peluso D, Kanki K, Yang Z, Majumdar MK, Morris EA (2005) Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature 434(7033): 644–648

    Article  PubMed  CAS  Google Scholar 

  • Griffith TS, Brunner T, Fletcher SM, Green DR, Ferguson TA (1995) Fas ligand-induced apoptosis as a mechanism of immune privilege. Science 270(5239):1189–1192

    Article  PubMed  CAS  Google Scholar 

  • Hacein-Bey-Abina S, Von Kalle C, Schmidt M, McCormack MP, Wulffraat N, Leboulch P, Lim A, Osborne CS, Pawliuk R, Morillon E, Sorensen R, Forster A, Fraser P, Cohen JI, de Saint BG, Alexander I, Wintergerst U, Frebourg T, Aurias A, Stoppa-Lyonnet D, Romana S, Radford-Weiss I, Gross F, Valensi F, Delabesse E, Macintyre E, Sigaux F, Soulier J, Leiva LE, Wissler M, Prinz C, Rabbitts TH, Le Deist F, Fischer A, Cavazzana-Calvo M (2003) LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 302(5644):415–419

    Article  PubMed  CAS  Google Scholar 

  • Han D, Ding Y, Liu SL, Wang G, Si IC, Wang X, Cui L, Huang D (2009) Double role of Fas ligand in the apoptosis of intervertebral disc cells in vitro. Acta Biochim Biophys Sin (Shanghai) 41(11):938–947

    Article  CAS  Google Scholar 

  • Hashimoto G, Aoki T, Nakamura H, Tanzawa K, Okada Y (2001) Inhibition of ADAMTS4 (aggrecanase-1) by tissue inhibitors of metalloproteinases (TIMP-1, 2, 3 and 4). FEBS Lett 494(3): 192–195

    Article  PubMed  CAS  Google Scholar 

  • Herzog RW, Cao O, Srivastava A (2010) Two decades of clinical gene therapy–success is finally mounting. Discov Med 9(45):105–111

    PubMed  Google Scholar 

  • Huston MW, van Til NP, Visser TP, Arshad S, Brugman MH, Cattoglio C, Nowrouzi A, Li Y, Schambach A, Schmidt M, Baum C, von Kalle C, Mavilio F, Zhang F, Blundell MP, Thrasher AJ, Verstegen MM, Wagemaker G (2011) Correction of murine SCID-X1 by lentiviral gene therapy using a codon-optimized IL2RG gene and minimal pretransplant conditioning. Mol Ther 19:1867–1877

    Article  PubMed  CAS  Google Scholar 

  • Jimbo K, Park JS, Yokosuka K, Sato K, Nagata K (2005) Positive feedback loop of interleukin-1beta upregulating production of inflammatory mediators in human intervertebral disc cells in vitro. J Neurosurg Spine 2(5):589–595

    Article  PubMed  Google Scholar 

  • 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(6):1271–1278

    Article  PubMed  CAS  Google Scholar 

  • Kaneyama S, Nishida K, Takada T, Suzuki T, Shimomura T, Maeno K, Kurosaka M, Doita M (2008) Fas ligand expression on human nucleus pulposus cells decreases with disc degeneration processes. J Orthop Sci 13(2):130–135

    Article  PubMed  CAS  Google Scholar 

  • Kang JD, Stefanovic-Racic M, McIntyre LA, Georgescu HI, Evans CH (1997) Toward a biochemical understanding of human intervertebral disc degeneration and herniation. Contributions of nitric oxide, interleukins, prostaglandin E2, and matrix metalloproteinases. Spine (Phila Pa 1976) 22(10):1065–1073

    Article  CAS  Google Scholar 

  • Kimelman-Bleich N, Pelled G, Zilberman Y, Kallai I, Mizrahi O, Tawackoli W, Gazit Z, Gazit D (2011) Targeted gene-and-host progenitor cell therapy for nonunion bone fracture repair. Mol Ther 19(1):53–59

    Article  PubMed  CAS  Google Scholar 

  • Kuh SU, Zhu Y, Li J, Tsai KJ, Fei Q, Hutton WC, Yoon ST (2008) The AdLMP-1 transfection in two different cells; AF cells, chondrocytes as potential cell therapy candidates for disc degeneration. Acta Neurochir (Wien) 150(8):803–810

    Article  CAS  Google Scholar 

  • Le Maitre CL, Freemont AJ, Hoyland JA (2005) The role of interleukin-1 in the pathogenesis of human intervertebral disc degeneration. Arthritis Res Ther 7(4):R732–R745

    Article  PubMed  Google Scholar 

  • 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(4):R83

    Article  PubMed  Google Scholar 

  • Lee JY, Hall R, Pelinkovic D, Cassinelli E, Usas A, Gilbertson L, Huard J, Kang J (2001) New use of a three-dimensional pellet culture system for human intervertebral disc cells: initial characterization and potential use for tissue engineering. Spine (Phila Pa 1976) 26(21):2316–2322

    Article  CAS  Google Scholar 

  • Lee EX, Lam DH, Wu C, Yang J, Ng WH, Wang S (2011) Glioma gene therapy using induced pluripotent stem cell-derived neural stem cells. Mol Pharm 8:1515–1524

    Article  PubMed  CAS  Google Scholar 

  • Leo BM, Li X, Balian G, Anderson DG (2004) In vivo bioluminescent imaging of virus-mediated gene transfer and transduced cell transplantation in the intervertebral disc. Spine (Phila Pa 1976) 29(8):838–844

    Article  Google Scholar 

  • Levicoff EA, Kim JS, Sobajima S, Wallach CJ, Larson JW 3rd, Robbins PD, Xiao X, Juan L, Vadala G, Gilbertson LG, Kang JD (2008) Safety assessment of intradiscal gene therapy II: effect of dosing and vector choice. Spine (Phila Pa 1976) 33(14):1509–1516; discussion 1517

    Article  Google Scholar 

  • Li X, Leo BM, Beck G, Balian G, Anderson GD (2004) Collagen and proteoglycan abnormalities in the GDF-5-deficient mice and molecular changes when treating disk cells with recombinant growth factor. Spine (Phila Pa 1976) 29(20):2229–2234

    Article  Google Scholar 

  • Liang H, Ma SY, Feng G, Shen FH, Joshua Li X (2010) Therapeutic effects of adenovirus-mediated growth and differentiation factor-5 in a mice disc degeneration model induced by annulus needle puncture. Spine J 10(1):32–41

    Article  PubMed  Google Scholar 

  • 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 (Phila Pa 1976) 31(7):732–735

    Article  Google Scholar 

  • Liu Y, Kong J, Chen BH, Hu YG (2010) Combined expression of CTGF and tissue inhibitor of metalloprotease-1 promotes synthesis of proteoglycan and collagen type II in rhesus monkey lumbar intervertebral disc cells in vitro. Chin Med J (Engl) 123(15):2082–2087

    CAS  Google Scholar 

  • Lohr F, Huang Q, Hu K, Dewhirst MW, Li CY (2001) Systemic vector leakage and transgene expression by intratumorally injected recombinant adenovirus vectors. Clin Cancer Res 7(11):3625–3628

    PubMed  CAS  Google Scholar 

  • Masuda K, An HS (2004) Growth factors and the intervertebral disc. Spine J 4(6 Suppl):330S–340S

    Article  PubMed  Google Scholar 

  • Matsumoto T, Masuda K, Chen S, An H, Andersson G, Aota Y, Horvath E, Thonar E (2001) Transfer of osteogenic protein-1 gene by gene gun system promotes matrix synthesis in bovine intervertebral disc and articular cartilage cells. Trans Orthop Res Soc 26:30

    Google Scholar 

  • Menendez MI, Clark DJ, Carlton M, Flanigan DC, Jia G, Sammet S, Weisbrode SE, Knopp MV, Bertone AL (2011) Direct delayed human adenoviral BMP-2 or BMP-6 gene therapy for bone and cartilage regeneration in a pony osteochondral model. Osteoarthritis Cartilage 19(8):1066–1075

    Article  PubMed  CAS  Google Scholar 

  • 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 (Phila Pa 1976) 25(20):2573–2579

    Article  CAS  Google Scholar 

  • Moon SH, Nishida K, Gilbertson LG, Lee HM, Kim H, Hall RA, Robbins PD, Kang JD (2008) Biologic response of human intervertebral disc cells to gene therapy cocktail. Spine (Phila Pa 1976) 33(17):1850–1855

    Article  Google Scholar 

  • Morrey ME, Anderson PA, Chambers G, Paul R (2008) Optimizing nonviral-mediated transfection of human intervertebral disc chondrocytes. Spine J 8(5):796–803

    Article  PubMed  CAS  Google Scholar 

  • Muona K, Makinen K, Hedman M, Manninen H, Yla-Herttuala S (2012) 10-year safety follow-up in patients with local VEGF gene transfer to ischemic lower limb. Gene Ther 19:392–395

    Article  PubMed  CAS  Google Scholar 

  • Nagase H, Woessner JF Jr (1999) Matrix metalloproteinases. J Biol Chem 274(31):21491–21494

    Article  PubMed  CAS  Google Scholar 

  • 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 (Phila Pa 1976) 23(22):2437–2442; discussion 2443

    Article  CAS  Google Scholar 

  • 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 (Phila Pa 1976) 24(23): 2419–2425

    Article  CAS  Google Scholar 

  • Nishida K, Gilbertson LG, Robbins PD, Evans CH Kang JD (2000) Potential applications of gene therapy to the treatment of intervertebral disc disorders. Clin Orthop Relat Res (379 Suppl): S234–S241

    Google Scholar 

  • 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 (Phila Pa 1976) 31(13):1415–1419

    Article  Google Scholar 

  • Nishida K, Suzuki T, Kakutani K, Yurube T, Maeno K, Kurosaka M, Doita M (2008) Gene therapy approach for disc degeneration and associated spinal disorders. Eur Spine J 17(Suppl 4):459–466

    Article  PubMed  Google Scholar 

  • Noel D, Gazit D, Bouquet C, Apparailly F, Bony C, Plence P, Millet V, Turgeman G, Perricaudet M, Sany J, Jorgensen C (2004) Short-term BMP-2 expression is sufficient for in vivo osteochondral differentiation of mesenchymal stem cells. Stem Cells 22(1):74–85

    Article  PubMed  CAS  Google Scholar 

  • Omlor GW, Bertram H, Kleinschmidt K, Fischer J, Brohm K, Guehring T, Anton M, Richter W (2010) Methods to monitor distribution and metabolic activity of mesenchymal stem cells following in vivo injection into nucleotomized porcine intervertebral discs. Eur Spine J 19(4):601–612

    Article  PubMed  CAS  Google Scholar 

  • Osada R, Ohshima H, Ishihara H, Yudoh K, Sakai K, Matsui H, Tsuji H (1996) Autocrine/paracrine mechanism of insulin-like growth factor-1 secretion, and the effect of insulin-like growth factor-1 on proteoglycan synthesis in bovine intervertebral discs. J Orthop Res 14(5):690–699

    Article  PubMed  CAS  Google Scholar 

  • 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 (Phila Pa 1976) 28(8):755–763

    Google Scholar 

  • Pleger ST, Shan C, Ksienzyk J, Bekeredjian R, Boekstegers P, Hinkel R, Schinkel S, Leuchs B, Ludwig J, Qiu G, Weber C, Raake P, Koch WJ, Katus HA, Muller OJ, Most P (2011) Cardiac AAV9-S100A1 gene therapy rescues post-ischemic heart failure in a preclinical large animal model. Sci Transl Med 3(92):92ra64

    Article  PubMed  CAS  Google Scholar 

  • Reddi AH, Reddi A (2009) Bone morphogenetic proteins (BMPs): from morphogens to metabologens. Cytokine Growth Factor Rev 20(5–6):341–342

    Article  PubMed  CAS  Google Scholar 

  • Risbud MV, Albert TJ, Guttapalli A, Vresilovic EJ, Hillibrand AS, Vaccaro AR, Shapiro IM (2004) Differentiation of mesenchymal stem cells towards a nucleus pulposus-like phenotype in vitro: implications for cell-based transplantation therapy. Spine (Phila Pa 1976) 29(23):2627–2632

    Article  Google Scholar 

  • Rowzee AM, Cawley NX, Chiorini JA, Di Pasquale G (2011) Glucagon-like Peptide-1 gene therapy. Exp Diabetes Res 2011:601047

    Article  PubMed  Google Scholar 

  • Schmidt-Wolf GD, Schmidt-Wolf IG (2003) Non-viral and hybrid vectors in human gene therapy: an update. Trends Mol Med 9(2): 67–72

    Article  PubMed  CAS  Google Scholar 

  • Seguin CA, Pilliar RM, Roughley PJ, Kandel RA (2005) Tumor necrosis factor-alpha modulates matrix production and catabolism in nucleus pulposus tissue. Spine (Phila Pa 1976) 30(17):1940–1948

    Article  Google Scholar 

  • Seki S, Asanuma-Abe Y, Masuda K, Kawaguchi Y, Asanuma K, Muehleman C, Iwai A, Kimura T (2009) Effect of small interference RNA (siRNA) for ADAMTS5 on intervertebral disc degeneration in the rabbit anular needle-puncture model. Arthritis Res Ther 11(6):R166

    Article  PubMed  Google Scholar 

  • Shen B, Melrose J, Ghosh P, Taylor F (2003) Induction of matrix metalloproteinase-2 and −3 activity in ovine nucleus pulposus cells grown in three-dimensional agarose gel culture by interleukin-1beta: a potential pathway of disc degeneration. Eur Spine J 12(1):66–75

    PubMed  CAS  Google Scholar 

  • Sheyn D, Kimelman-Bleich N, Pelled G, Zilberman Y, Gazit D, Gazit Z (2008) Ultrasound-based nonviral gene delivery induces bone formation in vivo. Gene Ther 15(4):257–266

    Article  PubMed  CAS  Google Scholar 

  • Somia N, Verma IM (2000) Gene therapy: trials and tribulations. Nat Rev Genet 1(2):91–99

    Article  PubMed  CAS  Google Scholar 

  • Sowa G, Westrick E, Pacek C, Coelho P, Patel D, Vadala G, Georgescu H, Vo N, Studer R, Kang J (2011) In vitro and in vivo testing of a novel regulatory system for gene therapy for intervertebral disc degeneration. Spine (Phila Pa 1976) 36(10):E623–E628

    Article  Google Scholar 

  • Suzuki T, Nishida K, Kakutani K, Maeno K, Yurube T, Takada T, Kurosaka M, Doita M (2009) Sustained long-term RNA interference in nucleus pulposus cells in vivo mediated by unmodified small interfering RNA. Eur Spine J 18(2):263–270

    Article  PubMed  Google Scholar 

  • Takada T, Nishida K, Doita M, Kurosaka M (2002) Fas ligand exists on intervertebral disc cells: a potential molecular mechanism for immune privilege of the disc. Spine (Phila Pa 1976) 27(14): 1526–1530

    Article  Google Scholar 

  • Thompson JP, Oegema TR Jr, Bradford DS (1991) Stimulation of mature canine intervertebral disc by growth factors. Spine (Phila Pa 1976) 16(3):253–260

    Article  CAS  Google Scholar 

  • Vadala G, Sowa GA, Smith L, Hubert MG, Levicoff EA, Denaro V, Gilbertson LG, Kang JD (2007) Regulation of transgene expression using an inducible system for improved safety of intervertebral disc gene therapy. Spine (Phila Pa 1976) 32(13):1381–1387

    Article  Google Scholar 

  • Wallach CJ, Gilbertson LG, Kang JD (2003a) Gene therapy applications for intervertebral disc degeneration. Spine (Phila Pa 1976) 28(15 Suppl):S93–S98

    Google Scholar 

  • Wallach CJ, Sobajima S, Watanabe Y, Kim JS, Georgescu HI, Robbins P, Gilbertson LG, Kang JD (2003b) Gene transfer of the catabolic inhibitor TIMP-1 increases measured proteoglycans in cells from degenerated human intervertebral discs. Spine (Phila Pa 1976) 28(20):2331–2337

    Article  Google Scholar 

  • 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(2):107–112

    Article  PubMed  Google Scholar 

  • Wang C, Ruan DK, Zhang C, Wang DL, Xin H, Zhang Y (2011) Effects of adeno-associated virus-2-mediated human BMP-7 gene transfection on the phenotype of nucleus pulposus cells. J Orthop Res 29(6):838–845

    Article  PubMed  CAS  Google Scholar 

  • Wehling P (2001) Transfer of genes to intervertebral disc cells: proposal for a treatment strategy of spinal disorders by local gene therapy. Joint Bone Spine 68(6):554–556

    Article  PubMed  CAS  Google Scholar 

  • 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 (Phila Pa 1976) 22(10):1092–1097

    Article  CAS  Google Scholar 

  • Xia C, Ding C, Yang X, Sun K, Tian S (2010) Effects of antisense transforming growth factor-beta1 gene transfer on the biological activities of tendon sheath fibroblasts. Orthopedics 33(8)

    Google Scholar 

  • Yang Z, Huang CY, Candiotti KA, Zeng X, Yuan T, Li J, Yu H, Abdi S (2011) Sox-9 facilitates differentiation of adipose tissue-derived stem cells into a chondrocyte-like phenotype in vitro. J Orthop Res 29(8):1291–1297

    Article  PubMed  CAS  Google Scholar 

  • Yasuda T, Hayakawa H, Nihira T, Ren YR, Nakata Y, Nagai M, Hattori N, Miyake K, Takada M, Shimada T, Mizuno Y, Mochizuki H (2011) Parkin-mediated protection of dopaminergic neurons in a chronic MPTP-minipump mouse model of Parkinson disease. J Neuropathol Exp Neurol 70:686–697

    Article  PubMed  Google Scholar 

  • Yoon ST, Park JS, Kim KS, Li J, Attallah-Wasif ES, Hutton WC, Boden SD (2004) ISSLS prize winner: LMP-1 upregulates intervertebral disc cell production of proteoglycans and BMPs in vitro and in vivo. Spine (Phila Pa 1976) 29(23):2603–2611

    Article  Google Scholar 

  • Zhang Y, An HS, Thonar EJ, Chubinskaya S, He TC, Phillips FM (2006) Comparative effects of bone morphogenetic proteins and sox9 overexpression on extracellular matrix metabolism of bovine nucleus pulposus cells. Spine (Phila Pa 1976) 31(19):2173–2179

    Article  Google Scholar 

  • Zhang Y, Phillips FM, Thonar EJ, Oegema T, An HS, Roman-Blas JA, He TC, Anderson DG (2008) Cell therapy using articular chondrocytes overexpressing BMP-7 or BMP-10 in a rabbit disc organ culture model. Spine (Phila Pa 1976) 33(8):831–838

    Article  Google Scholar 

  • Zhang Y, Markova D, Im HJ, Hu W, Thonar EJ, He TC, An HS, Phillips FM, Anderson DG (2009) Primary bovine intervertebral disc cells transduced with adenovirus overexpressing 12 BMPs and Sox9 maintain appropriate phenotype. Am J Phys Med Rehabil 88(6):455–463

    Article  PubMed  Google Scholar 

  • Zhang Y, Chee A, Thonar EJ, An HS (2011) Intervertebral disk repair by protein, gene, or cell injection: a framework for rehabilitation-focused biologics in the spine. PM R 3(6 Suppl):S88–S94

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors wish to thank the NIH and NIAMS for ongoing support through grant RO3AR057143 and the Israel Science Foundation (ISF) grants and the Levi Eshkol Scholarship for PhD Students, the Ministry of Science, Culture and Sport of the State of Israel.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Zulma Gazit .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer-Verlag Wien

About this chapter

Cite this chapter

Gazit, Z., Kimelman-Bleich, N., Mizrahi, O., Gazit, D. (2014). Gene Therapy Approaches for Disc Regeneration. In: Shapiro, I., Risbud, M. (eds) The Intervertebral Disc. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1535-0_24

Download citation

  • DOI: https://doi.org/10.1007/978-3-7091-1535-0_24

  • Published:

  • Publisher Name: Springer, Vienna

  • Print ISBN: 978-3-7091-1534-3

  • Online ISBN: 978-3-7091-1535-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics