Skip to main content

Antisense Makes Sense in Engineered Regenerative Medicine

Pharmaceutical Research volume 26, Article number: 263 (2009) Cite this article

Abstract

The use of antisense strategies such as ribozymes, oligodeoxynucleotides (ODNs) and small interfering RNA (siRNA) in gene therapy, in conjunction with the use of stem cells and tissue engineering, has opened up possibilities in curing degenerative diseases and injuries to non-regenerating organs and tissues. With their unique ability to down-regulate or silence gene expression, antisense oligonucleotides are uniquely suited in turning down the production of pathogenic or undesirable proteins and cytokines. Here, we review the antisense strategies and their applications in regenerative medicine with a focus on their efficacies in promoting cell viability, regulating cell functionalities as well as shaping an optimal microenvironment for therapeutic purposes.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. G. C. Gurtner, M. J. Callaghan, and M. T. Longaker. Progress and potential for regenerative medicine. Annu. Rev. Med. 58:299–312 (2007). doi:10.1146/annurev.med.58.082405.095329.

    PubMed  CAS  Google Scholar 

  2. G. C. Gurtner, S. Werner, Y. Barrandon, and M. T. Longaker. Wound repair and regeneration. Nature. 453:314–321 (2008). doi:10.1038/nature07039.

    PubMed  CAS  Google Scholar 

  3. S. J. Shieh, and J. P. Vacanti. State-of-the-art tissue engineering: from tissue engineering to organ building. Surgery. 137:1–7 (2005). doi:10.1016/j.surg.2004.04.002.

    PubMed  Google Scholar 

  4. J. Pomerantz, and H. M. Blau. Nuclear reprogramming: a key to stem cell function in regenerative medicine. Nat. Cell Biol. 6:810–816 (2004). doi:10.1038/ncb0904-810.

    PubMed  CAS  Google Scholar 

  5. R. J. Trent, and I. E. Alexander. Gene therapy: applications and progress towards the clinic. Intern. Med. J. 34:621–625 (2004). doi:10.1111/j.1445-5994.2004.00708.x.

    PubMed  CAS  Google Scholar 

  6. D. A. Wang, C. G. Williams, F. Yang, and J. H. Elisseeff. Enhancing the tissue-biomaterial interface: Tissue-initiated integration of biomaterials. Adv. Funct. Mater. 14:1152–1159 (2004). doi:10.1002/adfm.200305018.

    CAS  Google Scholar 

  7. T. Federici, and N. Boulis. Gene therapy for peripheral nervous system diseases. Curr. Gene Ther. 7:239–248 (2007). doi:10.2174/156652307781369083.

    PubMed  CAS  Google Scholar 

  8. P. Sazani, M. M. Vacek, and R. Kole. Short-term and long-term modulation of gene expression by antisense therapeutics. Curr. Opin. Biotechnol. 13:468–472 (2002). doi:10.1016/S0958-1669(02)00366-X.

    PubMed  CAS  Google Scholar 

  9. M. Khoury, C. Jorgensen, and F. Apparailly. RNAi in arthritis: prospects of a future antisense therapy in inflammation. Curr. Opin. Mol. Ther. 9:483–489 (2007).

    PubMed  CAS  Google Scholar 

  10. M. L. Stephenson, and P. C. Zamecnik. Inhibition of Rous sarcoma viral RNA translation by a specific oligodeoxyribonucleotide. Proc. Natl. Acad. Sci. U. S. A. 75:285–288 (1978). doi:10.1073/pnas.75.1.285.

    PubMed  CAS  Google Scholar 

  11. C. Guerrier-Takada, K. Gardiner, T. Marsh, N. Pace, and S. Altman. The RNA moiety of ribonuclease P is the catalytic subunit of the enzyme. Cell. 35:849–857 (1983). doi:10.1016/0092-8674(83)90117-4.

    PubMed  CAS  Google Scholar 

  12. A. C. Forster, and R. H. Symons. Self-cleavage of plus and minus RNAs of a virusoid and a structural model for the active sites. Cell. 49:211–220 (1987). doi:10.1016/0092-8674(87)90562-9.

    PubMed  CAS  Google Scholar 

  13. A. Hampel, and R. Tritz. RNA catalytic properties of the minimum (−)sTRSV sequence. Biochemistry. 28:4929–4933 (1989). doi:10.1021/bi00438a002.

    PubMed  CAS  Google Scholar 

  14. R. A. Collins, and B. J. Saville. Independent transfer of mitochondrial chromosomes and plasmids during unstable vegetative fusion in Neurospora. Nature. 345:177–179 (1990). doi:10.1038/345177a0.

    PubMed  CAS  Google Scholar 

  15. M. M. Lai. The molecular biology of hepatitis delta virus. Annu. Rev. Biochem. 64:259–286 (1995). doi:10.1146/annurev.bi.64.070195.001355.

    PubMed  CAS  Google Scholar 

  16. L. Beigelman, J. A. McSwiggen, K. G. Draper, C. Gonzalez, K. Jensen, A. M. Karpeisky, A. S. Modak, J. Matulic-Adamic, A. B. DiRenzo, P. Haeberli, et al. Chemical modification of hammerhead ribozymes. Catalytic activity and nuclease resistance. J. Biol. Chem. 270:25702–25708 (1995). doi:10.1074/jbc.270.43.25702.

    PubMed  CAS  Google Scholar 

  17. T. Kuwabara, M. Warashina, T. Tanabe, K. Tani, S. Asano, and K. Taira. A novel allosterically trans-activated ribozyme, the maxizyme, with exceptional specificity in vitro and in vivo. Mol. Cell. 2:617–627 (1998). doi:10.1016/S1097-2765(00)80160-4.

    PubMed  CAS  Google Scholar 

  18. C. J. Chen, A. C. Banerjea, G. G. Harmison, K. Haglund, and M. Schubert. Multitarget-ribozyme directed to cleave at up to nine highly conserved HIV-1 env RNA regions inhibits HIV-1 replication—potential effectiveness against most presently sequenced HIV-1 isolates. Nucleic Acids Res. 20:4581–4589 (1992). doi:10.1093/nar/20.17.4581.

    PubMed  CAS  Google Scholar 

  19. M. Shiota, M. Sano, M. Miyagishi, and K. Taira. Ribozymes: applications to functional analysis and gene discovery. J. Biochem. 136:133–147 (2004). doi:10.1093/jb/mvh119.

    PubMed  CAS  Google Scholar 

  20. F. K. Askari, and W. M. McDonnell. Antisense-oligonucleotide therapy. N. Engl. J. Med. 334:316–318 (1996). doi:10.1056/NEJM199602013340508.

    PubMed  CAS  Google Scholar 

  21. P. Sazani, and R. Kole. Therapeutic potential of antisense oligonucleotides as modulators of alternative splicing. J. Clin. Invest. 112:481–486 (2003).

    PubMed  CAS  Google Scholar 

  22. A. A. Levin. A review of the issues in the pharmacokinetics and toxicology of phosphorothioate antisense oligonucleotides. Biochim. Biophys. Acta. 1489:69–84 (1999).

    PubMed  CAS  Google Scholar 

  23. M. I. Phillips, and Y. C. Zhang. Basic principles of using antisense oligonucleotides in vivo. Methods Enzymol. 313:46–56 (2000). doi:10.1016/S0076-6879(00)13004-6.

    PubMed  CAS  Google Scholar 

  24. S. T. Crooke, K. M. Lemonidis, L. Neilson, R. Griffey, E. A. Lesnik, and B. P. Monia. Kinetic characteristics of Escherichia coli RNase H1: cleavage of various antisense oligonucleotide-RNA duplexes. Biochem. J. 312(Pt 2):599–608 (1995).

    PubMed  CAS  Google Scholar 

  25. J. Kurreck, E. Wyszko, C. Gillen, and V. A. Erdmann. Design of antisense oligonucleotides stabilized by locked nucleic acids. Nucleic Acids Res. 30:1911–1918 (2002). doi:10.1093/nar/30.9.1911.

    PubMed  CAS  Google Scholar 

  26. T. A. Vickers, S. Koo, C. F. Bennett, S. T. Crooke, N. M. Dean, and B. F. Baker. Efficient reduction of target RNAs by small interfering RNA and RNase H-dependent antisense agents. A comparative analysis. J. Biol. Chem. 278:7108–7118 (2003). doi:10.1074/jbc.M210326200.

    PubMed  CAS  Google Scholar 

  27. B. F. Baker, S. S. Lot, T. P. Condon, S. Cheng-Flournoy, E. A. Lesnik, H. M. Sasmor, and C. F. Bennett. 2′-O-(2-Methoxy)ethyl-modified anti-intercellular adhesion molecule 1 (ICAM-1) oligonucleotides selectively increase the ICAM-1 mRNA level and inhibit formation of the ICAM-1 translation initiation complex in human umbilical vein endothelial cells. J. Biol. Chem. 272:11994–12000 (1997). doi:10.1074/jbc.272.18.11994.

    PubMed  CAS  Google Scholar 

  28. A. Fire, S. Xu, M. K. Montgomery, S. A. Kostas, S. E. Driver, and C. C. Mello. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature. 391:806–811 (1998). doi:10.1038/35888.

    PubMed  CAS  Google Scholar 

  29. S. M. Elbashir, J. Harborth, W. Lendeckel, A. Yalcin, K. Weber, and T. Tuschl. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature. 411:494–498 (2001). doi:10.1038/35078107.

    PubMed  CAS  Google Scholar 

  30. T. Tuschl, P. D. Zamore, R. Lehmann, D. P. Bartel, and P. A. Sharp. Targeted mRNA degradation by double-stranded RNA in vitro. Genes Dev. 13:3191–3197 (1999). doi:10.1101/gad.13.24.3191.

    PubMed  CAS  Google Scholar 

  31. P. D. Zamore, T. Tuschl, P. A. Sharp, and D. P. Bartel. RNAi: double-stranded RNA directs the ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals. Cell. 101:25–33 (2000). doi:10.1016/S0092-8674(00)80620-0.

    PubMed  CAS  Google Scholar 

  32. S. M. Hammond, E. Bernstein, D. Beach, and G. J. Hannon. An RNA-directed nuclease mediates post-transcriptional gene silencing in Drosophila cells. Nature. 404:293–296 (2000). doi:10.1038/35005107.

    PubMed  CAS  Google Scholar 

  33. T. R. Brummelkamp, R. Bernards, and R. Agami. A system for stable expression of short interfering RNAs in mammalian cells. Science. 296:550–553 (2002). doi:10.1126/science.1068999.

    PubMed  CAS  Google Scholar 

  34. G. Sui, C. Soohoo, B. Affar el, F. Gay, Y. Shi, W. C. Forrester, and Y. Shi. A DNA vector-based RNAi technology to suppress gene expression in mammalian cells. Proc. Natl. Acad. Sci. U. S. A. 99:5515–5520 (2002). doi:10.1073/pnas.082117599.

    PubMed  CAS  Google Scholar 

  35. P. J. Paddison, A. A. Caudy, E. Bernstein, G. J. Hannon, and D. S. Conklin. Short hairpin RNAs (shRNAs) induce sequence-specific silencing in mammalian cells. Genes Dev. 16:948–958 (2002). doi:10.1101/gad.981002.

    PubMed  CAS  Google Scholar 

  36. P. D. Zamore, and N. Aronin. siRNAs knock down hepatitis. Nat. Med. 9:266–267 (2003). doi:10.1038/nm0303-266.

    PubMed  CAS  Google Scholar 

  37. P. C. Scacheri, O. Rozenblatt-Rosen, N. J. Caplen, T. G. Wolfsberg, L. Umayam, J. C. Lee, C. M. Hughes, K. S. Shanmugam, A. Bhattacharjee, M. Meyerson, and F. S. Collins. Short interfering RNAs can induce unexpected and divergent changes in the levels of untargeted proteins in mammalian cells. Proc. Natl. Acad. Sci. U. S. A. 101:1892–1897 (2004). doi:10.1073/pnas.0308698100.

    PubMed  CAS  Google Scholar 

  38. A. L. Jackson, J. Burchard, D. Leake, A. Reynolds, J. Schelter, J. Guo, J. M. Johnson, L. Lim, J. Karpilow, K. Nichols, W. Marshall, A. Khvorova, and P. S. Linsley. Position-specific chemical modification of siRNAs reduces “off-target” transcript silencing. RNA. 12:1197–1205 (2006). doi:10.1261/rna.30706.

    PubMed  CAS  Google Scholar 

  39. Y. Zeng, R. Yi, and B. R. Cullen. MicroRNAs and small interfering RNAs can inhibit mRNA expression by similar mechanisms. Proc. Natl. Acad. Sci. U. S. A. 100:9779–9784 (2003). doi:10.1073/pnas.1630797100.

    PubMed  CAS  Google Scholar 

  40. J. G. Doench, C. P. Petersen, and P. A. Sharp. siRNAs can function as miRNAs. Genes Dev. 17:438–442 (2003). doi:10.1101/gad.1064703.

    PubMed  CAS  Google Scholar 

  41. E. van Rooij, and E. N. Olson. MicroRNAs: powerful new regulators of heart disease and provocative therapeutic targets. J. Clin. Invest. 117:2369–2376 (2007). doi:10.1172/JCI33099.

    PubMed  Google Scholar 

  42. M. Puceat. Pharmacological approaches to regenerative strategies for the treatment of cardiovascular diseases. Curr. Opin. Pharmacol. 8:189–192 (2008). doi:10.1016/j.coph.2007.12.004.

    PubMed  CAS  Google Scholar 

  43. K. M. Kurian, C. J. Watson, and A. H. Wyllie. Retroviral vectors. Mol. Pathol. 53:173–176 (2000). doi:10.1136/mp.53.4.173.

    PubMed  CAS  Google Scholar 

  44. L. D. Kumar, and A. R. Clarke. Gene manipulation through the use of small interfering RNA (siRNA): from in vitro to in vivo applications. Adv. Drug Deliv. Rev. 59:87–100 (2007). doi:10.1016/j.addr.2007.03.009.

    PubMed  CAS  Google Scholar 

  45. J. M. Adams, and S. Cory. Life-or-death decisions by the Bcl-2 protein family. Trends Biochem. Sci. 26:61–66 (2001). doi:10.1016/S0968-0004(00)01740-0.

    PubMed  CAS  Google Scholar 

  46. M. Chen, and J. Wang. Initiator caspases in apoptosis signaling pathways. Apoptosis. 7:313–319 (2002). doi:10.1023/A:1016167228059.

    PubMed  CAS  Google Scholar 

  47. G. B. Carey, D. Donjerkovic, C. M. Mueller, S. Liu, J. A. Hinshaw, L. Tonnetti, W. Davidson, and D. W. Scott. B-cell receptor and Fas-mediated signals for life and death. Immunol. Rev. 176:105–115 (2000). doi:10.1034/j.1600-065X.2000.00502.x.

    PubMed  CAS  Google Scholar 

  48. J. F. Curtin, and T. G. Cotter. Live and let die: regulatory mechanisms in Fas-mediated apoptosis. Cell. Signal. 15:983–992 (2003). doi:10.1016/S0898-6568(03)00093-7.

    PubMed  CAS  Google Scholar 

  49. D. Klein, C. Ricordi, A. Pugliese, and R. L. Pastori. Inhibition of Fas-mediated apoptosis in mouse insulinoma beta TC-3 cells via an anti-Fas ribozyme. Hum. Gene Ther. 11:1033–1045 (2000). doi:10.1089/10430340050015347.

    PubMed  CAS  Google Scholar 

  50. V. Arora, and P. L. Iversen. Antisense oligonucleotides targeted to the p53 gene modulate liver regeneration in vivo. Drug Metab. Dispos. 28:131–138 (2000).

    PubMed  CAS  Google Scholar 

  51. L. Magnelli, M. Ruggiero, and V. Chiarugi. The old and the new in p53 functional regulation. Biochem. Mol. Med. 62:3–10 (1997). doi:10.1006/bmme.1997.2616.

    PubMed  CAS  Google Scholar 

  52. H. T. Mao, Q. Liu, J. Zhang, H. T. Gu, L. Wang, X. B. Zhou, H. P. Yin, L. Zhang, F. X. Xie, and G. S. Jiang. Effects of specific antisense oligonucleotide inhibition of Fas expression on T cell apoptosis induced by Fas ligand. International Immunopharmacology. 7:1714–1722 (2007). doi:10.1016/j.intimp.2007.09.010.

    PubMed  CAS  Google Scholar 

  53. A. H. Insua, A. D. Montaner, J. M. Rodriguez, F. Elias, J. Flo, R. A. Lopez, J. Zorzopulos, E. L. Hofer, and N. A. Chasseing. IMT504, the prototype of the immunostimulatory oligonucleotides of the PyNTTTTGT class, increases the number of progenitors of mesenchymal stem cells both in vitro and in vivo: potential use in tissue repair therapy. Stem Cells. 25:1047–1054 (2007). doi:10.1634/stemcells.2006-0479.

    CAS  Google Scholar 

  54. R. Mussmann, M. Geese, F. Harder, S. Kegel, U. Andag, A. Lomow, U. Burk, D. Onichtchouk, C. Dohrmann, and M. Austen. Inhibition of GSK3 promotes replication and survival of pancreatic beta cells. J. Biol. Chem. 282:12030–12037 (2007). doi:10.1074/jbc.M609637200.

    PubMed  CAS  Google Scholar 

  55. S. Chen, J. H. Ding, R. Bekeredjian, B. Z. Yang, R. V. Shohet, S. A. Johnston, H. E. Hohmeier, C. B. Newgard, and P. A. Grayburn. Efficient gene delivery to pancreatic islets with ultrasonic microbubble destruction technology. Proc. Natl. Acad. Sci. U. S. A. 103:8469–8474 (2006). doi:10.1073/pnas.0602921103.

    PubMed  CAS  Google Scholar 

  56. D. B. Ring, K. W. Johnson, E. J. Henriksen, J. M. Nuss, D. Goff, T. R. Kinnick, S. T. Ma, J. W. Reeder, I. Samuels, T. Slabiak, A. S. Wagman, M. E. Hammond, and S. D. Harrison. Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo. Diabetes. 52:588–595 (2003). doi:10.2337/diabetes.52.3.588.

    PubMed  CAS  Google Scholar 

  57. H. Song, Z. Zhang, and L. Wang. Small interference RNA against PTP-1B reduces hypoxia/reoxygenation induced apoptosis of rat cardiomyocytes. Apoptosis. 13:383–393 (2008). doi:10.1007/s10495-008-0181-1.

    PubMed  CAS  Google Scholar 

  58. P. Lingor, P. Koeberle, S. Kugler, and M. Bahr. Down-regulation of apoptosis mediators by RNAi inhibits axotomy-induced retinal ganglion cell death in vivo. Brain. 128:550–558 (2005). doi:10.1093/brain/awh382.

    PubMed  Google Scholar 

  59. F. Li, and R. I. Mahato. iNOS gene silencing prevents inflammatory cytokine-induced beta-cell apoptosis. Mol. Pharm. 5:407–417 (2008). doi:10.1021/mp700145f.

    PubMed  CAS  Google Scholar 

  60. B. Brune, A. von Knethen, and K. B. Sandau. Nitric oxide and its role in apoptosis. Eur. J. Pharmacol. 351:261–272 (1998). doi:10.1016/S0014-2999(98)00274-X.

    PubMed  CAS  Google Scholar 

  61. W. P. Arend, and J. M. Dayer. Cytokines and cytokine inhibitors or antagonists in rheumatoid arthritis. Arthritis Rheum. 33:305–315 (1990). doi:10.1002/art.1780330302.

    PubMed  CAS  Google Scholar 

  62. M. Feldmann, F. M. Brennan, and R. N. Maini. Role of cytokines in rheumatoid arthritis. Annu. Rev. Immunol. 14:397–440 (1996). doi:10.1146/annurev.immunol.14.1.397.

    PubMed  CAS  Google Scholar 

  63. M. Feldmann, and R. N. Maini. Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? Annu. Rev. Immunol. 19:163–196 (2001). doi:10.1146/annurev.immunol.19.1.163.

    PubMed  CAS  Google Scholar 

  64. J. Saklatvala. Tumour necrosis factor alpha stimulates resorption and inhibits synthesis of proteoglycan in cartilage. Nature. 322:547–549 (1986). doi:10.1038/322547a0.

    PubMed  CAS  Google Scholar 

  65. F. M. Brennan, A. Jackson, D. Chantry, R. Maini, and M. Feldmann. Inhibitory effect of Tnf-alpha antibodies on synovial cell interleukin-1 production in rheumatoid-arthritis. Lancet. 2:244–247 (1989). doi:10.1016/S0140-6736(89)90430-3.

    PubMed  CAS  Google Scholar 

  66. C. Haworth, F. M. Brennan, D. Chantry, M. Turner, R. N. Maini, and M. Feldmann. Expression of granulocyte-macrophage colony-stimulating factor in rheumatoid-arthritis — regulation by tumor-necrosis-factor-alpha. Eur. J. Immunol. 21:2575–2579 (1991). doi:10.1002/eji.1830211039.

    PubMed  CAS  Google Scholar 

  67. R. O. Williams, M. Feldmann, and R. N. Maini. Antitumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis. Proc. Natl. Acad. Sci. U. S. A. 89:9784–9788 (1992). doi:10.1073/pnas.89.20.9784.

    PubMed  CAS  Google Scholar 

  68. J. Keffer, L. Probert, H. Cazlaris, S. Georgopoulos, E. Kaslaris, D. Kioussis, and G. Kollias. Transgenic mice expressing human tumor-necrosis-factor — a predictive genetic model of arthritis. Embo J. 10:4025–4031 (1991).

    PubMed  CAS  Google Scholar 

  69. M. Takahashi, T. Funato, Y. Suzuki, H. Fujii, K. K. Ishii, M. Kaku, and T. Sasaki. Chemically modified ribozyme targeting TNF-alpha mRNA regulates TNF-alpha and IL-6 synthesis in synovial fibroblasts of patients with rheumatoid arthritis. J. Clin. Immunol. 22:228–236 (2002). doi:10.1023/A:1016092909365.

    PubMed  CAS  Google Scholar 

  70. R. Kumar, V. Dammai, P. K. Yadava, and S. Kleinau. Gene targeting by ribozyme against TNF-alpha mRNA inhibits autoimmune arthritis. Gene Ther. 12:1486–1493 (2005). doi:10.1038/sj.gt.3302583.

    PubMed  CAS  Google Scholar 

  71. M. Karin, and M. Delhase. The I kappa B kinase (IKK) and NF-kappa B: key elements of proinflammatory signalling. Semin. Immunol. 12:85–98 (2000). doi:10.1006/smim.2000.0210.

    PubMed  CAS  Google Scholar 

  72. M. A. Collart, P. Baeuerle, and P. Vassalli. Regulation of tumor necrosis factor alpha transcription in macrophages: involvement of four kappa B-like motifs and of constitutive and inducible forms of NF-kappa B. Mol. Cell. Biol. 10:1498–1506 (1990).

    PubMed  CAS  Google Scholar 

  73. T. A. Libermann, and D. Baltimore. Activation of interleukin-6 gene expression through the NF-kappa B transcription factor. Mol. Cell. Biol. 10:2327–2334 (1990).

    PubMed  CAS  Google Scholar 

  74. R. Marok, P. G. Winyard, A. Coumbe, M. L. Kus, K. Gaffney, S. Blades, P. I. Mapp, C. J. Morris, D. R. Blake, C. Kaltschmidt, and P. A. Baeuerle. Activation of the transcription factor nuclear factor-kappaB in human inflamed synovial tissue. Arthritis Rheum. 39:583–591 (1996). doi:10.1002/art.1780390407.

    PubMed  CAS  Google Scholar 

  75. T. Tomita, E. Takeuchi, N. Tomita, R. Morishita, M. Kaneko, K. Yamamoto, T. Nakase, H. Seki, K. Kato, Y. Kaneda, and T. Ochi. Suppressed severity of collagen-induced arthritis by in vivo transfection of nuclear factor kappaB decoy oligodeoxynucleotides as a gene therapy. Arthritis Rheum. 42:2532–2542 (1999). doi:10.1002/1529-0131(199912)42:12<2532::AID-ANR5>3.0.CO;2-2.

    PubMed  CAS  Google Scholar 

  76. L. X. Chen, L. Lin, H. J. Wang, X. L. Wei, X. Fu, J. Y. Zhang, and C. L. Yu. Suppression of early experimental osteoarthritis by in vivo delivery of the adenoviral vector-mediated NF-kappaBp65-specific siRNA. Osteoarthr. Cartil. 16:174–184 (2008). doi:10.1016/j.joca.2007.06.006.

    PubMed  CAS  Google Scholar 

  77. J. Schedel, C. A. Seemayer, T. Pap, M. Neidhart, S. Kuchen, B. A. Michel, R. E. Gay, U. Muller-Ladner, S. Gay, and W. Zacharias. Targeting cathepsin L (CL) by specific ribozymes decreases CL protein synthesis and cartilage destruction in rheumatoid arthritis. Gene Ther. 11:1040–1047 (2004). doi:10.1038/sj.gt.3302265.

    PubMed  CAS  Google Scholar 

  78. E. Rutkauskaite, W. Zacharias, J. Schedel, U. Muller-Ladner, C. Mawrin, C. A. Seemayer, D. Alexander, R. E. Gay, W. K. Aicher, B. A. Michel, S. Gay, and T. Pap. Ribozymes that inhibit the production of matrix metalloproteinase 1 reduce the invasiveness of rheumatoid arthritis synovial fibroblasts. Arthritis Rheum. 50:1448–1456 (2004). doi:10.1002/art.20186.

    PubMed  CAS  Google Scholar 

  79. Y. Smicun, M. W. Kilpatrick, J. Florer, I. Toudjarska, G. Wu, R. J. Wenstrup, and P. Tsipouras. Enhanced intracellular availability and survival of hammerhead ribozymes increases target ablation in a cellular model of osteogenesis imperfecta. Gene Ther. 10:2005–2012 (2003). doi:10.1038/sj.gt.3302108.

    PubMed  CAS  Google Scholar 

  80. E. Gazzerro, A. Smerdel-Ramoya, S. Zanotti, L. Stadmeyer, D. Durant, A. N. Economides, and E. Canalis. Conditional deletion of gremlin causes a transient increase in bone formation and bone mass. J. Biol. Chem. 282:31549–31557 (2007). doi:10.1074/jbc.M701317200.

    PubMed  CAS  Google Scholar 

  81. R. Zwicky, K. Muntener, M. B. Goldring, and A. Baici. Cathepsin B expression and down-regulation by gene silencing and antisense DNA in human chondrocytes. Biochem. J. 367:209–217 (2002). doi:10.1042/BJ20020210.

    PubMed  CAS  Google Scholar 

  82. L. Dong, R. Wang, Y. A. Zhu, C. Wang, H. Diao, C. Zhang, J. Zhao, and J. Zhang. Antisense oligonucleotide targeting TNF-alpha can suppress Co–Cr–Mo particle-induced osteolysis. J. Orthop. Res. 26:1114–1120 (2008). doi:10.1002/jor.20607.

    PubMed  CAS  Google Scholar 

  83. R. Natarajan, F. N. Salloum, B. J. Fisher, R. C. Kukreja, and A. A. Fowler 3rd. Hypoxia inducible factor-1 activation by prolyl 4-hydroxylase-2 gene silencing attenuates myocardial ischemia reperfusion injury. Circ. Res. 98:133–140 (2006). doi:10.1161/01.RES.0000197816.63513.27.

    PubMed  CAS  Google Scholar 

  84. R. Natarajan, F. N. Salloum, B. J. Fisher, E. D. Ownby, R. C. Kukreja, and A. A. Fowler 3rd. Activation of hypoxia-inducible factor-1 via prolyl-4 hydoxylase-2 gene silencing attenuates acute inflammatory responses in postischemic myocardium. Am. J. Physiol. Heart Circ. Physiol. 293:H1571–H1580 (2007). doi:10.1152/ajpheart.00291.2007.

    PubMed  CAS  Google Scholar 

  85. R. Natarajan, F. N. Salloum, B. J. Fisher, R. C. Kukreja, and A. A. Fowler 3rd. Hypoxia inducible factor-1 upregulates adiponectin in diabetic mouse hearts and attenuates post-ischemic injury. J. Cardiovasc. Pharmacol. 51:178–187 (2008).

    PubMed  CAS  Article  Google Scholar 

  86. A. Watanabe, M. Arai, M. Yamazaki, N. Koitabashi, F. Wuytack, and M. Kurabayashi. Phospholamban ablation by RNA interference increases Ca2+ uptake into rat cardiac myocyte sarcoplasmic reticulum. J. Mol. Cell. Cardiol. 37:691–698 (2004). doi:10.1016/j.yjmcc.2004.06.009.

    PubMed  CAS  Google Scholar 

  87. H. Fechner, L. Suckau, J. Kurreck, I. Sipo, X. Wang, S. Pinkert, S. Loschen, J. Rekittke, S. Weger, D. Dekkers, R. Vetter, V. A. Erdmann, H. P. Schultheiss, M. Paul, J. Lamers, and W. Poller. Highly efficient and specific modulation of cardiac calcium homeostasis by adenovector-derived short hairpin RNA targeting phospholamban. Gene Ther. 14:211–218 (2007). doi:10.1038/sj.gt.3302872.

    PubMed  CAS  Google Scholar 

  88. J. C. Braz, K. Gregory, A. Pathak, W. Zhao, B. Sahin, R. Klevitsky, T. F. Kimball, J. N. Lorenz, A. C. Nairn, S. B. Liggett, I. Bodi, S. Wang, A. Schwartz, E. G. Lakatta, A. A. DePaoli-Roach, J. Robbins, T. E. Hewett, J. A. Bibb, M. V. Westfall, E. G. Kranias, and J. D. Molkentin. PKC-alpha regulates cardiac contractility and propensity toward heart failure. Nat. Med. 10:248–254 (2004). doi:10.1038/nm1000.

    PubMed  CAS  Google Scholar 

  89. A. El-Armouche, J. Singh, H. Naito, K. Wittkopper, M. Didie, A. Laatsch, W. H. Zimmermann, and T. Eschenhagen. Adenovirus-delivered short hairpin RNA targeting PKCalpha improves contractile function in reconstituted heart tissue. J. Mol. Cell. Cardiol. 43:371–376 (2007). doi:10.1016/j.yjmcc.2007.05.021.

    PubMed  CAS  Google Scholar 

  90. H. Hayashita-Kinoh, M. Yamada, T. Yokota, Y. Mizuno, and H. Mochizuki. Down-regulation of alpha-synuclein expression can rescue dopaminergic cells from cell death in the substantia nigra of Parkinson’s disease rat model. Biochem. Biophys. Res. Commun. 341:1088–1095 (2006). doi:10.1016/j.bbrc.2006.01.057.

    PubMed  CAS  Google Scholar 

  91. Z. Ahmed, R. G. Dent, E. L. Suggate, L. B. Barrett, R. J. Seabright, M. Berry, and A. Logan. Disinhibition of neurotrophin-induced dorsal root ganglion cell neurite outgrowth on CNS myelin by siRNA-mediated knockdown of NgR, p75NTR and Rho-A. Mol. Cell. Neurosci. 28:509–523 (2005). doi:10.1016/j.mcn.2004.11.002.

    PubMed  CAS  Google Scholar 

  92. A. Pfeifer, S. Eigenbrod, S. Al-Khadra, A. Hofmann, G. Mitteregger, M. Moser, U. Bertsch, and H. Kretzschmar. Lentivector-mediated RNAi efficiently suppresses prion protein and prolongs survival of scrapie-infected mice. J. Clin. Invest. 116:3204–3210 (2006). doi:10.1172/JCI29236.

    PubMed  CAS  Google Scholar 

  93. R. Morosetti, M. Mirabella, C. Gliubizzi, A. Broccolini, L. De Angelis, E. Tagliafico, M. Sampaolesi, T. Gidaro, M. Papacci, E. Roncaglia, S. Rutella, S. Ferrari, P. A. Tonali, E. Ricci, and G. Cossu. MyoD expression restores defective myogenic differentiation of human mesoangioblasts from inclusion-body myositis muscle. Proc. Natl. Acad. Sci. U. S. A. 103:16995–17000 (2006). doi:10.1073/pnas.0603386103.

    PubMed  CAS  Google Scholar 

  94. J. Machen, J. Harnaha, R. Lakomy, A. Styche, M. Trucco, and N. Giannoukakis. Antisense oligonucleotides down-regulating costimulation confer diabetes-preventive properties to nonobese diabetic mouse dendritic cells. J. Immunol. 173:4331–4341 (2004).

    PubMed  CAS  Google Scholar 

  95. B. Phillips, K. Nylander, J. Harnaha, J. Machen, R. Lakomy, A. Styche, K. Gillis, L. Brown, D. Lafreniere, M. Gallo, J. Knox, K. Hogeland, M. Trucco, and N. Giannoukakis. A microsphere-based vaccine prevents and reverses new-onset autoimmune diabetes. Diabetes. 57:1544–1555 (2008). doi:10.2337/db07-0507.

    PubMed  CAS  Google Scholar 

  96. Y. B. Hu, D. G. Li, and H. M. Lu. Modified synthetic siRNA targeting tissue inhibitor of metalloproteinase-2 inhibits hepatic fibrogenesis in rats. J. Gene Med. 9:217–229 (2007). doi:10.1002/jgm.1009.

    PubMed  CAS  Google Scholar 

  97. Y. M. Chae, K. K. Park, I. K. Lee, J. K. Kim, C. H. Kim, and Y. C. Chang. Ring-Sp1 decoy oligonucleotide effectively suppresses extracellular matrix gene expression and fibrosis of rat kidney induced by unilateral ureteral obstruction. Gene Ther. 13:430–439 (2006). doi:10.1038/sj.gt.3302696.

    PubMed  CAS  Google Scholar 

  98. M. F. Cordeiro, A. Mead, R. R. Ali, R. A. Alexander, S. Murray, C. Chen, C. York-Defalco, N. M. Dean, G. S. Schultz, and P. T. Khaw. Novel antisense oligonucleotides targeting TGF-beta inhibit in vivo scarring and improve surgical outcome. Gene Ther. 10:59–71 (2003). doi:10.1038/sj.gt.3301865.

    PubMed  CAS  Google Scholar 

  99. C. H. Heldin, K. Miyazono, and P. ten Dijke. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature. 390:465–471 (1997). doi:10.1038/37284.

    PubMed  CAS  Google Scholar 

  100. Z. Y. Gao, Z. M. Wang, Y. Shi, Z. H. Lin, H. Jiang, T. S. Hou, Q. G. Wang, X. B. Yuan, Y. Z. Zhao, H. Wu, and Y. X. Jin. Modulation of collagen synthesis in keloid fibroblasts by silencing Smad2 with siRNA. Plast. Reconstr. Surg. 118:1328–1337 (2006). doi:10.1097/01.prs.0000239537.77870.2c.

    PubMed  CAS  Google Scholar 

  101. Z. Wang, Z. Gao, Y. Shi, Y. Sun, Z. H. Lin, H. Jiang, T. S. Hou, Q. G. Wang, X. B. Yuan, X. H. Zhu, H. Wu, and Y. X. Jin. Inhibition of Smad3 expression decreases collagen synthesis in keloid disease fibroblasts. J. Plast. Reconstr. Aesthet. Surg. 60:1193–1199 (2007). doi:10.1016/j.bjps.2006.05.007.

    PubMed  Google Scholar 

  102. J. Silver, and J. H. Miller. Regeneration beyond the glial scar. Nat. Rev. Neurosci. 5:146–156 (2004). doi:10.1038/nrn1326.

    PubMed  CAS  Google Scholar 

  103. T. L. Laabs, H. Wang, Y. Katagiri, T. McCann, J. W. Fawcett, and H. M. Geller. Inhibiting glycosaminoglycan chain polymerization decreases the inhibitory activity of astrocyte-derived chondroitin sulfate proteoglycans. J. Neurosci. 27:14494–14501 (2007). doi:10.1523/JNEUROSCI.2807-07.2007.

    PubMed  CAS  Google Scholar 

  104. J. A. Bradley, E. M. Bolton, and R. A. Pedersen. Stem cell medicine encounters the immune system. Nat. Rev. Immunol. 2:859–871 (2002). doi:10.1038/nri934.

    PubMed  CAS  Google Scholar 

  105. C. Figueiredo, A. Seltsam, and R. Blasczyk. Class-, gene-, and group-specific HLA silencing by lentiviral shRNA delivery. J. Mol. Med. 84:425–437 (2006). doi:10.1007/s00109-005-0024-2.

    PubMed  CAS  Google Scholar 

  106. C. Figueiredo, P. A. Horn, R. Blasczyk, and A. Seltsam. Regulating MHC expression for cellular therapeutics. Transfusion. 47:18–27 (2007). doi:10.1111/j.1537-2995.2007.01059.x.

    PubMed  CAS  Google Scholar 

  107. K. Haga, N. A. Lemp, C. R. Logg, J. Nagashima, E. Faure-Kumar, G. G. Gomez, C. A. Kruse, R. Mendez, R. Stripecke, N. Kasahara, and J. C. Cicciarelli. Permanent, lowered HLA class I expression using lentivirus vectors with shRNA constructs: averting cytotoxicity by alloreactive T lymphocytes. Transplant. Proc. 38:3184–3188 (2006). doi:10.1016/j.transproceed.2006.10.158.

    PubMed  CAS  Google Scholar 

  108. W. H. Hancock, W. D. Whitley, S. G. Tullius, U. W. Heemann, B. Wasowska, W. M. Baldwin 3rd, and N. L. Tilney. Cytokines, adhesion molecules, and the pathogenesis of chronic rejection of rat renal allografts. Transplantation. 56:643–650 (1993). doi:10.1097/00007890-199309000-00028.

    PubMed  CAS  Google Scholar 

  109. D. Dragun, I. Lukitsch, S. G. Tullius, Y. Qun, J. K. Park, W. Schneider, F. C. Luft, and H. Haller. Inhibition of intercellular adhesion molecule-1 with antisense deoxynucleotides prolongs renal isograft survival in the rat. Kidney Int. 54:2113–2122 (1998). doi:10.1046/j.1523-1755.1998.00189.x.

    PubMed  CAS  Google Scholar 

  110. R. S. Poston, M. J. Mann, E. G. Hoyt, M. Ennen, V. J. Dzau, and R. C. Robbins. Antisense oligodeoxynucleotides prevent acute cardiac allograft rejection via a novel, nontoxic, highly efficient transfection method. Transplantation. 68:825–832 (1999). doi:10.1097/00007890-199909270-00015.

    PubMed  CAS  Google Scholar 

  111. B. Johnstone, T. M. Hering, A. I. Caplan, V. M. Goldberg, and J. U. Yoo. In vitro chondrogenesis of bone marrow-derived mesenchymal progenitor cells. Exp. Cell Res. 238:265–272 (1998). doi:10.1006/excr.1997.3858.

    PubMed  CAS  Google Scholar 

  112. A. Vats, R. C. Bielby, N. Tolley, S. C. Dickinson, A. R. Boccaccini, A. P. Hollander, A. E. Bishop, and J. M. Polak. Chondrogenic differentiation of human embryonic stem cells: the effect of the micro-environment. Tissue Eng. 12:1687–1697 (2006). doi:10.1089/ten.2006.12.1687.

    PubMed  CAS  Google Scholar 

  113. S. A. Lietman, C. Ding, D. W. Cooke, and M. A. Levine. Reduction in Gsalpha induces osteogenic differentiation in human mesenchymal stem cells. Clin. Orthop. Relat. Res. (434):231–238 (2005). doi:10.1097/01.blo.0000153279.90512.38.

  114. D. Wegmuller, I. Raineri, B. Gross, E. J. Oakeley, and C. Moroni. A cassette system to study embryonic stem cell differentiation by inducible RNA interference. Stem Cells. 25:1178–1185 (2007). doi:10.1634/stemcells.2006-0106.

    PubMed  CAS  Google Scholar 

  115. Y. Xu, S. H. Mirmalek-Sani, X. Yang, J. Zhang, and R. O. Oreffo. The use of small interfering RNAs to inhibit adipocyte differentiation in human preadipocytes and fetal-femur-derived mesenchymal cells. Exp. Cell Res. 312:1856–1864 (2006). doi:10.1016/j.yexcr.2006.02.016.

    PubMed  CAS  Google Scholar 

  116. P. Zhang, M. J. Pazin, C. M. Schwartz, K. G. Becker, R. P. Wersto, C. M. Dilley, and M. P. Mattson. Nontelomeric TRF2-REST interaction modulates neuronal gene silencing and fate of tumor and stem cells. Curr. Biol. 18(19):1489–1494 (2008).

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This study is supported by Grant ARC 10/06, Ministry of Education (MoE), Singapore. The authors are grateful to Mr. He Junjing for the drawings in Fig. 5.

Author information

Affiliations

  1. Division of BioEngineering, School of Chemical and Biomedical Engineering, Nanyang Technological University, 70 Nanyang Drive, N1.3-B2-13, Singapore, 637457, Singapore

    Yongchang Yao, Chunming Wang, Rohan R. Varshney & Dong-An Wang

Authors
  1. Yongchang Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chunming Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rohan R. Varshney
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dong-An Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dong-An Wang.

Additional information

Chunming Wang, and Yongchang Yao contributed equally.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Yao, Y., Wang, C., Varshney, R.R. et al. Antisense Makes Sense in Engineered Regenerative Medicine. Pharm Res 26, 263 (2009). https://doi.org/10.1007/s11095-008-9772-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11095-008-9772-3

KEY WORDS

  • antisense
  • oligodeoxynucleotides
  • regenerative medicine
  • ribozyme
  • RNA interference (RNAi)