Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Gene therapy progress and prospects: non-viral gene therapy by systemic delivery

Abstract

Non-viral vectors continue to be an attractive alternative to viral vectors due to their safety, versatility and ease of preparation and scale-up. Over the past few years, investigators have been successful in developing gene carriers that can be targeted to the disease site. Several different delivery vectors for systemic use have been developed by different groups for plasmid DNA and oligonucleotide. Most of them are designed for targeted tumor therapy. The mechanism of inflammatory toxicity, the major toxicity of cationic lipoplex, has been studied and managed. In this review, we focus on the progress made over the last 2 years. We also discuss some future prospects for gene delivery.

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

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Roth CM, Sundaram S . Engineering synthetic vectors for improved DNA delivery: insights from intracellular pathways. Annu Rev Biomed Eng 2004; 6: 397–426.

    Article  CAS  Google Scholar 

  2. Dean DA, Strong DD, Zimmer WE . Nuclear entry of non-viral vectors. Gene Therapy 2005; 12: 881–890.

    Article  CAS  Google Scholar 

  3. Medina-Kauwe LK, Xie J, Hamm-Alvarez S . Intracellular trafficking of non-viral vectors. Gene Therapy 2005; 12: 1734–1751.

    Article  CAS  Google Scholar 

  4. Song E, Zhu P, Lee SK, Chowdhury D, Kussman S, Dykxhoorn DM et al. Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors. Nat Biotechnol 2005; 23: 709–717.

    Article  CAS  Google Scholar 

  5. Yu W, Pirollo KF, Rait A, Yu B, Xiang LM, Huang WQ et al. A sterically stabilized immunolipoplex for systemic administration of a therapeutic gene. Gene Therapy 2004; 11: 1434–1440.

    Article  CAS  Google Scholar 

  6. Zhang Y, Zhang YF, Bryant J, Charles A, Boado RJ, Pardridge WM . Intravenous RNA interference gene therapy targeting the human epidermal growth factor receptor prolongs survival in intracranial brain cancer. Clin Cancer Res 2004; 10: 3667–3677.

    Article  CAS  Google Scholar 

  7. Morrissey DV, Lockridge JA, Shaw L, Blanchard K, Jensen K, Breen W et al. Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs. Nat Biotechnol 2005; 23: 1002–1007.

    Article  CAS  Google Scholar 

  8. Kaul G, Amiji M . Tumor-targeted gene delivery using poly(ethylene glycol)-modified gelatin nanoparticles: in vitro and in vivo studies. Pharm Res 2005; 22: 951–961.

    Article  CAS  Google Scholar 

  9. Walker GF, Fella C, Pelisek J, Fahrmeir J, Boeckle S, Ogris M et al. Toward synthetic viruses: endosomal pH-triggered deshielding of targeted polyplexes greatly enhances gene transfer in vitro and in vivo. Mol Ther 2005; 11: 418–425.

    Article  CAS  Google Scholar 

  10. Judge A, McClintock K, Phelps JR, Maclachlan I . Hypersensitivity and loss of disease site targeting caused by antibody responses to PEGylated liposomes. Mol Ther 2006; 13: 328–337.

    Article  CAS  Google Scholar 

  11. Schiffelers RM, Ansari A, Xu J, Zhou Q, Tang Q, Storm G et al. Cancer siRNA therapy by tumor selective delivery with ligand-targeted sterically stabilized nanoparticle. Nucleic Acids Res 2004; 32: e149.

    Article  Google Scholar 

  12. Hu-Lieskovan S, Heidel JD, Bartlett DW, Davis ME, Triche TJ . Sequence-specific knockdown of EWS-FLI1 by targeted, nonviral delivery of small interfering RNA inhibits tumor growth in a murine model of metastatic Ewing's sarcoma. Cancer Res 2005; 65: 8984–8992.

    Article  CAS  Google Scholar 

  13. Brannon-Peppas L, Blanchette JO . Nanoparticle and targeted systems for cancer therapy. Adv Drug Deliv Rev 2004; 56: 1649–1659.

    Article  CAS  Google Scholar 

  14. Wu X, Gao H, Pasupathy S, Tan PH, Ooi LL, Hui KM . Systemic administration of naked DNA with targeting specificity to mammalian kidneys. Gene Therapy 2005; 12: 477–486.

    Article  CAS  Google Scholar 

  15. Pirollo KF, Zon G, Rait A, Zhou Q, Yu W, Hogrefe R et al. Tumor-targeting nanoimmunoliposome complex for short interfering RNA delivery. Hum Gene Ther 2006; 17: 117–124.

    Article  CAS  Google Scholar 

  16. Ogris M, Walker G, Blessing T, Kircheis R, Wolschek M, Wagner E . Tumor-targeted gene therapy: strategies for the preparation of ligand-polyethylene glycol-polyethylenimine/DNA complexes. J Control Rel 2003; 91: 173–181.

    Article  CAS  Google Scholar 

  17. Kaul G, Amiji M . Biodistribution and targeting potential of poly(ethylene glycol)-modified gelatin nanoparticles in subcutaneous murine tumor model. J Drug Target 2004; 12: 585–591.

    Article  CAS  Google Scholar 

  18. Bitko V, Musiyenko A, Shulyayeva O, Barik S . Inhibition of respiratory viruses by nasally administered siRNA. Nat Med 2005; 11: 50–55.

    Article  CAS  Google Scholar 

  19. Lu QL, Rabinowitz A, Chen YC, Yokota T, Yin H, Alter J et al. Systemic delivery of antisense oligoribonucleotide restores dystrophin expression in body-wide skeletal muscles. Proc Natl Acad Sci USA 2005; 102: 198–203.

    Article  CAS  Google Scholar 

  20. Lu QL, Mann CJ, Lou F, Bou-Gharios G, Morris GE, Xue SA et al. Functional amounts of dystrophin produced by skipping the mutated exon in the mdx dystrophic mouse. Nat Med 2003; 9: 1009–1014.

    Article  CAS  Google Scholar 

  21. Soutschek J, Akinc A, Bramlage B, Charisse K, Constien R, Donoghue M et al. Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature 2004; 432: 173–178.

    Article  CAS  Google Scholar 

  22. Takeshita F, Minakuchi Y, Nagahara S, Honma K, Sasaki H, Hirai K et al. Efficient delivery of small interfering RNA to bone-metastatic tumors by using atelocollagen in vivo. Proc Natl Acad Sci USA 2005; 102: 12177–12182.

    Article  CAS  Google Scholar 

  23. Zimmermann TS, Lee AC, Akinc A, Bramlage B, Bumcrot D, Fedoruk MN et al. RNAi-mediated gene silencing in non-human primates. Nature 2006; 441: 111–114.

    Article  CAS  Google Scholar 

  24. Geisbert TW, Hensley LE, Kagan E, Yu EZ, Geisbert JB, Daddario-DiCaprio K et al. Postexposure protection of guinea pigs against a lethal ebola virus challenge is conferred by RNA interference. J Infect Dis 2006; 193: 1650–1657.

    Article  CAS  Google Scholar 

  25. Sellins K, Fradkin L, Liggitt D, Dow S . Type I interferons potently suppress gene expression following gene delivery using liposome(-)DNA complexes. Mol Ther 2005; 12: 451–459.

    Article  CAS  Google Scholar 

  26. Liu F, Shollenberger LM, Huang L . Non-immunostimulatory nonviral vectors. FASEB J 2004; 18: 1779–1781.

    Article  CAS  Google Scholar 

  27. Zhang JS, Liu F, Huang L . Implications of pharmacokinetic behavior of lipoplex for its inflammatory toxicity. Adv Drug Deliv Rev 2005; 57: 689–698.

    Article  CAS  Google Scholar 

  28. Zhang JS, Liu F, Conwell CC, Tan Y, Huang L . Mechanistic studies of sequential injection of cationic liposome and plasmid DNA. Mol Ther 2006; 13: 429–437.

    Article  CAS  Google Scholar 

  29. Judge AD, Sood V, Shaw JR, Fang D, McClintock K, MacLachlan I . Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA. Nat Biotechnol 2005; 23: 457–462.

    Article  CAS  Google Scholar 

  30. Judge AD, Bola G, Lee AC, MacLachlan I . Design of noninflammatory synthetic siRNA mediating potent gene silencing in vivo. Mol Ther 2006; 13: 494–505.

    Article  CAS  Google Scholar 

  31. O’Malley Jr BW, Li D, McQuone SJ, Ralston R . Combination nonviral interleukin-2 gene immunotherapy for head and neck cancer: from bench top to bedside. Laryngoscope 2005; 115: 391–404.

    Article  Google Scholar 

  32. Wells DJ . Gene therapy progress and prospects: electroporation and other physical methods. Gene Therapy 2004; 11: 1363–1369.

    Article  CAS  Google Scholar 

  33. Kolonin MG, Sun J, Do KA, Vidal CI, Ji Y, Baggerly KA et al. Synchronous selection of homing peptides for multiple tissues by in vivo phage display. FASEB J 2006; 20: 979–981.

    Article  CAS  Google Scholar 

  34. Lechardeur D, Verkman AS, Lukacs GL . Intracellular routing of plasmid DNA during non-viral gene transfer. Adv Drug Deliv Rev 2005; 57: 755–767.

    Article  CAS  Google Scholar 

  35. Riu E, Grimm D, Huang Z, Kay MA . Increased maintenance and persistence of transgenes by excision of expression cassettes from plasmid sequences in vivo. Hum Gene Ther 2005; 16: 558–570.

    Article  CAS  Google Scholar 

  36. Caldas H, Jaynes FO, Boyer MW, Hammond S, Altura RA . Survivin and Granzyme B-induced apoptosis, a novel anticancer therapy. Mol Cancer Ther 2006; 5: 693–703.

    Article  CAS  Google Scholar 

  37. Chu TC, Marks III JW, Lavery LA, Faulkner S, Rosenblum MG, Ellington AD et al. Aptamer:toxin conjugates that specifically target prostate tumor cells. Cancer Res 2006; 66: 5989–5992.

    Article  CAS  Google Scholar 

  38. Farokhzad OC, Cheng J, Teply BA, Sherifi I, Jon S, Kantoff PW et al. Targeted nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivo. Proc Natl Acad Sci USA 2006; 103: 6315–6320.

    Article  CAS  Google Scholar 

  39. Pestourie C, Tavitian B, Duconge F . Aptamers against extracellular targets for in vivo applications. Biochimie 2005; 87: 921–930.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The original work in this lab has been supported by NIH Grants AI48851 and DK68556. We thank Lisa M Shollenberger, Dr Christine C Conwell and Michael J Hackett for help in preparing the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to L Huang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, SD., Huang, L. Gene therapy progress and prospects: non-viral gene therapy by systemic delivery. Gene Ther 13, 1313–1319 (2006). https://doi.org/10.1038/sj.gt.3302838

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3302838

Keywords

This article is cited by

Search

Quick links