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Dendrimer delivery of an anti-VEGF oligonucleotide into the eye: a long-term study into inhibition of laser-induced CNV, distribution, uptake and toxicity

Gene Therapy volume 12, pages 1544–1550 (2005)Cite this article

Abstract

We have performed a long-term study into the use of a lipophilic amino-acid dendrimer to deliver an anti-vascular endothelial growth factor (VEGF) oligonucleotide (ODN-1) into the eyes of rats and inhibit laser-induced choroidal neovascularization (CNV). In addition, the uptake, distribution and retinal tolerance of the dendrimer plus oligonucleotide conjugates were examined. Analysis of fluorescein angiograms of laser photocoagulated eyes revealed that dendrimer plus ODN-1 significantly inhibited (P<0.05) the development of CNV for 4–6 months by up to 95% in the initial stages. Eyes similarly injected with ODN-1 alone showed no significant difference (P>0.05) in mean severity score at 2 months (2.86±0.09), 4 months (2.15±0.17) or 6 months (2.7±0.12) compared to the vehicle-injected controls. Furthermore, we showed that intravitreally injected ODN-1 tagged with 6-fam was absorbed by a wide area of the retina and penetrated all of the retinal cell layers to the retinal pigment epithelium. Ophthalmological examinations indicated that the dendrimers plus ODN-1 conjugates were well tolerated in vivo, which was later confirmed using immunohistochemistry, which showed no observable increase in antigens associated with inflammation. We conclude that the use of such dendrimers may provide a viable mechanism for the delivery of therapeutic oligonucleotides for the treatment of angiogenic eye diseases.

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References

  1. Ohno-Matsui K et al. Novel mechanism for age-related macular degeneration: an equilibrium shift between the angiogenesis factors VEGF and PEDF. J Cell Physiol 2001; 189: 323–333.

    Article  CAS  Google Scholar 

  2. Aiello LP et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 1994; 331: 1480–1487.

    Article  CAS  Google Scholar 

  3. Boulton M, Foreman D, Williams G, McLeod D . VEGF localisation in diabetic retinopathy. Br J Ophthalmol 1998; 82: 561–568.

    Article  CAS  Google Scholar 

  4. Siemeister G, Martiny-Baron G, Marme D . The pivotal role of VEGF in tumor angiogenesis: molecular facts and therapeutic opportunities. Cancer Metast Rev 1998; 17: 241–248.

    Article  CAS  Google Scholar 

  5. Bainbridge JW et al. Inhibition of retinal neovascularisation by gene transfer of soluble VEGF receptor sFlt-1. Gene Therapy 2002; 9: 320–326.

    Article  CAS  Google Scholar 

  6. Lai YK et al. Potential long-term inhibition of ocular neovascularisation by recombinant adeno-associated virus-mediated secretion gene therapy. Gene Therapy 2002; 9: 804–813.

    Article  CAS  Google Scholar 

  7. Carrasquillo KG et al. Controlled delivery of the anti-VEGF aptamer EYE001 with poly(lactic-co-glycolic)acid microspheres. Invest Ophthalmol Vis Sci 2003; 44: 290–299.

    Article  Google Scholar 

  8. Alama A, Barbieri F, Cagnoli M, Schettini G . Antisense oligonucleotides as therapeutic agents. Pharmacol Res 1997; 36: 171–178.

    Article  CAS  Google Scholar 

  9. Rojanasakul Y . Antisense oligonucleotide therapeutics: drug delivery and targeting. Adv Drug Deliv Rev 1996; 18: 115–131.

    Article  CAS  Google Scholar 

  10. Urban E, Noe CR . Structural modifications of antisense oligonucleotides. Farmaco 2003; 58: 243–258.

    Article  CAS  Google Scholar 

  11. Garrett KL, Shen WY, Rakoczy PE . In vivo use of oligonucleotides to inhibit choroidal neovascularisation in the eye. J Gene Med 2001; 3: 373–383.

    Article  CAS  Google Scholar 

  12. Marano RJ et al. Inhibition of in vitro VEGF expression and choroidal neovascularization by synthetic dendrimer peptide mediated delivery of a sense oligonucleotide. Exp Eye Res 2004; 79: 525–535.

    Article  CAS  Google Scholar 

  13. Wimmer N et al. Syntheses of polycationic dendrimers on lipophilic peptide core for complexation and transport of oligonucleotides. Bioorg Med Chem Lett 2002; 12: 2635–2637.

    Article  CAS  Google Scholar 

  14. Marano RJ, Rakoczy PE . Treatments for choroidal and retinal neovascularisation of the retina: a focus on oligonucleotide therapy and their delivery, for the regulation of gene function. Clin Exp Ophthalmol 2005; 33: 81–89.

    Article  Google Scholar 

  15. Group TES . Anti-vascular endothelial growth factor therapy for subfoveal choroidal neovascularization secondary to age-related macular degeneration: phase II study results. Ophthalmology 2003; 110: 979–986.

    Article  Google Scholar 

  16. Tolentino MJ et al. Intravitreal injection of vascular endothelial growth factor small interfering RNA inhibits growth and leakage in a nonhuman primate, laser-induced model of choroidal neovascularization. Retina 2004; 24: 132–138.

    Article  Google Scholar 

  17. Shen WY et al. Expression of cell adhesion molecules and vascular endothelial growth factor in experimental choroidal neovascularisation in the rat. Br J Ophthalmol 1998; 82: 1063–1071.

    Article  CAS  Google Scholar 

  18. Stephens AC, Rivers RP . Antisense oligonucleotide therapy in cancer. Curr Opin Mol Ther 2003; 5: 118–122.

    CAS  PubMed  Google Scholar 

  19. Stein CA, Cheng YC . Antisense oligonucleotides as therapeutic agents – is the bullet really magical? Science 1993; 261: 1004–1012.

    Article  CAS  Google Scholar 

  20. Bell C et al. Oligonucleotide NX1838 inhibits VEGF165-mediated cellular responses in vitro. In vitro Cell Dev Biol Anim 1999; 35: 533–542.

    Article  CAS  Google Scholar 

  21. Group TES . Preclinical and phase 1A clinical evaluation of an anti-VEGF pegylated aptamer (EYE001) for the treatment of exudative age-related macular degeneration. Retina 2002; 22: 143–152.

    Article  Google Scholar 

  22. Axel DI et al. Toxicity, uptake kinetics and efficacy of new transfection reagents: increase of oligonucleotide uptake. J Vasc Res 2000; 37: 221–234; discussion 303–304..

    Article  CAS  Google Scholar 

  23. Neerman MF, Zhang W, Parrish AR, Simanek EE . In vitro and in vivo evaluation of a melamine dendrimer as a vehicle for drug delivery. Int J Pharm 2004; 281: 129–132.

    Article  CAS  Google Scholar 

  24. Shah DS et al. DNA transfection and transfected cell viability using amphipathic asymmetric dendrimers. Int J Pharm 2000; 208: 41–48.

    Article  CAS  Google Scholar 

  25. Marano RJ, Rakoczy EP . Use of densitometry for evaluating severity of laser photocoagulation induced CNV: an improved method. Biotech and Histochem 2005 (in press).

  26. Lambert V et al. Influence of plasminogen activator inhibitor type 1 on choroidal neovascularization. FASEB J 2001; 15: 1021–1027.

    Article  CAS  Google Scholar 

  27. Schols P, Smets E . Carnoy: analysis software for LM, SEM and TEM images. 2001, Leuven: distributed by the authors, http://www.carnoy.org.

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Acknowledgements

This project was funded by the NH&MRC.

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Authors and Affiliations

  1. Department of Molecular Ophthalmology, Lions Eye Institute, Nedlands, WA, Australia

    R J Marano & M Brankov

  2. School of Molecular and Microbial Sciences, University of Queensland, Brisbane, QLD, Australia

    I Toth & N Wimmer

  3. School of Pharmacy, University of Queensland, Brisbane, QLD, Australia

    I Toth & N Wimmer

  4. Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Nedlands, WA, Australia

    P E Rakoczy

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  1. R J Marano
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Marano, R., Toth, I., Wimmer, N. et al. Dendrimer delivery of an anti-VEGF oligonucleotide into the eye: a long-term study into inhibition of laser-induced CNV, distribution, uptake and toxicity. Gene Ther 12, 1544–1550 (2005). https://doi.org/10.1038/sj.gt.3302579

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  • DOI: https://doi.org/10.1038/sj.gt.3302579

Keywords

  • dendrimer
  • oligonucleotide
  • VEGF
  • neovascularization
  • angiogenesis
  • laser photocoagulation

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