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Prevention of posterior capsule opacification by the induction of therapeutic apoptosis of residual lens cells

Gene Therapy volume 13, pages 440–448 (2006)Cite this article

Abstract

Posterior capsule opacification (PCO) is a common complication of cataract surgery. Using adenovirus(Ad)-mediated gene transfer, we overexpressed the proapoptotic molecules p53, procaspase 3, Bax, and TRAIL to induce therapeutic programmed cell death of residual lens cells to prevent PCO. Overexpressed TRAIL did not induce apoptosis in cultured rabbit lens cells or in human lens cells. Overexpressed p53 induced apoptosis of lens cells in vitro and ex vivo, but was unable to prevent PCO in vivo. Overexpressed procaspase 3 was associated with engagement of many components of the apoptotic pathway, including cleavage of intracellular caspase targets such as PARP and inter-nucleosome DNA fragmentation. Even when only slightly overexpressed, Bax caused apoptosis of transduced rabbit and human lens cells by engaging the mitochondrial pathway, including catalytic activation of the caspases. A single in vivo injection of Ad vectors expressing either Bax or procaspase 3 into the capsular bag at the end of phacoemulsification prevented PCO in rabbits. These experiments show that Ad-mediated Bax or procaspase 3 overexpression is capable of inducing therapeutic programmed cell death in vitro and in vivo in residual lens cells and preventing PCO in a rabbit model of PCO. Manipulation of proapoptotic molecule expression could be a novel gene therapy approach for prevention of PCO.

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Abbreviations

HSV-tk:

herpes simplex virus 1 thymidine kinase

GCV:

ganciclovir

FCS:

fetal calf serum

CMV:

cytomegalovirus

GFP:

green fluorescent protein

luc:

luciferase

MOI:

multiplicity of infection

TUNEL:

terminal deoxynucleotidyl transferase-mediated uridine 5′-triphosphate nick-end labeling.

References

  1. Apple DJ, Solomon KD, Tetz MR, Assia EI, Holland EY, Legler UF et al. Posterior capsule opacification. Surv Ophthalmol 1992; 37: 73–116.

    Article  CAS  Google Scholar 

  2. Nishi O, Nishi K . Preventing posterior capsule opacification by creating a discontinuous sharp bend in the capsule. J Cataract Refract Surg 1999; 25: 521–526.

    Article  CAS  Google Scholar 

  3. Kuchle M, Seitz B, Langenbucher A, Gusek-Schneider GC, Martus P, Nguyen NX . Comparison of 6-month results of implantation of the 1CU accommodative intraocular lens with conventional intraocular lenses. Ophthalmology 2004; 111: 318–324.

    Article  Google Scholar 

  4. Nishi O . Posterior capsule opacification. Part 1: Experimental investigations. J Cataract Refract Surg 1999; 25: 106–117.

    Article  CAS  Google Scholar 

  5. Germano IM, Fable J, Gultekin SH, Silvers A . Adenovirus/herpes simplex-thymidine kinase/ganciclovir complex: preliminary results of a phase I trial in patients with recurrent malignant gliomas. J Neurooncol 2003; 65: 279–289.

    Article  Google Scholar 

  6. Hassan W, Sanford MA, Woo SL, Chen SH, Hall SJ . Prospects for herpes-simplex-virus thymidine-kinase and cytokine gene transduction as immunomodulatory gene therapy for prostate cancer. World J Urol 2000; 18: 130–135.

    Article  CAS  Google Scholar 

  7. Verzeletti S, Bonini C, Marktel S, Nobili N, Ciceri F, Traversari C et al. Herpes simplex virus thymidine kinase gene transfer for controlled graft-versus-host disease and graft-versus-leukemia: clinical follow-up and improved new vectors. Hum Gene Ther 1998; 9: 2243–2251.

    Article  CAS  Google Scholar 

  8. Couderc BC, de Neuville S, Douin-Echinard V, Serres B, Manenti S, Darbon JM et al. Retrovirus-mediated transfer of a suicide gene into lens epithelial cells in vitro and in an experimental model of posterior capsule opacification. Curr Eye Res 1999; 19: 472–482.

    Article  CAS  Google Scholar 

  9. Malecaze F, Couderc B, de Neuville S, Serres B, Mallet J, Douin-Echinard V et al. Adenovirus-mediated suicide gene transduction: feasibility in lens epithelium and in prevention of posterior capsule opacification in rabbits. Hum Gene Ther 1999; 10: 2365–2372.

    Article  CAS  Google Scholar 

  10. Nicholson DW, Thornberry NA . Apoptosis. Life and death decisions. Science 2003; 299: 214–215.

    Article  CAS  Google Scholar 

  11. Ashkenazi A . Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat Rev Cancer 2002; 2: 420–430.

    Article  CAS  Google Scholar 

  12. Kagawa S, Pearson SA, Ji L, Xu K, McDonnell TJ, Swisher SG et al. A binary adenoviral vector system for expressing high levels of the proapoptotic gene bax. Gene Therapy 2000; 7: 75–79.

    Article  CAS  Google Scholar 

  13. Kagawa S, Gu J, Swisher SG, Ji L, Roth JA, Lai D et al. Antitumor effect of adenovirus-mediated Bax gene transfer on p53-sensitive and p53-resistant cancer lines. Cancer Res 2000; 60: 1157–1161.

    CAS  Google Scholar 

  14. McNeish IA, Bell SJ, Lemoine NR . Gene therapy progress and prospects: cancer gene therapy using tumour suppressor genes. Gene Therapy 2004; 11: 497–503.

    Article  CAS  Google Scholar 

  15. Lemoine NR, McNeish IA . Gene transfer: Bax to the future for cancer therapy. Gut 2004; 53: 478–479.

    Article  CAS  Google Scholar 

  16. Nakamura T, Williams-Simons L, Westphal H . A human papillomavirus type 18 E6/E7 transgene sensitizes mouse lens cells to human wild-type p53-mediated apoptosis. Oncogene 1997; 14: 2991–2998.

    Article  CAS  Google Scholar 

  17. Griffith TS, Anderson RD, Davidson BL, Williams RD, Ratliff TL . Adenoviral-mediated transfer of the TNF-related apoptosis-inducing ligand/Apo-2 ligand gene induces tumor cell apoptosis. J Immunol 2000; 165: 2886–2894.

    Article  CAS  Google Scholar 

  18. Poulaki V, Mitsiades CS, Kotoula V, Tseleni-Balafouta S, Ashkenazi A, Koutras DA et al. Regulation of Apo2L/tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in thyroid carcinoma cells. Am J Pathol 2002; 161: 643–654.

    Article  CAS  Google Scholar 

  19. Oltvai ZN, Milliman CL, Korsmeyer SJ . Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 1993; 74: 609–619.

    Article  CAS  Google Scholar 

  20. Pataer A, Fang B, Yu R, Kagawa S, Hunt KK, McDonnell TJ et al. Adenoviral Bak overexpression mediates caspase-dependent tumor killing. Cancer Res 2000; 60: 788–792.

    CAS  Google Scholar 

  21. Ashcroft M, Vousden KH . Regulation of p53 stability. Oncogene 1999; 18: 7637–7643.

    Article  CAS  Google Scholar 

  22. Kokontis JM, Wagner AJ, O'Leary M, Liao S, Hay N . A transcriptional activation function of p53 is dispensable for and inhibitory of its apoptotic function. Oncogene 2001; 20: 659–668.

    Article  CAS  Google Scholar 

  23. Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P et al. p53 has a direct apoptogenic role at the mitochondria. Mol Cell 2003; 11: 577–590.

    Article  CAS  Google Scholar 

  24. Chen Q, Ash JD, Branton P, Fromm L, Overbeek PA . Inhibition of crystallin expression and induction of apoptosis by lens-specific E1A expression in transgenic mice. Oncogene 2002; 21: 1028–1037.

    Article  CAS  Google Scholar 

  25. Brand K, Klocke R, Possling A, Paul D, Strauss M . Induction of apoptosis and G2/M arrest by infection with replication-deficient adenovirus at high multiplicity of infection. Gene Therapy 1999; 6: 1054–1063.

    Article  CAS  Google Scholar 

  26. Gwon AE, Jones RL, Gruber LJ, Mantras C . Lens regeneration in juvenile and adult rabbits measured by image analysis. Invest Ophthalmol Vis Sci 1992; 33: 2279–2283.

    CAS  PubMed  Google Scholar 

  27. Gwon A, Gruber L, Mantras C, Cunanan C . Lens regeneration in New Zealand albino rabbits after endocapsular cataract extraction. Invest Ophthalmol Vis Sci 1993; 34: 2124–2129.

    CAS  PubMed  Google Scholar 

  28. McAvoy JW, Chamberlain CG, de Iongh RU, Hales AM, Lovicu FJ . Peter Bishop Lecture: growth factors in lens development and cataract: key roles for fibroblast growth factor and TGF-beta. Clin Experiment Ophthalmol 2000; 28: 133–139.

    Article  CAS  Google Scholar 

  29. Morgenbesser SD, Williams BO, Jacks T, DePinho RA . p53-dependent apoptosis produced by Rb-deficiency in the developing mouse lens. Nature 1994; 371: 72–74.

    Article  CAS  Google Scholar 

  30. Krag S, Andreassen TT . Mechanical properties of the human posterior lens capsule. Invest Ophthalmol Vis Sci 2003; 44: 691–696.

    Article  Google Scholar 

  31. Krag S, Andreassen TT . Mechanical properties of the human lens capsule. Prog Retin Eye Res 2003; 22: 749–767.

    Article  Google Scholar 

  32. Maloof A, Neilson G, Milverton EJ, Pandey SK . Selective and specific targeting of lens epithelial cells during cataract surgery using sealed-capsule irrigation. J Cataract Refract Surg 2003; 29: 1566–1568.

    Article  Google Scholar 

  33. Kaliberov SA, Buchsbaum DJ, Gillespie GY, Curiel DT, Arafat WO, Carpenter M et al. Adenovirus-mediated transfer of BAX driven by the vascular endothelial growth factor promoter induces apoptosis in lung cancer cells. Mol Ther 2002; 6: 190–198.

    Article  CAS  Google Scholar 

  34. Hogan MJ, Kimura SJ, Thygeson P . Signs and symptoms of uveitis. I. Anterior uveitis. Am J Ophthalmol 1959; 47: 155–170.

    Article  CAS  Google Scholar 

  35. Malecaze F, Chollet P, Cavrois E, Vita N, Arne JL, Ferrara P . Role of interleukin 6 in the inflammatory response after cataract surgery. An experimental and clinical study. Arch Ophthalmol 1991; 109: 1681–1683.

    Article  CAS  Google Scholar 

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Acknowledgements

We are grateful to H Grandjean for the statistical analysis. We thank Alain Regan from the animal facility and Helen Hutchings for the careful reading of this manuscript.

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Authors and Affiliations

  1. Department Ophtalmologie et Pathologie des épithéliums, INSERM U563, Hôpital Purpan, Toulouse, France

    F Malecaze, A Decha, B Serre & M Duboue

  2. Department Innovations thérapeutiques et Oncologie moléculaire, INSERM U563, Institut Claudius Regaud, Toulouse, France

    M Penary, D Berg & B Couderc

  3. UPS, Faculté des Sciences Pharmaceutiques, Toulouse, France

    M Penary & B Couderc

  4. Inserm U466, Toulouse, France

    T Levade

  5. Radboud Universiteit Nijmegen, Nijmegen, The Netherlands

    N H Lubsen

  6. CNRS UMR 5535, Institut de Génétique moléculaire, Montpellier, France

    E J Kremer

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  1. F Malecaze
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  2. A Decha
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Correspondence to F Malecaze or B Couderc.

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Malecaze, F., Decha, A., Serre, B. et al. Prevention of posterior capsule opacification by the induction of therapeutic apoptosis of residual lens cells. Gene Ther 13, 440–448 (2006). https://doi.org/10.1038/sj.gt.3302667

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  • DOI: https://doi.org/10.1038/sj.gt.3302667

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