Development of Viral Vectors with Optimal Transgene Expression for Ocular Gene Therapies

  • Takao Hashimoto
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 613)

Various efforts have been dedicated to the development of effective strategies to treat ocular diseases. Investigators have demonstrated that gene therapies using viral vectors are one of the promising technologies. For an ideal therapeutic effect, a variety of vector designs have been tested. Especially, selection of a promoter to drive a transgene is important to obtain adequate level of expression. In this brief chapter, reviewed are the promoters for viral vectors for ocular gene therapies.


Retinal Pigment Epithelium Retinitis Pigmentosa Trabecular Meshwork Choroidal Neovascularization Retinal Degeneration 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Acland, G. M., et al., 2001, Gene therapy restores vision in a canine model of childhood blindness, Nat. Genet. 28: 92–95.PubMedCrossRefGoogle Scholar
  2. Akimoto, M., et al., 1999, Adenovirally expressed basic fibroblast growth factor rescues photoreceptor cells in RCS rats, Invest. Ophthalmol. Vis. Sci. 40: 273–279.PubMedGoogle Scholar
  3. Ali, R. R., et al., 1996, Gene transfer into the mouse retina mediated by an adeno-associated viral vector, Hum. Mol. Genet. 5: 591–594.PubMedCrossRefGoogle Scholar
  4. Ali, R. R., et al., 2000, Restoration of photoreceptor ultrastructure and function in retinal degeneration slow mice by gene therapy, Nat. Genet. 25: 306–310.PubMedCrossRefGoogle Scholar
  5. Bainbridge, J. W. B., et al., 2001, in vivo gene transfer to the mouse eye using an HIV-based lentiviral vector; efficient long-term transduction of corneal endothelium and retinal pigment epithelium, Gene Ther. 8: 1665–1668.PubMedCrossRefGoogle Scholar
  6. Bainbridge, J. W. B., et al., 2002, Inhibition of retinal neovascularisation by gene transfer of soluble VEGF receptor sFlt-1, Gene Ther. 9: 320–326.PubMedCrossRefGoogle Scholar
  7. Bainbridge, J. W. B., et al., 2003, Hypoxia-regulated transgene expression in experimental retinal and choroidal neovascularization, Gene Ther. 10: 1049–1054.PubMedCrossRefGoogle Scholar
  8. Bemelmans, A.-P., et al., 2005, Retinal cell type expression specificity of HIV-1-derived gene transfer vectors upon subretinal injection in the adult rat: influence of pseudotyping and promoter, J. Gene Med. 7: 1367–1374.PubMedCrossRefGoogle Scholar
  9. Bennett, J., et al., 1996, Photoreceptor cell rescue in retinal degeneration (rd) mice by in vivo gene therapy, Nat. Med. 2: 649–654.PubMedCrossRefGoogle Scholar
  10. Bennett, J., et al., 1999, Stable transgene expression in rod photoreceptors after recombinant adeno-associated virus-mediated gene transfer to monkey retina, Proc. Natl. Acad. Sci. U. S. A. 96: 9920–9925.PubMedCrossRefGoogle Scholar
  11. Beutelspacher, S. C., et al., 2005, Comparison of HIV-1 and EIAV-based lentiviral vectors in corneal transduction, Exp. Eye Res. 80: 787–794.PubMedCrossRefGoogle Scholar
  12. Bok, D., et al., 2002, Effects of adeno-associated virus-vectored ciliary neurotrophic factor on retinal structure and function in mice with a P216L rds/peripherin mutation, Exp. Eye Res. 74: 719–735.PubMedCrossRefGoogle Scholar
  13. Gehlbach, P., et al., 2003, Periocular injection of an adenoviral vector encoding pigment epithelium-derived factor inhibits choroidal neovascularization, Gene Ther. 10: 637–646.PubMedCrossRefGoogle Scholar
  14. Glushakova, L. G., et al., 2006, Human blue-opsin promoter preferentially targets reporter gene expression to rat s-cone photoreceptors, Invest. Ophthalmol. Vis. Sci. 47: 3505–3513.PubMedCrossRefGoogle Scholar
  15. Grant, C. A., et al., 1997, Evaluation of recombinant adeno-associated virus as a gene transfer vector for the retina, Curr. Eye Res. 16: 949–956.PubMedCrossRefGoogle Scholar
  16. Greenberg, K. P., et al., 2007, Targeted transgene expression in müller glia of normal and diseased retinas using lentiviral vectors, Invest. Ophthalmol. Vis. Sci. 48: 1844–1852.PubMedCrossRefGoogle Scholar
  17. Guy, J., et al., 1999, Reporter expression persists 1 year after adeno-associated virus-mediated gene transfer to the optic nerve, Arch. Ophthalmol. 117: 929–937.PubMedGoogle Scholar
  18. Hashimoto, T., et al., 2007, Lentiviral gene replacement therapy of retinas in a mouse model for Usher syndrome type 1B, Gene Ther. 14: 584–594.PubMedCrossRefGoogle Scholar
  19. Jomary, C., et al., 1997, Rescue of photoreceptor function by AAV-mediated gene transfer in a mouse model of inherited retinal degeneration, Gene Ther. 4: 683–690.PubMedCrossRefGoogle Scholar
  20. Jomary, C., et al., 2001, Epitope-tagged recombinant AAV vectors for expressing neurturin and its receptor in retinal cells, Mol. Vis. 7: 36–41.PubMedGoogle Scholar
  21. Kostic, C., et al., 2003, Activity analysis of housekeeping promoters using self-inactivating lentiviral vector delivery into the mouse retina, Gene Ther. 10: 818–821.PubMedCrossRefGoogle Scholar
  22. Kügler, S., et al., 1999, Transduction of axotomized retinal ganglion cells by adenoviral vector administration at the optic newline nerve stump: an in vivo model system for the inhibition of neuronal apoptotic cell death, Gene Ther. 6: 1759–1767.PubMedCrossRefGoogle Scholar
  23. Kügler, S., et al., 2003, Differential transgene expression in brain cells in vivo and in vitro from AAV-2 vectors with small transcriptional control units, Virology 311: 89–95.PubMedCrossRefGoogle Scholar
  24. Lai, C.-M., et al., 2002, Inhibition of corneal neovascularization by recombinant adenovirus mediated antisense VEGF RNA, Exp. Eye Res. 75: 625–634.PubMedCrossRefGoogle Scholar
  25. Lau, D., et al., 2000, Retinal degeneration is slowed in transgenic rats by AAV-mediated delivery of FGF-2, Invest. Ophthalmol. Vis. Sci. 41: 3622–3633.PubMedGoogle Scholar
  26. Le Meur, G., et al., 2007, Restoration of vision in RPE65-deficient Briard dogs using an AAV serotype 4 vector that specifically targets the retinal pigmented epithelium, Gene Ther. 14: 292–303.PubMedCrossRefGoogle Scholar
  27. Li, Y., et al., 2005, Neuronal gene transfer by baculovirus-derived vectors accommodating a neurone-specific promoter, Exp. Physiol. 90: 39–44.PubMedCrossRefGoogle Scholar
  28. Liton, P. B., et al., 2005, Specific targeting of gene expression to a subset of human trabecular meshwork cells using the chitinase 3-like 1 promoter, Invest. Ophthalmol. Vis. Sci. 46: 183–190.PubMedCrossRefGoogle Scholar
  29. Malecaze, F., et al., 2006, Lens cell targetting for gene therapy of prevention of posterior capsule opacification, Gene Ther. 13: 1422–1429.PubMedCrossRefGoogle Scholar
  30. Martin, K. R. G., et al., 2002, Gene delivery to the eye using adeno-associated viral vectors, Methods 28: 267–275.PubMedCrossRefGoogle Scholar
  31. Mckinnon, S. J., et al., 2002, Baculoviral IAP repeat-containing-4 protects optic nerve axons in a rat glaucoma model, Mol. Ther. 5: 780–787.PubMedCrossRefGoogle Scholar
  32. Min, S. H., et al., 2005, Prolonged recovery of retinal structure/function after gene therapy in an Rs1h-deficient mouse model of x-linked juvenile retinoschisis, Mol. Ther. 12: 644–651.PubMedCrossRefGoogle Scholar
  33. Miyoshi, H. , et al., 1997, Stable and efficient gene transfer into the retina using an HIV-based lentiviral vector, Proc. Natl. Acad. Sci. U. S. A. 94: 10319–10323.PubMedCrossRefGoogle Scholar
  34. Mori, K., et al., 2002, AAV-mediated gene transfer of pigment epithelium-derived factor inhibits choroidal neovascularization, Invest. Ophthalmol. Vis. Sci. 43: 1994–2000.PubMedGoogle Scholar
  35. Parker, D. G. A., et al., 2007, Lentivirus-mediated gene transfer to the rat, ovine and human cornea, Gene Ther. 14: 760–767.PubMedCrossRefGoogle Scholar
  36. Pawlyk, B. S., et al., 2005, Gene replacement therapy rescues photoreceptor degeneration in a murine model of Leber congenital amaurosis lacking RPGRIP, Invest. Ophthalmol. Vis. Sci. 46: 3039–3045.PubMedCrossRefGoogle Scholar
  37. Raisler, B. J., et al., 2002, Adeno-associated virus type-2 expression of pigmented epithelium-derived factor or Kringles 1–3 of angiostatin reduce retinal neovascularization, Proc. Natl. Acad. Sci. U. S. A. 99: 8909–8914.PubMedCrossRefGoogle Scholar
  38. Saika, S., et al., 2004, Transient adenoviral gene transfer of Smad7 prevents injury-induced epithelial-mesenchymal transition of lens epithelium in mice, Lab. Invest. 84: 1259–1270.PubMedCrossRefGoogle Scholar
  39. Shen, W.-Y., et al., 2003, Practical considerations of recombinant adeno-associated virus-mediated gene transfer for treatment of retinal degenerations, J. Gene Med. 5: 576–587.PubMedCrossRefGoogle Scholar
  40. Smith, A. J., et al., 2003, AAV-Mediated gene transfer slows photoreceptor loss in the RCS rat model of retinitis pigmentosa, Mol. Ther. 8: 188–195.PubMedCrossRefGoogle Scholar
  41. Sutanto, E. N., et al., 2005, Development and evaluation of the specificity of a cathepsin D proximal promoter in the eye, Curr. Eye Res. 30: 53–61.PubMedCrossRefGoogle Scholar
  42. Takahashi, M., et al., 1999, Rescue from photoreceptor degeneration in the rd mouse by human immunodeficiency virus vector-mediated gene transfer, J. Virol. 73: 7812–7816.PubMedGoogle Scholar
  43. Tschernutter, M., et al., 2005, Long-term preservation of retinal function in the RCS rat model of retinitis pigmentosa following lentivirus-mediated gene therapy, Gene Ther. 12: 694–701.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.Jules Stein Eye InstituteUniversity of California Los AngelesU.S.A

Personalised recommendations