Cell and Tissue Banking

, Volume 12, Issue 2, pp 105–110

Adeno-associated virus (AAV) based gene therapy for eye diseases

  • Shuang Wang
  • Peng Liu
  • Lei Song
  • Lei Lu
  • Wensong Zhang
  • Yazhen Wu


Gene therapy emerged as important approach in treatment for many inborn disorders caused by genetic defects, as well as other diseases. This manuscript focused on Adeno-associated virus (AAV) based gene therapy to eye diseases. The paper firstly introduced the AAV vectors and the techniques of eye delivery, then summarized some tested genes that were used in past treatment to retinal degeneration disorders. Finally the paper discussed the updated optogenetics and its roles in AAV based gene therapy for eye diseases.


AAV Gene therapy Optogenetics Neovascularization Trophic factor Neuroprotection 


  1. Acland GM, Aguirre GD, Ray J, Zhang Q, Aleman TS et al (2001) Gene therapy restores vision in a canine model of childhood blindness. Nat Genet 28:92–95PubMedGoogle Scholar
  2. Acland GM, Aguirre GD, Bennett J, Aleman TS, Cideciyan AV et al (2005) Long-term restoration of rod and cone vision by single dose rAAV-mediated gene transfer to the retina in a canine model of childhood blindness. Mol Ther 12:1072–1082PubMedCrossRefGoogle Scholar
  3. Ali RR, Sarra GM, Stephens C, Alwis MD, Bainbridge JW et al (2000) Restoration of photoreceptor ultrastructure and function in retinal degeneration slow mice by gene therapy. Nat Genet 25:306–310PubMedCrossRefGoogle Scholar
  4. Apte RS, Barreiro RA, Duh E, Volpert O, Ferguson TA (2004) Stimulation of neovascularization by the anti-angiogenic factor PEDF. Invest Ophthalmol Vis Sci 45:4491–4497PubMedCrossRefGoogle Scholar
  5. Arrenberg AB, Stainier DY, Baier H, Huisken J (2010) Optogenetic control of cardiac function. Science 330:971–974PubMedCrossRefGoogle Scholar
  6. Barnstable CJ, Tombran-Tink J (2004) Neuroprotective and antiangiogenic actions of PEDF in the eye: molecular targets and therapeutic potential. Prog Retin Eye Res 23:561–577PubMedCrossRefGoogle Scholar
  7. Bi A, Cui J, Ma YP, Olshevskaya E, Pu M et al (2006) Ectopic expression of a microbial-type rhodopsin restores visual responses in mice with photoreceptor degeneration. Neuron 50:23–33PubMedCrossRefGoogle Scholar
  8. Bok D (2004) Gene therapy of retinal dystrophies: achievements, challenges and prospects. Novartis Found Symp 255:4–12 discussion -6, 177–8PubMedCrossRefGoogle Scholar
  9. Bok D, Yasumura D, Matthes MT, Ruiz A, Duncan JL 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 74:719–735PubMedCrossRefGoogle Scholar
  10. Busskamp V, Duebel J, Balya D, Fradot M, Viney TJ et al (2010) Genetic reactivation of cone photoreceptors restores visual responses in retinitis pigmentosa. Science 329:413–417PubMedCrossRefGoogle Scholar
  11. Chong NV, Adewoyin T (2007) Intravitreal injection: balancing the risks. Eye (Lond) 21:313–316Google Scholar
  12. da Cruz L, Rakoczy P, Constable I (1997) Ocular gene therapy: the basic science and current state of research. Aust N Z J Ophthalmol 25:97–104PubMedCrossRefGoogle Scholar
  13. Dejneka NS, Rex TS, Bennett J (2003) Gene therapy and animal models for retinal disease. Dev Ophthalmol 37:188–198PubMedCrossRefGoogle Scholar
  14. Deng WT, Yan Z, Dinculescu A, Pang J, Teusner JT et al (2005) Adeno-associated virus-mediated expression of vascular endothelial growth factor peptides inhibits retinal neovascularization in a mouse model of oxygen-induced retinopathy. Hum Gene Ther 16:1247–1254PubMedCrossRefGoogle Scholar
  15. Dinculescu A, Glushakova L, Min SH, Hauswirth WW (2005) Adeno-associated virus-vectored gene therapy for retinal disease. Hum Gene Ther 16:649–663PubMedCrossRefGoogle Scholar
  16. Drenser KA, Timmers AM, Hauswirth WW, Lewin AS (1998) Ribozyme-targeted destruction of RNA associated with autosomal-dominant retinitis pigmentosa. Invest Ophthalmol Vis Sci 39:681–689PubMedGoogle Scholar
  17. Ek ET, Dass CR, Choong PF (2006) Pigment epithelium-derived factor: a multimodal tumor inhibitor. Mol Cancer Ther 5:1641–1646PubMedCrossRefGoogle Scholar
  18. Eriksson K, Magnusson P, Dixelius J, Claesson-Welsh L, Cross MJ (2003) Angiostatin and endostatin inhibit endothelial cell migration in response to FGF and VEGF without interfering with specific intracellular signal transduction pathways. FEBS Lett 536:19–24PubMedCrossRefGoogle Scholar
  19. Ernst OP, Sanchez Murcia PA, Daldrop P, Tsunoda SP, Kateriya S, Hegemann P (2008) Photoactivation of channelrhodopsin. J Biol Chem 283:1637–1643PubMedCrossRefGoogle Scholar
  20. Farah N, Reutsky I, Shoham S (2007) Patterned optical activation of retinal ganglion cells. Conf Proc IEEE Eng Med Biol Soc 2007:6369–6371Google Scholar
  21. Fiala A, Suska A, Schluter OM (2010) Optogenetic approaches in neuroscience. Curr Biol 20:R897–R903PubMedCrossRefGoogle Scholar
  22. Friedmann T, Roblin R (1972) Gene therapy for human genetic disease? Science 175:949–955PubMedCrossRefGoogle Scholar
  23. Green ES, Rendahl KG, Zhou S, Ladner M, Coyne M et al (2001) Two animal models of retinal degeneration are rescued by recombinant adeno-associated virus-mediated production of FGF-5 and FGF-18. Mol Ther 3:507–515PubMedCrossRefGoogle Scholar
  24. Hauswirth WW, Li Q, Raisler B, Timmers AM, Berns KI et al (2004) Range of retinal diseases potentially treatable by AAV-vectored gene therapy. Novartis Found Symp 255:179–188 discussion 88–94PubMedCrossRefGoogle Scholar
  25. Ivanova E, Pan ZH (2009) Evaluation of the adeno-associated virus mediated long-term expression of channelrhodopsin-2 in the mouse retina. Mol Vis 15:1680–1689PubMedGoogle Scholar
  26. Ivanova E, Hwang GS, Pan ZH, Troilo D (2010) Evaluation of AAV-mediated expression of Chop2-GFP in the marmoset retina. Invest Ophthalmol Vis Sci 51:5288–5296PubMedCrossRefGoogle Scholar
  27. Jacobson SG, Cideciyan AV (2010) Treatment possibilities for retinitis pigmentosa. N Engl J Med 363:1669–1671PubMedCrossRefGoogle Scholar
  28. Janovjak H, Szobota S, Wyart C, Trauner D, Isacoff EY (2010) A light-gated, potassium-selective glutamate receptor for the optical inhibition of neuronal firing. Nat Neurosci 13:1027–1032PubMedCrossRefGoogle Scholar
  29. Jia H, Jezequel S, Lohr M, Shaikh S, Davis D et al (2001) Peptides encoded by exon 6 of VEGF inhibit endothelial cell biological responses and angiogenesis induced by VEGF. Biochem Biophys Res Commun 283:164–173PubMedCrossRefGoogle Scholar
  30. Knopfel T, Lin MZ, Levskaya A, Tian L, Lin JY, Boyden ES (2010) Toward the second generation of optogenetic tools. J Neurosci 30:14998–15004PubMedCrossRefGoogle Scholar
  31. Lagali PS, Balya D, Awatramani GB, Munch TA, Kim DS et al (2008) Light-activated channels targeted to ON bipolar cells restore visual function in retinal degeneration. Nat Neurosci 11:667–675PubMedCrossRefGoogle Scholar
  32. Lai YK, Shen WY, Brankov M, Lai CM, Constable IJ, Rakoczy PE (2002) Potential long-term inhibition of ocular neovascularisation by recombinant adeno-associated virus-mediated secretion gene therapy. Gene Ther 9:804–813PubMedCrossRefGoogle Scholar
  33. Lau D, McGee LH, Zhou S, Rendahl KG, Manning WC et al (2000) Retinal degeneration is slowed in transgenic rats by AAV-mediated delivery of FGF-2. Invest Ophthalmol Vis Sci 41:3622–3633PubMedGoogle Scholar
  34. LaVail MM, Yasumura D, Matthes MT, Drenser KA, Flannery JG et al (2000) Ribozyme rescue of photoreceptor cells in P23H transgenic rats: long-term survival and late-stage therapy. Proc Natl Acad Sci USA 97:11488–11493PubMedCrossRefGoogle Scholar
  35. Lewin AS, Drenser KA, Hauswirth WW, Nishikawa S, Yasumura D et al (1998) Ribozyme rescue of photoreceptor cells in a transgenic rat model of autosomal dominant retinitis pigmentosa. Nat Med 4:967–971PubMedCrossRefGoogle Scholar
  36. Liang FQ, Aleman TS, Dejneka NS, Dudus L, Fisher KJ et al (2001) Long-term protection of retinal structure but not function using RAAV.CNTF in animal models of retinitis pigmentosa. Mol Ther 4:461–472PubMedCrossRefGoogle Scholar
  37. Lin B, Koizumi A, Tanaka N, Panda S, Masland RH (2008) Restoration of visual function in retinal degeneration mice by ectopic expression of melanopsin. Proc Natl Acad Sci USA 105:16009–16014PubMedCrossRefGoogle Scholar
  38. Liu X, Tonegawa S (2010) Optogenetics 3.0. Cell 141:22–24PubMedCrossRefGoogle Scholar
  39. Mata NL, Moghrabi WN, Lee JS, Bui TV, Radu RA et al (2004) Rpe65 is a retinyl ester binding protein that presents insoluble substrate to the isomerase in retinal pigment epithelial cells. J Biol Chem 279:635–643PubMedCrossRefGoogle Scholar
  40. McGee Sanftner LH, Abel H, Hauswirth WW, Flannery JG (2001) Glial cell line derived neurotrophic factor delays photoreceptor degeneration in a transgenic rat model of retinitis pigmentosa. Mol Ther 4:622–629PubMedCrossRefGoogle Scholar
  41. Miller G (2006) Optogenetics. Shining new light on neural circuits. Science 314:1674–1676PubMedCrossRefGoogle Scholar
  42. Murata T, Kimura H, Sakamoto T, Osusky R, Spee C et al (1997) Ocular gene therapy: experimental studies and clinical possibilities. Ophthalmic Res 29:242–251PubMedCrossRefGoogle Scholar
  43. Narfstrom K, Katz ML, Bragadottir R, Seeliger M, Boulanger A et al (2003a) Functional and structural recovery of the retina after gene therapy in the RPE65 null mutation dog. Invest Ophthalmol Vis Sci 44:1663–1672PubMedCrossRefGoogle Scholar
  44. Narfstrom K, Katz ML, Ford M, Redmond TM, Rakoczy E, Bragadottir R (2003b) In vivo gene therapy in young and adult RPE65-/- dogs produces long-term visual improvement. J Hered 94:31–37PubMedCrossRefGoogle Scholar
  45. Sampat KM, Garg SJ (2010) Complications of intravitreal injections. Curr Opin Ophthalmol 21:178–183PubMedCrossRefGoogle Scholar
  46. Sarra GM, Stephens C, de Alwis M, Bainbridge JW, Smith AJ et al (2001) Gene replacement therapy in the retinal degeneration slow (rds) mouse: the effect on retinal degeneration following partial transduction of the retina. Hum Mol Genet 10:2353–2361PubMedCrossRefGoogle Scholar
  47. Schlichtenbrede FC, da Cruz L, Stephens C, Smith AJ, Georgiadis A et al (2003a) Long-term evaluation of retinal function in Prph2Rd2/Rd2 mice following AAV-mediated gene replacement therapy. J Gene Med 5:757–764PubMedCrossRefGoogle Scholar
  48. Schlichtenbrede FC, MacNeil A, Bainbridge JW, Tschernutter M, Thrasher AJ et al (2003b) Intraocular gene delivery of ciliary neurotrophic factor results in significant loss of retinal function in normal mice and in the Prph2Rd2/Rd2 model of retinal degeneration. Gene Ther 10:523–527PubMedCrossRefGoogle Scholar
  49. Smith AJ, Schlichtenbrede FC, Tschernutter M, Bainbridge JW, Thrasher AJ, Ali RR (2003) AAV-Mediated gene transfer slows photoreceptor loss in the RCS rat model of retinitis pigmentosa. Mol Ther 8:188–195PubMedCrossRefGoogle Scholar
  50. Thyagarajan S, van Wyk M, Lehmann K, Lowel S, Feng G, Wassle H (2010) Visual function in mice with photoreceptor degeneration and transgenic expression of channelrhodopsin 2 in ganglion cells. J Neurosci 30:8745–8758PubMedCrossRefGoogle Scholar
  51. Tomita H, Sugano E, Isago H, Hiroi T, Wang Z et al (2010) Channelrhodopsin-2 gene transduced into retinal ganglion cells restores functional vision in genetically blind rats. Exp Eye Res 90:429–436PubMedCrossRefGoogle Scholar
  52. Tong JP, Yao YF (2006) Contribution of VEGF and PEDF to choroidal angiogenesis: a need for balanced expressions. Clin Biochem 39:267–276PubMedCrossRefGoogle Scholar
  53. Tsao YP, Ho TC, Chen SL, Cheng HC (2006) Pigment epithelium-derived factor inhibits oxidative stress-induced cell death by activation of extracellular signal-regulated kinases in cultured retinal pigment epithelial cells. Life Sci 79:545–550PubMedCrossRefGoogle Scholar
  54. Wei L (2005) Adenovector pigment epithelium-derived factor (AdPEDF) delivery for wet age-related macular degeneration. Retina 25:S48–S49PubMedCrossRefGoogle Scholar
  55. Wright AF (1997) Gene therapy for the eye. Br J Ophthalmol 81:620–623PubMedCrossRefGoogle Scholar
  56. Yabe T, Sanagi T, Yamada H (2010) The neuroprotective role of PEDF: implication for the therapy of neurological disorders. Curr Mol Med 10:259–266PubMedCrossRefGoogle Scholar
  57. Zhang Y, Ivanova E, Bi A, Pan ZH (2009) Ectopic expression of multiple microbial rhodopsins restores ON and OFF light responses in retinas with photoreceptor degeneration. J Neurosci 29:9186–9196PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Shuang Wang
    • 1
    • 2
  • Peng Liu
    • 2
  • Lei Song
    • 3
  • Lei Lu
    • 3
  • Wensong Zhang
    • 3
  • Yazhen Wu
    • 1
  1. 1.Department of OphthalmologyThe Second Hospital of Ji Lin UniversityJi LinChina
  2. 2.China-Japan Union Hospital of Jilin UniversityJi LinChina
  3. 3.Department of NeurologyThe First Hospital of Ji Lin UniversityJi LinChina

Personalised recommendations