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:

AAV-mediated gene therapy for retinal disorders: from mouse to man

Gene Therapy volume 15, pages 849–857 (2008)Cite this article

Abstract

A wide range of retinal disorders can potentially be treated using viral vector-mediated gene therapy. The most widely used vectors for ocular gene delivery are based on adeno-associated virus (AAV), because they elicit minimal immune responses and mediate long-term transgene expression in a variety of retinal cell types. Proof-of-concept experiments have demonstrated the efficacy of AAV-mediated transgene delivery in a number of animal models of inherited and acquired retinal disorders. Following extensive preclinical evaluation in large animal models, gene therapy for one form of inherited retinal degeneration due to RPE65 deficiency is now being tested in three concurrent clinical trials. Here, we review different approaches for treating inherited retinal degenerations and more common acquired retinal disorders using AAV-based vectors.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Similar content being viewed by others

References

  1. Bessant DA, Ali RR, Bhattacharya SS . Molecular genetics and prospects for therapy of the inherited retinal dystrophies. Curr Opin Genet Dev 2001; 11: 307–316.

    Article  CAS  PubMed  Google Scholar 

  2. Klein R, Klein BE, Knudtson MD, Meuer SM, Swift M, Gangnon RE . Fifteen-year cumulative incidence of age-related macular degeneration: the Beaver Dam Eye Study. Ophthalmology 2007; 114: 253–262.

    Article  PubMed  Google Scholar 

  3. Montezuma SR, Sobrin L, Seddon JM . Review of genetics in age related macular degeneration. Semin Ophthalmol 2007; 22: 229–240.

    Article  PubMed  Google Scholar 

  4. Fauser S, Luberichs J, Schuttauf F . Genetic animal models for retinal degeneration. Surv Ophthalmol 2002; 47: 357–367.

    Article  PubMed  Google Scholar 

  5. Chang B, Hawes NL, Hurd RE, Davisson MT, Nusinowitz S, Heckenlively JR . Retinal degeneration mutants in the mouse. Vision Res 2002; 42: 517–525.

    Article  CAS  PubMed  Google Scholar 

  6. Spencer B, Agarwala S, Miskulin M, Smith M, Brandt CR . Herpes simplex virus-mediated gene delivery to the rodent visual system. Invest Ophthalmol Vis Sci 2000; 41: 1392–1401.

    CAS  PubMed  Google Scholar 

  7. Reichel MB, Ali RR, Thrasher AJ, Hunt DM, Bhattacharya SS, Baker D . Immune responses limit adenovirally mediated gene expression in the adult mouse eye. Gene Therapy 1998; 5: 1038–1046.

    Article  CAS  PubMed  Google Scholar 

  8. Miyoshi H, Takahashi M, Gage FH, Verma IM . Stable and efficient gene transfer into the retina using an HIV-based lentiviral vector. Proc Natl Acad Sci USA 1997; 94: 10319–10323.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lotery AJ, Derksen TA, Russell SR, Mullins RF, Sauter S, Affatigato LM et al. Gene transfer to the nonhuman primate retina with recombinant feline immunodeficiency virus vectors. Hum Gene Ther 2002; 13: 689–696.

    Article  CAS  PubMed  Google Scholar 

  10. Balaggan KS, Binley K, Esapa M, Iqball S, Askham Z, Kan O et al. Stable and efficient intraocular gene transfer using pseudotyped EIAV lentiviral vectors. J Gene Med 2006; 8: 275–285.

    Article  CAS  PubMed  Google Scholar 

  11. Ali RR, Reichel MB, Thrasher AJ, Levinsky RJ, Kinnon C, Kanuga N et al. Gene transfer into the mouse retina mediated by an adeno-associated viral vector. Hum Mol Genet 1996; 5: 591–594.

    Article  CAS  PubMed  Google Scholar 

  12. Sarra GM, Stephens C, Schlichtenbrede FC, Bainbridge JW, Thrasher AJ, Luthert PJ et al. Kinetics of transgene expression in mouse retina following sub-retinal injection of recombinant adeno-associated virus. Vision Res 2002; 42: 541–549.

    Article  CAS  PubMed  Google Scholar 

  13. Gentile M, Adrian T, Scheidler A, Ewald M, Dianzani F, Pauli G et al. Determination of the size of HIV using adenovirus type 2 as an internal length marker. J Virol Methods 1994; 48: 43–52.

    Article  CAS  PubMed  Google Scholar 

  14. Kronenberg S, Kleinschmidt JA, Bottcher B . Electron cryo-microscopy and image reconstruction of adeno-associated virus type 2 empty capsids. EMBO Rep 2001; 2: 997–1002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ali RR, Reichel MB, de AM, Kanuga N, Kinnon C, Levinsky RJ et al. Adeno-associated virus gene transfer to mouse retina. Hum Gene Ther 1998; 9: 81–86.

    Article  CAS  PubMed  Google Scholar 

  16. Martin KR, Klein RL, Quigley HA . Gene delivery to the eye using adeno-associated viral vectors. Methods 2002; 28: 267–275.

    Article  CAS  PubMed  Google Scholar 

  17. Harvey AR, Hu Y, Leaver SG, Mellough CB, Park K, Verhaagen J et al. Gene therapy and transplantation in CNS repair: the visual system. Prog Retin Eye Res 2006; 25: 449–489.

    Article  CAS  PubMed  Google Scholar 

  18. Erles K, Sebokova P, Schlehofer JR . Update on the prevalence of serum antibodies (IgG and IgM) to adeno-associated virus (AAV). J Med Virol 1999; 59: 406–411.

    Article  CAS  PubMed  Google Scholar 

  19. Halbert CL, Miller AD, McNamara S, Emerson J, Gibson RL, Ramsey B et al. Prevalence of neutralizing antibodies against adeno-associated virus (AAV) types 2, 5, and 6 in cystic fibrosis and normal populations: implications for gene therapy using AAV vectors. Hum Gene Ther 2006; 17: 440–447.

    Article  CAS  PubMed  Google Scholar 

  20. Auricchio A . Pseudotyped AAV vectors for constitutive and regulated gene expression in the eye. Vision Res 2003; 43: 913–918.

    Article  CAS  PubMed  Google Scholar 

  21. Summerford C, Samulski RJ . Membrane-associated heparan sulfate proteoglycan is a receptor for adeno-associated virus type 2 virions. J Virol 1998; 72: 1438–1445.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Summerford C, Bartlett JS, Samulski RJ . AlphaVbeta5 integrin: a co-receptor for adeno-associated virus type 2 infection. Nat Med 1999; 5: 78–82.

    Article  CAS  PubMed  Google Scholar 

  23. Qing K, Mah C, Hansen J, Zhou S, Dwarki V, Srivastava A . Human fibroblast growth factor receptor 1 is a co-receptor for infection by adeno-associated virus 2. Nat Med 1999; 5: 71–77.

    Article  CAS  PubMed  Google Scholar 

  24. Yang GS, Schmidt M, Yan Z, Lindbloom JD, Harding TC, Donahue BA et al. Virus-mediated transduction of murine retina with adeno-associated virus: effects of viral capsid and genome size. J Virol 2002; 76: 7651–7660.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Auricchio A, Kobinger G, Anand V, Hildinger M, O'Connor E, Maguire AM et al. Exchange of surface proteins impacts on viral vector cellular specificity and transduction characteristics: the retina as a model. Hum Mol Genet 2001; 10: 3075–3081.

    Article  CAS  PubMed  Google Scholar 

  26. Lotery AJ, Yang GS, Mullins RF, Russell SR, Schmidt M, Stone EM et al. Adeno-associated virus type 5: transduction efficiency and cell-type specificity in the primate retina. Hum Gene Ther 2003; 14: 1663–1671.

    Article  CAS  PubMed  Google Scholar 

  27. Di PG, Davidson BL, Stein CS, Martins I, Scudiero D, Monks A et al. Identification of PDGFR as a receptor for AAV-5 transduction. Nat Med 2003; 9: 1306–1312.

    Article  CAS  Google Scholar 

  28. Allocca M, Mussolino C, Garcia-Hoyos M, Sanges D, Iodice C, Petrillo M et al. Novel adeno-associated virus serotypes efficiently transduce murine photoreceptors. J Virol 2007; 81: 11372–11380.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Natkunarajah M, Trittibach P, McIntosh J, Duran Y, Barker SE, Smith AJ et al. Assessment of ocular transduction using single-stranded and self-complementary recombinant adeno-associated virus serotype 2/8. Gene Therapy 2008; 15: 463–467.

    Article  CAS  PubMed  Google Scholar 

  30. Weber M, Rabinowitz J, Provost N, Conrath H, Folliot S, Briot D et al. Recombinant adeno-associated virus serotype 4 mediates unique and exclusive long-term transduction of retinal pigmented epithelium in rat, dog, and nonhuman primate after subretinal delivery. Mol Ther 2003; 7: 774–781.

    Article  CAS  PubMed  Google Scholar 

  31. Anand V, Duffy B, Yang Z, Dejneka NS, Maguire AM, Bennett J . A deviant immune response to viral proteins and transgene product is generated on subretinal administration of adenovirus and adeno-associated virus. Mol Ther 2002; 5: 125–132.

    Article  CAS  PubMed  Google Scholar 

  32. Le MG, Weber M, Pereon Y, Mendes-Madeira A, Nivard D, Deschamps JY et al. Postsurgical assessment and long-term safety of recombinant adeno-associated virus-mediated gene transfer into the retinas of dogs and primates. Arch Ophthalmol 2005; 123: 500–506.

    Article  Google Scholar 

  33. Folliot S, Briot D, Conrath H, Provost N, Cherel Y, Moullier P et al. Sustained tetracycline-regulated transgene expression in vivo in rat retinal ganglion cells using a single type 2 adeno-associated viral vector. J Gene Med 2003; 5: 493–501.

    Article  CAS  PubMed  Google Scholar 

  34. Lebherz C, Auricchio A, Maguire AM, Rivera VM, Tang W, Grant RL et al. Long-term inducible gene expression in the eye via adeno-associated virus gene transfer in nonhuman primates. Hum Gene Ther 2005; 16: 178–186.

    Article  CAS  PubMed  Google Scholar 

  35. Smith JR, Verwaerde C, Rolling F, Naud MC, Delanoye A, Thillaye-Goldenberg B et al. Tetracycline-inducible viral interleukin-10 intraocular gene transfer, using adeno-associated virus in experimental autoimmune uveoretinitis. Hum Gene Ther 2005; 16: 1037–1046.

    Article  CAS  PubMed  Google Scholar 

  36. Yokoi K, Kachi S, Zhang HS, Gregory PD, Spratt SK, Samulski RJ et al. Ocular gene transfer with self-complementary AAV vectors. Invest Ophthalmol Vis Sci 2007; 48: 3324–3328.

    Article  PubMed  Google Scholar 

  37. Khani SC, Pawlyk BS, Bulgakov OV, Kasperek E, Young JE, Adamian M et al. AAV-mediated expression targeting of rod and cone photoreceptors with a human rhodopsin kinase promoter. Invest Ophthalmol Vis Sci 2007; 48: 3954–3961.

    Article  PubMed  Google Scholar 

  38. Li Q, Timmers AM, Guy J, Pang J, Hauswirth WW . Cone-specific expression using a human red opsin promoter in recombinant AAV. Vision Res 2008; 48: 332–338.

    Article  CAS  PubMed  Google Scholar 

  39. Glushakova LG, Timmers AM, Pang J, Teusner JT, Hauswirth WW . Human blue-opsin promoter preferentially targets reporter gene expression to rat s-cone photoreceptors. Invest Ophthalmol Vis Sci 2006; 47: 3505–3513.

    Article  PubMed  Google Scholar 

  40. Ali RR, Sarra GM, Stephens C, Alwis MD, Bainbridge JW, Munro PM et al. Restoration of photoreceptor ultrastructure and function in retinal degeneration slow mice by gene therapy. Nat Genet 2000; 25: 306–310.

    Article  CAS  PubMed  Google Scholar 

  41. Schlichtenbrede FC, da Cruz L, Stephens C, Smith AJ, Georgiadis A, Thrasher AJ et al. Long-term evaluation of retinal function in Prph2Rd2/Rd2 mice following AAV-mediated gene replacement therapy. J Gene Med 2003; 5: 757–764.

    Article  CAS  PubMed  Google Scholar 

  42. Pawlyk BS, Smith AJ, Buch PK, Adamian M, Hong DH, Sandberg MA et al. Gene replacement therapy rescues photoreceptor degeneration in a murine model of leber congenital amaurosis lacking RPGRIP. Invest Ophthalmol Vis Sci 2005; 46: 3039–3045.

    Article  PubMed  Google Scholar 

  43. Zeng Y, Takada Y, Kjellstrom S, Hiriyanna K, Tanikawa A, Wawrousek E et al. RS-1 gene delivery to an adult Rs1h knockout mouse model restores ERG b-wave with reversal of the electronegative waveform of X-linked retinoschisis. Invest Ophthalmol Vis Sci 2004; 45: 3279–3285.

    Article  PubMed  Google Scholar 

  44. Min SH, Molday LL, Seeliger MW, Dinculescu A, Timmers AM, Janssen A et al. Prolonged recovery of retinal structure/function after gene therapy in an Rs1h-deficient mouse model of x-linked juvenile retinoschisis. Mol Ther 2005; 12: 644–651.

    Article  CAS  PubMed  Google Scholar 

  45. Smith AJ, Schlichtenbrede FC, Tschernutter M, Bainbridge JW, Thrasher AJ, Ali RR . AAV-mediated gene transfer slows photoreceptor loss in the RCS rat model of retinitis pigmentosa. Mol Ther 2003; 8: 188–195.

    Article  CAS  PubMed  Google Scholar 

  46. Surace EM, Domenici L, Cortese K, Cotugno G, Di VU, Venturi C et al. Amelioration of both functional and morphological abnormalities in the retina of a mouse model of ocular albinism following AAV-mediated gene transfer. Mol Ther 2005; 12: 652–658.

    Article  CAS  PubMed  Google Scholar 

  47. Dejneka NS, Surace EM, Aleman TS, Cideciyan AV, Lyubarsky A, Savchenko A et al. In utero gene therapy rescues vision in a murine model of congenital blindness. Mol Ther 2004; 9: 182–188.

    Article  CAS  PubMed  Google Scholar 

  48. Narfstrom K, Katz ML, Ford M, Redmond TM, Rakoczy E, Bragadottir R . In vivo gene therapy in young and adult RPE65−/− dogs produces long-term visual improvement. J Hered 2003; 94: 31–37.

    Article  CAS  PubMed  Google Scholar 

  49. Narfstrom K, Katz ML, Bragadottir R, Seeliger M, Boulanger A, Redmond TM et al. Functional and structural recovery of the retina after gene therapy in the RPE65 null mutation dog. Invest Ophthalmol Vis Sci 2003; 44: 1663–1672.

    Article  PubMed  Google Scholar 

  50. Acland GM, Aguirre GD, Bennett J, Aleman TS, Cideciyan AV, Bennicelli J et al. 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 2005; 12: 1072–1082.

    Article  CAS  PubMed  Google Scholar 

  51. Acland GM, Aguirre GD, Ray J, Zhang Q, Aleman TS, Cideciyan AV et al. Gene therapy restores vision in a canine model of childhood blindness. Nat Genet 2001; 28: 92–95.

    CAS  PubMed  Google Scholar 

  52. Le MG, Stieger K, Smith AJ, Weber M, Deschamps JY, Nivard D et al. Restoration of vision in RPE65-deficient Briard dogs using an AAV serotype 4 vector that specifically targets the retinal pigmented epithelium. Gene Therapy 2007; 14: 292–303.

    Article  CAS  Google Scholar 

  53. Gorbatyuk M, Justilien V, Liu J, Hauswirth WW, Lewin AS . Preservation of photoreceptor morphology and function in P23H rats using an allele independent ribozyme. Exp Eye Res 2007; 84: 44–52.

    Article  CAS  PubMed  Google Scholar 

  54. Gorbatyuk MS, Pang JJ, Thomas Jr J, Hauswirth WW, Lewin AS . Knockdown of wild-type mouse rhodopsin using an AAV vectored ribozyme as part of an RNA replacement approach. Mol Vis 2005; 11: 648–656.

    CAS  PubMed  Google Scholar 

  55. http://www.sph.uth.tmc.edu/RetNet/disease.htm#03.202d.

  56. Xia H, Mao Q, Eliason SL, Harper SQ, Martins IH, Orr HT et al. RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia. Nat Med 2004; 10: 816–820.

    Article  CAS  PubMed  Google Scholar 

  57. Ralph GS, Radcliffe PA, Day DM, Carthy JM, Leroux MA, Lee DC et al. Silencing mutant SOD1 using RNAi protects against neurodegeneration and extends survival in an ALS model. Nat Med 2005; 11: 429–433.

    Article  CAS  PubMed  Google Scholar 

  58. Cashman SM, Binkley EA, Kumar-Singh R . Towards mutation-independent silencing of genes involved in retinal degeneration by RNA interference. Gene Ther 2005; 12: 1223–1228.

    Article  CAS  PubMed  Google Scholar 

  59. Kiang AS, Palfi A, Ader M, Kenna PF, Millington-Ward S, Clark G et al. Toward a gene therapy for dominant disease: validation of an RNA interference-based mutation-independent approach. Mol Ther 2005; 12: 555–561.

    Article  CAS  PubMed  Google Scholar 

  60. O'reilly M, Palfi A, Chadderton N, Millington-Ward S, Ader M, Cronin T et al. RNA interference-mediated suppression and replacement of human rhodopsin in vivo. Am J Hum Genet 2007; 81: 127–135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Kohl S, Baumann B, Rosenberg T, Kellner U, Lorenz B, Vadala M et al. Mutations in the cone photoreceptor G-protein alpha-subunit gene GNAT2 in patients with achromatopsia. Am J Hum Genet 2002; 71: 422–425.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Kohl S, Marx T, Giddings I, Jagle H, Jacobson SG, pfelstedt-Sylla E et al. Total colourblindness is caused by mutations in the gene encoding the alpha-subunit of the cone photoreceptor cGMP-gated cation channel. Nat Genet 1998; 19: 257–259.

    Article  CAS  PubMed  Google Scholar 

  63. Kohl S, Baumann B, Broghammer M, Jagle H, Sieving P, Kellner U et al. Mutations in the CNGB3 gene encoding the beta-subunit of the cone photoreceptor cGMP-gated channel are responsible for achromatopsia (ACHM3) linked to chromosome 8q21. Hum Mol Genet 2000; 9: 2107–2116.

    Article  CAS  PubMed  Google Scholar 

  64. Chang B, Dacey MS, Hawes NL, Hitchcock PF, Milam AH, tmaca-Sonmez P et al. Cone photoreceptor function loss-3, a novel mouse model of achromatopsia due to a mutation in Gnat2. Invest Ophthalmol Vis Sci 2006; 47: 5017–5021.

    Article  PubMed  Google Scholar 

  65. Alexander JJ, Umino Y, Everhart D, Chang B, Min SH, Li Q et al. Restoration of cone vision in a mouse model of achromatopsia. Nat Med 2007; 13: 685–687.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Leonard KC, Petrin D, Coupland SG, Baker AN, Leonard BC, LaCasse EC et al. XIAP protection of photoreceptors in animal models of retinitis pigmentosa. PLoS ONE 2007; 2: e314.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. LaVail MM, Yasumura D, Matthes MT, Lau-Villacorta C, Unoki K, Sung CH et al. Protection of mouse photoreceptors by survival factors in retinal degenerations. Invest Ophthalmol Vis Sci 1998; 39: 592–602.

    CAS  PubMed  Google Scholar 

  68. LaVail MM, Unoki K, Yasumura D, Matthes MT, Yancopoulos GD, Steinberg RH . Multiple growth factors, cytokines, and neurotrophins rescue photoreceptors from the damaging effects of constant light. Proc Natl Acad Sci USA 1992; 89: 11249–11253.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Liang FQ, Aleman TS, Dejneka NS, Dudus L, Fisher KJ, Maguire AM et al. Long-term protection of retinal structure but not function using RAAV. CNTF in animal models of retinitis pigmentosa. Mol Ther 2001; 4: 461–472.

    Article  CAS  PubMed  Google Scholar 

  70. Bok D, Yasumura D, Matthes MT, Ruiz A, Duncan JL, Chappelow AV et al. 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 2002; 74: 719–735.

    Article  CAS  PubMed  Google Scholar 

  71. Buch PK, MacLaren RE, Duran Y, Balaggan KS, MacNeil A, Schlichtenbrede FC et al. In contrast to AAV-mediated Cntf expression, AAV-mediated Gdnf expression enhances gene replacement therapy in rodent models of retinal degeneration. Mol Ther 2006; 14: 700–709.

    CAS  PubMed  Google Scholar 

  72. Rhee KD, Ruiz A, Duncan JL, Hauswirth WW, LaVail MM, Bok D et al. Molecular and cellular alterations induced by sustained expression of ciliary neurotrophic factor in a mouse model of retinitis pigmentosa. Invest Ophthalmol Vis Sci 2007; 48: 1389–1400.

    Article  PubMed  Google Scholar 

  73. McGill TJ, Prusky GT, Douglas RM, Yasumura D, Matthes MT, Nune G et al. Intraocular CNTF reduces vision in normal rats in a dose-dependent manner. Invest Ophthalmol Vis Sci 2007; 48: 5756–5766.

    Article  PubMed  Google Scholar 

  74. Wen R, Song Y, Kjellstrom S, Tanikawa A, Liu Y, Li Y et al. Regulation of rod phototransduction machinery by ciliary neurotrophic factor. J Neurosci 2006; 26: 13523–13530.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Faktorovich EG, Steinberg RH, Yasumura D, Matthes MT, LaVail MM . Photoreceptor degeneration in inherited retinal dystrophy delayed by basic fibroblast growth factor. Nature 1990; 347: 83–86.

    Article  CAS  PubMed  Google Scholar 

  76. Unoki K, LaVail MM . Protection of the rat retina from ischemic injury by brain-derived neurotrophic factor, ciliary neurotrophic factor, and basic fibroblast growth factor. Invest Ophthalmol Vis Sci 1994; 35: 907–915.

    CAS  PubMed  Google Scholar 

  77. Lau D, McGee LH, Zhou S, Rendahl KG, Manning WC, Escobedo JA et al. Retinal degeneration is slowed in transgenic rats by AAV-mediated delivery of FGF-2. Invest Ophthalmol Vis Sci 2000; 41: 3622–3633.

    CAS  PubMed  Google Scholar 

  78. Flammer J, Mozaffarieh M . What is the present pathogenetic concept of glaucomatous optic neuropathy? Surv Ophthalmol 2007; 52: S162–S173.

    Article  PubMed  Google Scholar 

  79. Harvey AR, Hu Y, Leaver SG, Mellough CB, Park K, Verhaagen J et al. Gene therapy and transplantation in CNS repair: the visual system. Prog Retin Eye Res 2006; 25: 449–489.

    Article  CAS  PubMed  Google Scholar 

  80. Osborne NN, Chidlow G, Layton CJ, Wood JP, Casson RJ, Melena J . Optic nerve and neuroprotection strategies. Eye 2004; 18: 1075–1084.

    Article  CAS  PubMed  Google Scholar 

  81. Di PA, Aigner LJ, Dunn RJ, Bray GM, Aguayo AJ . Prolonged delivery of brain-derived neurotrophic factor by adenovirus-infected Muller cells temporarily rescues injured retinal ganglion cells. Proc Natl Acad Sci USA 1998; 95: 3978–3983.

    Article  Google Scholar 

  82. Cheng L, Sapieha P, Kittlerova P, Hauswirth WW, Di Polo A . TrkB gene transfer protects retinal ganglion cells from axotomy-induced death in vivo. J Neurosci 2002; 22: 3977–3986.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Sapieha PS, Peltier M, Rendahl KG, Manning WC, Di PA . Fibroblast growth factor-2 gene delivery stimulates axon growth by adult retinal ganglion cells after acute optic nerve injury. Mol Cell Neurosci 2003; 24: 656–672.

    Article  CAS  PubMed  Google Scholar 

  84. Leaver SG, Cui Q, Plant GW, Arulpragasam A, Hisheh S, Verhaagen J et al. AAV-mediated expression of CNTF promotes long-term survival and regeneration of adult rat retinal ganglion cells. Gene Ther 2006; 13: 1328–1341.

    Article  CAS  PubMed  Google Scholar 

  85. MacLaren RE, Buch PK, Smith AJ, Balaggan KS, MacNeil A, Taylor JS et al. CNTF gene transfer protects ganglion cells in rat retinae undergoing focal injury and branch vessel occlusion. Exp Eye Res 2006; 83: 1118–1127.

    Article  CAS  PubMed  Google Scholar 

  86. Malik JM, Shevtsova Z, Bahr M, Kugler S . Long-term in vivo inhibition of CNS neurodegeneration by Bcl-XL gene transfer. Mol Ther 2005; 11: 373–381.

    Article  CAS  PubMed  Google Scholar 

  87. Shevtsova Z, Malik I, Garrido M, Scholl U, Bahr M, Kugler S . Potentiation of in vivo neuroprotection by BclX(L) and GDNF co-expression depends on post-lesion time in deafferentiated CNS neurons. Gene Ther 2006; 13: 1569–1578.

    Article  CAS  PubMed  Google Scholar 

  88. Pedotti R, De Voss JJ, Steinman L, Galli SJ . Involvement of both ‘allergic’ and ‘autoimmune’ mechanisms in EAE, MS and other autoimmune diseases. Trends Immunol 2003; 24: 479–484.

    Article  CAS  PubMed  Google Scholar 

  89. Qi X, Sun L, Lewin AS, Hauswirth WW, Guy J . Long-term suppression of neurodegeneration in chronic experimental optic neuritis: antioxidant gene therapy. Invest Ophthalmol Vis Sci 2007; 48: 5360–5370.

    Article  PubMed  Google Scholar 

  90. Qi X, Lewin AS, Sun L, Hauswirth WW, Guy J . Suppression of mitochondrial oxidative stress provides long-term neuroprotection in experimental optic neuritis. Invest Ophthalmol Vis Sci 2007; 48: 681–691.

    Article  PubMed  Google Scholar 

  91. Deng WT, Yan Z, Dinculescu A, Pang J, Teusner JT, Cortez NG et al. 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 2005; 16: 1247–1254.

    Article  CAS  PubMed  Google Scholar 

  92. Rakoczy PE, Brankov M, Fonceca A, Zaknich T, Rae BC, Lai CM . Enhanced recombinant adeno-associated virus-mediated vascular endothelial growth factor expression in the adult mouse retina: a potential model for diabetic retinopathy. Diabetes 2003; 52: 857–863.

    Article  CAS  PubMed  Google Scholar 

  93. Rota R, Riccioni T, Zaccarini M, Lamartina S, Gallo AD, Fusco A et al. Marked inhibition of retinal neovascularization in rats following soluble-flt-1 gene transfer. J Gene Med 2004; 6: 992–1002.

    Article  CAS  PubMed  Google Scholar 

  94. Lai CC, Wu WC, Chen SL, Sun MH, Xiao X, Ma L et al. Recombinant adeno-associated virus vector expressing angiostatin inhibits preretinal neovascularization in adult rats. Ophthalmic Res 2005; 37: 50–56.

    Article  CAS  PubMed  Google Scholar 

  95. Auricchio A, Behling KC, Maguire AM, O'Connor EM, Bennett J, Wilson JM et al. Inhibition of retinal neovascularization by intraocular viral-mediated delivery of anti-angiogenic agents. Mol Ther 2002; 6: 490–494.

    Article  CAS  PubMed  Google Scholar 

  96. Yokoi K, Zhang HS, Kachi S, Balaggan KS, Yu Q, Guschin D et al. Gene transfer of an engineered zinc finger protein enhances the anti-angiogenic defense system. Mol Ther 2007; 15: 1917–1923.

    Article  CAS  PubMed  Google Scholar 

  97. Campochiaro PA, Dong NQ, Mahmood SS, Klein ML, Holz E, Frank RN et al. Adenoviral vector-delivered pigment epithelium-derived factor for neovascular age-related macular degeneration: results of a phase I clinical trial. Hum Gene Ther 2006: 167–176.

  98. Dick AD . Immune regulation of uveoretinal inflammation. Dev Ophthalmol 1999; 30: 187–202.

    Article  CAS  PubMed  Google Scholar 

  99. Broderick CA, Smith AJ, Balaggan KS, Georgiadis A, Buch PK, Trittibach PC et al. Local administration of an adeno-associated viral vector expressing IL-10 reduces monocyte infiltration and subsequent photoreceptor damage during experimental autoimmune uveitis. Mol Ther 2005; 12: 369–373.

    Article  CAS  PubMed  Google Scholar 

  100. MacLaren RE, Pearson RA, MacNeil A, Douglas RH, Salt TE, Akimoto M et al. Retinal repair by transplantation of photoreceptor precursors. Nature 2006; 444: 203–207.

    Article  CAS  PubMed  Google Scholar 

  101. Winter JO, Cogan SF, Rizzo III JF . Retinal prostheses: current challenges and future outlook. J Biomater Sci Polym Ed 2007; 18: 1031–1055.

    Article  CAS  PubMed  Google Scholar 

  102. Bi A, Cui J, Ma YP, Olshevskaya E, Pu M, Dizhoor AM et al. Ectopic expression of a microbial-type rhodopsin restores visual responses in mice with photoreceptor degeneration. Neuron 2006; 50: 23–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Tomita H, Sugano E, Yawo H, Ishizuka T, Isago H, Narikawa S et al. Restoration of visual response in aged dystrophic RCS rats using AAV-mediated channelopsin-2 gene transfer. Invest Ophthalmol Vis Sci 2007; 48: 3821–3826.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors are supported by grants from the UK Department of Health, The Wellcome Trust, The UK Medical Research Council, The British Retinitis Pigmentosa Society; Fighting Blindness Ireland, Foundation Fighting Blindness (USA), European Union (EVI-GenoRet and NoE CliniGene).

Author information

Authors and Affiliations

  1. Division of Molecular Therapy, UCL Institute of Ophthalmology and UCL/Moorfields Eye Hospital Biomedical Research Centre for Ophthalmology, London, UK

    P K Buch, J W Bainbridge & R R Ali

Authors
  1. P K Buch
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J W Bainbridge
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R R Ali
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R R Ali.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Buch, P., Bainbridge, J. & Ali, R. AAV-mediated gene therapy for retinal disorders: from mouse to man. Gene Ther 15, 849–857 (2008). https://doi.org/10.1038/gt.2008.66

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gt.2008.66

Keywords

This article is cited by

Search

Advanced search

Quick links