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.

  • Article
  • Published:

Retina transduction by rAAV2 after intravitreal injection: comparison between mouse and rat

Gene Therapy volume 26, pages 479–490 (2019)Cite this article

Subjects

Abstract

Adeno-associated virus vectors (rAAV) are currently the most common vehicle used in clinical trials of retinal gene therapy, usually delivered through subretinal injections to target cells of the outer retina. However, targeting the inner retina requires intravitreal injections, a simple and safe procedure, which is effective for transducing the rodent retina, but still of low efficiency in the eyes of primates. We investigated whether adjuvant pharmacological agents may enhance rAAV transduction of the retinas of mouse and rat after intravitreal delivery. Tyrosine kinase inhibitors were highly efficient in mice, especially imatinib and genistein, and promoted transduction even of the outer retina. In rats, however, we report that they were not effective. Even with direct proteasomal inhibition in rats, the effects upon transduction were only minimal and restricted to the inner retina. Even tyrosine capsid mutant rAAVs in rats had a transduction profile similar to wtAAV. Thus, the differences between mouse and rat, in both eye size and the inner limiting membrane, compromise the efficiency of AAV vectors penetration from the vitreous into the retina, and impact the efficacy of strategies developed to enhance intravitreal retinal rAAV transduction. Further improvement of strategies, then are required.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Naso MF, Tomkowicz B, Perry WL, Strohl WR. Adeno-Associated Virus (AAV) as a vector for gene therapy. BioDrugs. 2017;31:317–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Colella P, Ronzitti G, Mingozzi F. Emerging issues in AAV-mediated in vivo gene therapy. Mol Ther Methods Clin Dev. 2018;16:87–104.

    Google Scholar 

  3. Russell S, Bennett J, Wellman JA, Chung DC, Yu ZF, Tillman A, et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet. 2017;390:849–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Flannery JG, Zolotukhin S, Vaquero MI, LaVail MM, Muzyczka N, Hauswirth WW. Efficient photoreceptor-targeted gene expression in vivo by recombinant adeno-associated virus. Proc Natl Acad Sci USA. 1997;94:6916–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Dudus L, Anand V, Acland GM, Chen SJ, Wilson JM, Fisher KJ, et al. Persistent transgene product in retina, optic nerve and brain after intraocular injection of rAAV. Vision Res. 1999;39:2545–53.

    CAS  PubMed  Google Scholar 

  6. Peng Y, Tang L, Zhou Y. Subretinal injection: a review on the novel route of therapeutic delivery for vitreoretinal diseases. Opthalmic Res. 2017;58:217–26.

    CAS  Google Scholar 

  7. Bennett J. Taking stock of retinal gene therapy: looking back and moving forward. Mol Ther. 2017;25:1076–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Ochakovski GA, Bartz-Schmidt KU, Fischer MD. Retinal gene therapy: surgical vector delivery in the translation to clinical trials. Front Neurosci. 2017;11(Apr):174.

    PubMed  PubMed Central  Google Scholar 

  9. Xing L, Dorrepaal SJ, Gale J. Survey of intravitreal injection techniques and treatment protocols among retina specialists in Canada. Can J Ophthalmol. 2014;49:261–6.

    PubMed  Google Scholar 

  10. Ali RR, Reichel MB, De Alwis M, Kanuga N, Kinnon C, Levinsky RJ, et al. Adeno-associated virus gene transfer to mouse retina. Hum Gene Ther. 1998;9:81–6.

    CAS  PubMed  Google Scholar 

  11. Mowat FM, Gornik KR, Dinculescu A, Boye SL, Hauswirth WW, Petersen-Jones SM, et al. Tyrosine capsid-mutant AAV vectors for gene delivery to the canine retina from a subretinal or intravitreal approach. Gene Ther. 2014;21(Jan):96–105.

    CAS  PubMed  Google Scholar 

  12. Yin L, Greenberg K, Hunter JJ, Dalkara D, Kolstad KD, Masella BD, et al. Intravitreal Injection of AAV2 Transduces Macaque Inner Retina. IOVS. 2011;52:2775–83.

    CAS  Google Scholar 

  13. Kaplan HJ, Chiang CW, Chen J, Song SK. Vitreous Volume of the Mouse Measured by Quantitative High-Resolution MRI. Investigative Ophthalmology & Visual Science. 2010;51(April):4214.

    Google Scholar 

  14. Sebag J. Ageing of the vitreous. Eye (Lond). 1987;1(Pt 2):254–62.

    Google Scholar 

  15. Bekerman I, Gottlieb P, Vaiman M. Variations in eyeball diameters of the healthy adults. J Ophthalmol. 2014;2014:503645.

    PubMed  PubMed Central  Google Scholar 

  16. Puk O, Dalke C, Favor J, de Angelis MH, Graw J. Variations of eye size parameters among different strains of mice. Mamm Genome. 2006;17(Aug):851–7.

    PubMed  Google Scholar 

  17. Matsumoto B, Blanks JCM, Ryan SJ. Topographic Variations in the Rabbit and Primate Internal Limiting Membrane. IOVS. 1984;25:71–82.

    CAS  Google Scholar 

  18. Hu H, Candiello J, Zhang P, Ball SL, Cameron DA, Halfter W. Retinal ectopias and mechanically weakened basement membrane in a mouse model of muscle-eye-brain (MEB) disease congenital muscular dystrophy. Mol Vis. 2010;16(Jul):1415–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Woodard KT, Liang KJ, Bennett WC, Samulski RJ. Heparan Sulfate Binding Promotes Accumulation of Intravitreally Delivered Adeno-associated Viral Vectors at the Retina for Enhanced Transduction but Weakly Influences Tropism. J Virol. 2016;90(Oct):9878–88. https://doi.org/10.1128/JVI.01568-16. Print 2016 Nov 1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Fu X, Anh V, Huu N, Duan Y, Kermany DS, Valentim CCS, et al. Clinical applications of retinal gene therapies. Precision Clinical Medicine. 2018;1(June):5–20.

    Google Scholar 

  21. Calkins DJ, Pekny M, Cooper ML, Benowitz L. The challenge of regenerative therapies for the optic nerve in glaucoma. Experimental Eye Research. 2017;157:28–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Petrs-Silva H, Dinculescu A, Li Q, Min SH, Chiodo V, Pang JJ, et al. High-efficiency transduction of the mouse retina by tyrosine-mutant AAV serotype vectors. Mol Ther. 2009;17:463–71.

    CAS  PubMed  Google Scholar 

  23. Petrs-Silva H, Dinculescu A, Li Q, Deng WT, Pang JJ, Min SH, et al. Novel properties of tyrosine-mutant AAV2 vectors in the mouse retina. Mol Ther. 2011;19:293–301.

    CAS  PubMed  Google Scholar 

  24. Dalkara D, Byrne LC, Klimczak RR, Visel M, Yin L, Merigan WH, et al. In Vivo–Directed Evolution of a New Adeno-Associated Virus for Therapeutic Outer Retinal Gene Delivery from the Vitreous. Sci Transl Med. 2013;5(Jun):189ra76.

    PubMed  Google Scholar 

  25. Da Costa R, Röger C, Segelken J, Barben M, Grimm C, Neidhardt J. A Novel Method Combining Vitreous Aspiration and Intravitreal AAV2/8 Injection Results in Retina-Wide Transduction in Adult Mice. Invest Ophthalmol Vis Sci. 2016;57(Oct):5326–34.

    PubMed  Google Scholar 

  26. Dalkara D, Kolstad KD, Caporale N, Visel M, Klimczak RR, Schaffer DV, et al. Inner limiting membrane barriers to AAV-mediated retinal transduction from the vitreous. Mol Ther. 2009;17(Dec):2096–102.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Cehajic-Kapetanovic J, Le Goff MM, Allen A, Lucas RJ, Bishop PN. Glycosidic enzymes enhance retinal transduction following intravitreal delivery of AAV2. Mol Vis. 2011;17:1771–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Song H, Bush RA, Zeng Y, Qian H, Wu Z, Sieving PA. Trans-ocular Electric Current In Vivo Enhances AAV-Mediated Retinal Gene Transduction after Intravitreal Vector Administration. Mol Ther Methods Clin Dev. 2018;13(Dec):77–85.

    PubMed  PubMed Central  Google Scholar 

  29. Gamlin PD, Alexander JJ, Boye SL, Witherspoon CD, Boye SE. SubILM Injection of AAV for Gene Delivery to the Retina. Methods Mol Biol. 2019;1950:249–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Duan D, Yue Y, Yan Z, Yang J, Engelhardt JF. Endosomal processing limits gene transfer to polarized airway epithelia by adeno-associated virus. J Clin Invest. 2000;105(Jun):1573–87.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Johnson JS, Samulski RJ. Enhancement of adeno-associated virus infection by mobilizing capsids into and out of the nucleolus. J Virol. 2009;83(Mar):2632–42.

    CAS  PubMed  Google Scholar 

  32. Zhong L, Li B, Mah CS, Govindasamy L, Agbandje-McKenna M, Cooper M, et al. Next generation of adeno-associated virus 2 vectors: point mutations in tyrosines lead to high-efficiency transduction at lower doses. Proc Natl Acad Sci USA. 2008;105:7827–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Gabriel N, Hareendran S, Sen D, Gadkari RA, Sudha G, Selot R, et al. Bioengineering of AAV2 capsid at specific serine, threonine, or lysine residues improves its transduction efficiency in vitro and in vivo. Hum Gene Ther Methods. 2013;24:80–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Yan Z, Zak R, Luxton GW, Ritchie TC, Bantel-Schaal U, Engelhardt JF. Ubiquitination of both adeno-associated virus type 2 and 5 capsid proteins affects the transduction efficiency of recombinant vectors. J Virol. 2002;76(Mar):2043–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Boyd RF, Sledge DG, Boye SL, Boye SE, Hauswirth WW, Komáromy AM, et al. Photoreceptor-targeted gene delivery using intravitreally administered AAV vectors in dogs. Gene Ther. 2016;23(Feb):223–30.

    CAS  PubMed  Google Scholar 

  36. Boyd RF, Boye SL, Conlon TJ, Erger KE, Sledge DG, Langohr IM, et al. Reduced retinal transduction and enhanced transgene-directed immunogenicity with intravitreal delivery of rAAV following posterior vitrectomy in dogs. Gene Ther. 2016;23(Jun):548–56. https://doi.org/10.1038/gt.2016.31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ramachandran PS, Lee V, Wei Z, Song JY, Casal G, Cronin T, et al. Evaluation of Dose and Safety of AAV7m8 and AAV8BP2 in the Non-Human Primate Retina. Hum Gene Ther. 2017;28(Feb):154–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Denby L, Nicklin SA, Baker AH. Adeno-associated virus (AAV)-7 and -8 poorly transduce vascular endothelial cells and are sensitive to proteasomal degradation. Gene Ther. 2005;12:1534–8.

    CAS  PubMed  Google Scholar 

  39. Chaanine AH, Nonnenmacher M, Kohlbrenner E, Jin D, Kovacic JC, Akar FG, et al. Effect of bortezomib on the efficacy of AAV9.SERCA2a treatment to preserve cardiac function in a rat pressure-overload model of heart failure. Gene Ther. 2014;21:379–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Zhang FL, Jia SQ, Zheng SP, Ding W. Celastrol enhances AAV1-mediated gene expression in mice adipose tissues. Gene Ther. 2011;18:128–34.

    PubMed  Google Scholar 

  41. Monahan PE, Lothrop CD, Sun J, Hirsch ML, Kafri T, Kantor B, et al. Proteasome inhibitors enhance gene delivery by AAV virus vectors expressing large genomes in hemophilia mouse and dog models: a strategy for broad clinical application. Mol Ther. 2010;18(Nov):1907–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Mitchell AM, Samulski RJ. Mechanistic insights into the enhancement of adeno-associated virus transduction by proteasome inhibitors. J Virol. 2013;87(no. 8):4571–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Remtulla S, Hallett PE. A schematic eye for the mouse, and comparisons with the rat. Vision Res. 1985;25:21–31.

    CAS  PubMed  Google Scholar 

  44. Zolotukhin S, Byrne BJ, Mason E, Zolotukhin I, Potter M, Chesnut K, et al. Recombinant adeno-associated virus purification using novel methods improves infectious titer and yield. Gene Ther. 1999;6:973–985.37.

    CAS  PubMed  Google Scholar 

  45. Igarashi T, Miyake K, Asakawa N, Miyake N, Shimada T, Takahashi H. Direct comparison of administration routes for AAV8-mediated ocular gene therapy. Curr. Eye Res. 2013;38:569–77.

    CAS  PubMed  Google Scholar 

  46. Zhong L, Zhao W, Wu J, Li B, Zolotukhin S, Govindasamy L, et al. A dual role of EGFR protein tyrosine kinase signaling in ubiquitination of AAV2 capsids and viral second-strand DNA synthesis. Mol Ther. 2007;15:1323–30.

    CAS  PubMed  Google Scholar 

  47. Hanke JH, Gardner JP, Dow RL, Changelian PS, Brissette WH, Weringer EJ, et al. Discovery of a novel, potent, and Src family-selective tyrosine kinase inhibitor. Study of Lck- and FynT-dependent T cell activation. J Biol Chem. 1996;271(Jan):695–701.12.

    CAS  PubMed  Google Scholar 

  48. Werdich XQ, Penn JS. Specific involvement of SRC family kinase activation in the pathogenesis of retinal neovascularization. Invest Ophthalmol Vis Sci. 2006;47(Nov):5047–56.

    PubMed  Google Scholar 

  49. Dong LD, Gao F, Wang XH, Miao Y, Wang SY, Wu Y, et al. GluA2 trafficking is involved in apoptosis of retinal ganglion cells induced by activation of EphB/EphrinB reverse signaling in a rat chronic ocular hypertension model. Neurosci. 2015;35(Apr):5409–2142.

    CAS  Google Scholar 

  50. Kovalenko M, Gazit A, Böhmer A, Rorsman C, Rönnstrand L, Heldin CH, et al. Selective platelet-derived growth factor receptor kinase blockers reverse sis-transformation. Cancer Res. 1994;54(Dec):6106–14.

    CAS  PubMed  Google Scholar 

  51. Xiong L, Quan YL, Zheng YP, Zhang LM, Zhang LY, Xiong QC. Effects of platelet-derived growth factor α receptor in experimental rabbit PVR. Int J Ophthalmol. 2009;2:261–5.

    Google Scholar 

  52. Han Y, Caday CG, Nanda A, Cavenee WK, Huang HJ, Tyrphostin AG. 1478 preferentially inhibits human glioma cells expressing truncated rather than wild-type epidermal growth factor receptors. Cancer Res. 1996;56(Sep):3859–61.

    CAS  PubMed  Google Scholar 

  53. Sugimoto M, Cutler A, Shen B, Moss SE, Iyengar SK, Klein R, et al. Inhibition of EGF signaling protects the diabetic retina from insulin-induced vascular leakage. Am J Pathol. 2013;183(Sep):987–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Ju X, Yang X, Yan T, Chen H, Song Z, Zhang Z, et al. EGFR inhibitor, AG1478, inhibits inflammatory infiltration and angiogenesis in mice with diabetic retinopathy. Clin Exp Pharmacol Physiol. 2019;46(Jan):75–85.

    CAS  PubMed  Google Scholar 

  55. Nikkhah H, Ahmadieh H, Ramezani A, Kanavi M, Hosseini SB, Sadeghi N, et al. Safe dose of intravitreal imatinib and its effect on laser-induced choroidal neovascularization: a rat-model experiment. Int J Retina Vitreous. 2015;1:16.

    PubMed  PubMed Central  Google Scholar 

  56. Qing K, Khuntirat B, Mah C, Kube DM, Wang XS, Ponnazhagan S, et al. Adeno-associated virus type 2-mediated gene transfer: correlation of tyrosine phosphorylation of the cellular single-stranded D sequence-binding protein with transgene expression in human cells in vitro and murine tissues in vivo. J Virol. 1998;72(Feb):1593–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Ibrahim AS, El-Shishtawy MM, Peña A Jr, Liou GI. Genistein attenuates retinal inflammation associated with diabetes by targeting of microglial activation. Mol Vis. 2010;16:2033–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Fisher RI, Bernstein SH, Kahl BS, Djulbegovic B, Robertson MJ, de Vos S, et al. Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. Journal of Clinical Oncology. 2006;24:4867–74.

    PubMed  Google Scholar 

  59. Chen FT, Yang CM, Yang CH. The protective effects of the proteasome inhibitor bortezomib (velcade) on ischemia-reperfusion injury in the rat retina. PLoS ONE. 2013;8(May):e64262.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Pechan P, Rubin H, Lukason M, Ardinger J, DuFresne E, Hauswirth WW, et al. Novel anti-VEGF chimeric molecules delivered by AAV vectors for inhibition of retinal neovascularization. Gene Ther. 2009;16:10–6.

    CAS  PubMed  Google Scholar 

  61. Russell DW, Alexander IE, Miller AD. DNA synthesis and topoisomerase inhibitors increase transduction by adeno-associated virus vectors. Proc Natl Acad Sci USA. 1995;92:5719–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Qing K, Wang XS, Kube DM, Ponnazhagan S, Bajpai A, Srivastava A. Role of tyrosine phosphorylation of a cellular protein in adeno-associated virus 2-mediated transgene expression. Proc Natl Acad Sci USA. 1997;94(Sep):10879–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Dey A, Manthey AL, Chiu K, Do C. Methods to Induce Chronic Ocular Hypertension: Reliable Rodent Models as a Platform for Cell Transplantation and Other Therapies. Cell Transplantation. 2018;27:213–29.

    PubMed  PubMed Central  Google Scholar 

  64. Koch S, Sothilingam V, Garcia Garrido M, Tanimoto N, Becirovic E, Koch F, et al. Gene therapy restores vision and delays degeneration in the CNGB1(-/-) mouse model of retinitis pigmentosa. Hum Mol Genet. 2012;21(Oct):4286–96.

    Google Scholar 

  65. Bruewer AR, Mowat FM, Bartoe JT, Boye SL, Hauswirth WW, Petersen-Jones SM. Evaluation of lateral spread of transgene expression following subretinal AAV-mediated gene delivery in dogs. PLoS ONE. 2013;8:e60218.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Donati S, Caprani SM, Airaghi G, Vinciguerra R, Bartalena L, Testa F, et al. Vitreous substitutes: the present and the future. Biomed Res Int. 2014;2014:351804.

    PubMed  PubMed Central  Google Scholar 

  67. Dureau P, Bonnel S, Menasche M, Dufier JL, Abitbol M. Quantitative analysis of intravitreal injections in the rat. Curr Eye Res. 2001;22(Jan):74–7.

    CAS  PubMed  Google Scholar 

  68. Tian J, Liu J, Liu X, Xiao Y, Tang L. Intravitreal infusion: a novel approach for intraocular drug delivery. Sci Rep. 2016;6:37676.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Takahashi K, Igarashi T, Miyake K, Kobayashi M, Yaguchi C, Iijima O. Improved Intravitreal AAV-Mediated Inner Retinal Gene Transduction after Surgical Internal Limiting Membrane Peeling in Cynomolgus Monkeys. Mol Ther. 2017;25:296–302.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Boye SL, Bennett A, Scalabrino ML, McCullough KT, Van Vliet K, Choudhury S, et al. Impact of Heparan Sulfate Binding on Transduction of Retina by Recombinant Adeno-Associated Virus Vectors. J Virol. 2016;90:4215–31.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Jose Nilson dos Santos, Daianne Neves Mandarino Torres, Jose Francisco Tiburcio, and Gildo Brito de Souza at Universidade Federal do Rio de Janeiro for technical support. This study was financed in part by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001". Financial support also included grants to Dr. Linden and Dr. Petrs-Silva by Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). This work was also partially supported by an unrestricted grant to the Department of Ophthalmology at the University of Florida by the Research to Prevent Blindness (RPB; New York).

Author information

Authors and Affiliations

  1. Laboratorio de Neurogenese, Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

    Mariana S. Dias, Victor G. Araujo, Taliane Vasconcelos, Rafael Linden & Hilda Petrs-Silva

  2. Department of Ophthalmology, University of Florida, Gainesville, FL, USA

    Qiuhong Li & William W. Hauswirth

Authors
  1. Mariana S. Dias
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Victor G. Araujo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Taliane Vasconcelos
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qiuhong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. William W. Hauswirth
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rafael Linden
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hilda Petrs-Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Mariana S. Dias or Hilda Petrs-Silva.

Ethics declarations

Conflict of interest

WWH and the University of Florida have a financial interest in the use of AAV therapies, and WWH is a consultant for and owns equity in a company (AGTC Inc.) that might, in the future, commercialize some aspects of this work. The other authors declare no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dias, M.S., Araujo, V.G., Vasconcelos, T. et al. Retina transduction by rAAV2 after intravitreal injection: comparison between mouse and rat. Gene Ther 26, 479–490 (2019). https://doi.org/10.1038/s41434-019-0100-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41434-019-0100-9

This article is cited by

Search

Advanced search

Quick links