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AAV-mediated expression of CNTF promotes long-term survival and regeneration of adult rat retinal ganglion cells

Abstract

We compared the effects of intravitreal injection of bi-cistronic adeno-associated viral (AAV-2) vectors encoding enhanced green fluorescent protein (GFP) and either ciliary neurotrophic factor (CNTF), brain-derived neurotrophic factor (BDNF) or growth-associated protein-43 (GAP43) on adult retinal ganglion cell (RGC) survival and regeneration following (i) optic nerve (ON) crush or (ii) after ON cut and attachment of a peripheral nerve (PN). At 7 weeks after ON crush, quantification of βIII-tubulin immunostaining revealed that, compared to AAV-GFP controls, RGC survival was not enhanced by AAV-GAP43-GFP but was increased in AAV-CNTF-GFP (mean RGCs/retina: 17 450±358 s.e.m.) and AAV-BDNF-GFP injected eyes (10 200±4064 RGCs/retina). Consistent with increased RGC viability in AAV-CNTF-GFP and AAV-BDNF-GFP injected eyes, these animals possessed many βIII-tubulin- and GFP-positive fibres proximal to the ON crush. However, only in the AAV-CNTF-GFP group were regenerating RGC axons seen in distal ON (1135±367 axons/nerve, 0.5 mm post-crush), some reaching the optic chiasm. RGCs were immunoreactive for CNTF and quantitative RT-PCR revealed a substantial increase in CNTF mRNA expression in retinas transduced with AAV-CNTF-GFP. The combination of AAV-CNTF-GFP transduction of RGCs with autologous PN-ON transplantation resulted in even greater RGC survival and regeneration. At 7 weeks after PN transplantation there were 27 954 (±2833) surviving RGCs/retina, about 25% of the adult RGC population. Of these, 13 352 (±1868) RGCs/retina were retrogradely labelled after fluorogold injections into PN grafts. In summary, AAV-mediated expression of CNTF promotes long-term survival and regeneration of injured adult RGCs, effects that are substantially enhanced by combining gene and cell-based therapies/interventions.

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References

  1. Berkelaar M, Clarke DB, Wang YC, Bray GM, Aguayo AJ . Axotomy results in delayed death and apoptosis of retinal ganglion cells in adult rats. J Neurosci 1994; 14: 4368–4374.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. Jo SA, Wang E, Benowitz LI . Ciliary neurotrophic factor is an axogenesis factor for retinal ganglion cells. Neuroscience 1999; 89: 579–591.

    CAS  PubMed  Article  Google Scholar 

  3. Cui Q, Lu Q, So KF, Yip HK . CNTF, not other trophic factors, promotes axonal regeneration of axotomized retinal ganglion cells in adult hamsters. Invest Ophthalmol Vis Sci 1999; 40: 760–766.

    CAS  PubMed  Google Scholar 

  4. Cui Q, Harvey AR . CNTF promotes the regrowth of retinal ganglion cell axons into murine peripheral nerve grafts. Neuroreport 2000; 11: 3999–4002.

    CAS  PubMed  Google Scholar 

  5. Cui Q, Yip HK, Zhao RC, So KF, Harvey AR . Intraocular elevation of cyclic AMP potentiates ciliary neurotrophic factor-induced regeneration of adult rat retinal ganglion cell axons. Mol Cell Neurosci 2003; 22: 49–61.

    CAS  PubMed  Article  Google Scholar 

  6. Mey J, Thanos S . Intravitreal injections of neurotrophic factors support the survival of axotomized retinal ganglion cells in adult rats in vivo. Brain Res 1993; 602: 304–317.

    CAS  Article  PubMed  Google Scholar 

  7. Mansour-Robaey S, Clarke DB, Wang YC, Bray GM, Aguayo AJ . Effects of ocular injury and administration of brain-derived neurotrophic factor on survival and regrowth of axotomized retinal ganglion cells. Proc Natl Acad Sci 1994; 91: 1632–1636.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  8. Di Polo A, 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 1998; 95: 3978–3983.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  9. Klöcker N, Jung M, Stuermer CA, Bähr M . BDNF increases the number of axotomized rat retinal ganglion cells expressing GAP-43, L1, and TAG-1 mRNA – a supportive role for nitric oxide? Neurobiol Dis 2001; 8: 101–113.

    Article  Google Scholar 

  10. Peinado-Ramon P, Salvador M, Villegas-Perez MP, Vidal-Sanz M . Effects of axotomy and intraocular administration of NT-4, NT-3, and brain-derived neurotrophic factor on the survival of adult rat retinal ganglion cells. A quantitative in vivo study. Invest Ophthalmol Vis Sci 1996; 37: 489–500.

    CAS  PubMed  Google Scholar 

  11. Meyer-Franke A, Wilkinson GA, Kruttgen A, Hu M, Munro E, Hanson Jr MG et al. Depolarization and cAMP elevation rapidly recruit TrkB to the plasma membrane of CNS neurons. Neuron 1998; 21: 681–693.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. Spalding KL, Cui Q, Harvey AR . Retinal ganglion cell neurotrophin receptor levels and trophic requirements following target ablation in the neonatal rat. Neuroscience 2005; 131: 387–395.

    CAS  PubMed  Article  Google Scholar 

  13. Frank L, Weigand S, Siuciak JA, Lindsay RM, Rudge JS . Effects of BDNF infusion on the regulation of the TrkB protein and message in adult rat brain. Exp Neurol 1997; 145: 62–70.

    CAS  Article  PubMed  Google Scholar 

  14. Fischer D, Pavlidis M, Thanos S . Cataractogenic lens injury prevents traumatic ganglion cell death and promotes axonal regeneration both in vivo and in culture. Invest Ophthalmol Vis Sci 2000; 41: 3943–3954.

    CAS  PubMed  Google Scholar 

  15. Leon S, Yin Y, Nguyen J, Irwin N, Benowitz LI . Lens injury stimulates axon regeneration in the mature rat optic nerve. J Neurosci 2000; 20: 4615–4626.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  16. Yin Y, Cui Q, Li Y, Irwin N, Fischer D, Harvey AR et al. Macrophage-derived factors stimulate optic nerve regeneration. J Neurosci 2003; 23: 2284–2293.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  17. Monsul NT, Geisendorfer AR, Han PJ, Banik R, Pease ME, Skolasky Jr RL et al. Intraocular injection of dibutyryl cyclic AMP promotes axon regeneration in rat optic nerve. Exp Neurol 2004; 186: 124–133.

    CAS  PubMed  Article  Google Scholar 

  18. Cui Q, Cho KS, So KF, Yip HK . Synergistic effect of Nogo-neutralizing antibody IN-1 and ciliary neurotrophic factor on axonal regeneration in adult rodent visual systems. J Neurotrauma 2004; 21: 617–625.

    PubMed  Article  Google Scholar 

  19. Fischer D, Petkova V, Thanos S, Benowitz LI . Switching mature retinal ganglion cells to a robust growth state in vivo: gene expression and synergy with RhoA inactivation. J Neurosci 2004; 24: 8726–8740.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  20. Fischer D, He Z, Benowitz LI . Counteracting the Nogo receptor enhances optic nerve regeneration if retinal ganglion cells are in an active growth state. J Neurosci 2004; 24: 1646–1651.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  21. Bertrand J, Winton MJ, Rodriguez-Hernandez N, Campenott RB, McKerracher L . Application of rho antagonist to neuronal cell bodies promotes neurite growth in compartmented cultures and regeneration of retinal ganglion cell axons in the optic nerve of adult rats. J Neurosci 2005; 25: 1113–1121.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  22. Bähr M . Live or let die – retinal ganglion cell death and survival during development and in the lesioned adult CNS. Trends Neurosci 2000; 23: 483–490.

    PubMed  Article  Google Scholar 

  23. Doster SK, Lozano AM, Aguayo AJ, Willard MB . Expression of the growth-associated protein GAP-43 in adult rat retinal ganglion cells following axon injury. Neuron 1991; 6: 635–647.

    CAS  PubMed  Article  Google Scholar 

  24. Reh TA, Tetzlaff W, Ertlmaier A, Zwiers H . Developmental study of the expression of B50/GAP-43 in rat retina. J Neurobiol 1993; 24: 949–958.

    CAS  PubMed  Article  Google Scholar 

  25. Aigen L, Arber S, Kapfhammer JP, Laux T, Schneider C, Botteri F et al. Overexpression of the neural growth-associated protein GAP-43 induces nerve sprouting in the adult nervous system of transgenic mice. Cell 1995; 83: 269–278.

    Article  Google Scholar 

  26. Holtmaat AJGD, Dijkhuizen PA, Oestreicher AB, Romijn HJ, Van der Lugt NMT, Berns A et al. Directed expression of the growth-associated protein B-50/GAP-43 to olfactory neurons in transgenic mice results in changes in axon morphology and extraglomerular fiber growth. J Neurosci 1995; 15: 7953–7965.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  27. Ali RR . Restoration of photoreceptor ultrastructure and function in retinal degeneration slow mice by gene therapy. Nat Gen 2000; 25: 306–310.

    CAS  Article  Google Scholar 

  28. Surace EM, Auricchio A . Adeno-associated viral vectors for retinal gene transfer. Prog Retin Eye Res 2003; 22: 705–719.

    CAS  Article  PubMed  Google Scholar 

  29. Dinculescu A, Glushakova L, Min SH, Hauswirth WW . Adeno-associated virus-vectored gene therapy for retinal disease. Hum Gene Ther 2005; 16: 649–663.

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  31. Sapieha PS, Peltier M, Rendahl KG, Manning WC, Di Polo A . 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.

    CAS  PubMed  Article  Google Scholar 

  32. Schuettauf F, Vorwerk C, Naskar R, Orlin A, Quinto K, Zurakowski D et al. Adeno-associated viruses containing bFGF or BDNF are neuroprotective against excitotoxicity. Curr Eye Res 2004; 29: 379–386.

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  34. Michel U, Malik I, Ebert S, Bähr M, Kugler S . Long-term in vivo and in vitro AAV-2-mediated RNA interference in rat retinal ganglion cells and cultured primary neurons. Biochem Biophys Res Commun 2005; 326: 307–312.

    CAS  PubMed  Article  Google Scholar 

  35. Zhou Y, Pernet V, Hauswirth WW, Di Polo A . Activation of the extracellular signal-regulated kinase 1/2 pathway by AAV gene transfer protects retinal ganglion cells in glaucoma. Mol Ther 2005; 12: 402–412.

    CAS  PubMed  Article  Google Scholar 

  36. Koprivica V, Cho KS, Park JB, Yiu G, Atwal J, Gore B et al. EGFR activation mediates inhibition of axon regeneration by myelin and chondroitin sulfate proteoglycans. Science 2005; 310: 106–110.

    CAS  PubMed  Article  Google Scholar 

  37. Sefton AJ, Dreher B, Harvey AR . Visual system. In: Paxinos G (ed). The Rat Nervous System, 3rd edn, Academic Press: San Diego, 2004,pp 1083–1165.

    Chapter  Google Scholar 

  38. 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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. Mizuguchi H, Xu Z, Ishii-Watabe A, Uchida E, Hayakawa T . IRES-dependent second gene expression is significantly lower than cap-dependent first gene expression in a bicistronic vector. Mol Ther 2000; 1: 376–382.

    CAS  Article  PubMed  Google Scholar 

  40. Liang FQ, Dejneka NS, Cohen DR, Krasnoperova NV, Lem J, Maguire AM et al. AAV-mediated delivery of ciliary neurotrophic factor prolongs photoreceptor survival in the rhodopsin knockout mouse. Mol Ther 2001; 3: 241–248.

    CAS  PubMed  Article  Google Scholar 

  41. Fischer KJ, Gao G, Weitzman MD, DeMatteo R, Burda JF, Wilson JM . Transduction with recombinant adeno-associated virus for gene therapy is limited by leading-strand synthesis. J Virol 1996; 70: 520–532.

    Google Scholar 

  42. Hermens WT, Verhaagen J . Viral vectors, tools for gene transfer in the nervous system. Prog Neurobiol 1998; 55: 399–432.

    CAS  Article  PubMed  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  44. Harvey AR, Kamphuis W, Eggers R, Symons NA, Blits B, Niclou SP et al. Intravitreal injection of adeno-associated viral vectors results in the transduction of different types of retinal neurons in neonatal and adult rats: a comparison with lentiviral vectors. Mol Cell Neurosci 2002; 21: 141–157.

    CAS  PubMed  Article  Google Scholar 

  45. Cho EY, So K-F . Rate of regrowth of damaged retinal ganglion cell axons regenerating in a peripheral nerve graft in adult hamsters. Brain Res 1987; 419: 369–374.

    CAS  PubMed  Article  Google Scholar 

  46. Sawai H, Clarke DB, Littlerova P, Bray GM, Aguayo AJ . Brain-derived neurotrophic factor and neurotrophin-4/5 stimulate growth of axonal branches from regenerating retinal ganglion cells. J Neurosci 1996; 16: 3887–3894.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  47. Cui Q, Pollett MA, Symons NA, Plant GW, Harvey AR . A new approach to CNS repair using chimeric peripheral nerve grafts. J Neurotrauma 2003; 20: 17–31.

    CAS  PubMed  Article  Google Scholar 

  48. Hu Y, Leaver SG, Plant GW, Hendricks WTJ, Niclou SP, Verhaagen J et al. Lentiviral-mediated transfer of CNTF to Schwann cells within reconstructed peripheral nerve grafts enhances adult retinal ganglion cell survival and axonal regeneration. Mol Ther 2005; 11: 906–915.

    CAS  PubMed  Article  Google Scholar 

  49. Al-Bader MD, Al-Sarraf HA . Housekeeping gene expression during fetal brain development in the rat-validation by semi-quantitative RT-PCR. Dev Brain Res 2005; 156: 38–45.

    Article  Google Scholar 

  50. Danias J, Shen F, Goldblum D, Chen B, Ramos-Esteban J, Podos SM et al. Cytoarchitecture of the retinal ganglion cells in the rat. Invest Ophthalmol Vis Sci 2002; 43: 587–594.

    PubMed  Google Scholar 

  51. Thanos S . Neurobiology of the regenerating retina and its functional reconnection with the brains by means of peripheral nerve transplants in adult rats. Surv Ophthalmol 1997; 42: S5–S26.

    PubMed  Article  Google Scholar 

  52. Weise J, Isenmann S, Klöcker N, Kugler S, Hirsch S, Gravel C et al. Adenovirus-mediated expression of ciliary neurotrophic factor (CNTF) rescues axotomized rat retinal ganglion cells but does not support axonal regeneration in vivo. Neurobiol Dis 2000; 7: 212–223.

    CAS  Article  PubMed  Google Scholar 

  53. van Adel BA, Kostic C, Deglon N, Ball AK, Arsenijevic Y . Delivery of ciliary neurotrophic factor via lentiviral-mediated transfer protects axotomized retinal ganglion cells for an extended period of time. Hum Gene Ther 2003; 14: 103–115.

    CAS  Article  PubMed  Google Scholar 

  54. van Adel BA, Arnold JM, Phipps J, Doering LC, Ball AK . Ciliary neurotrophic factor protects retinal ganglion cells from axotomy-induced apoptosis via modulation of retinal glia in vivo. J Neurobiol 2005; 63: 215–234.

    CAS  PubMed  Article  Google Scholar 

  55. Biffo S, Verhaagen J, Schrama LH, Schotman P, Danho W, Margolis FL . B-50/GAP43 expression correlates with process outgrowth in the embryonic mouse nervous system. Eur J Neurosci 1990; 2: 487–499.

    PubMed  Article  Google Scholar 

  56. Baumgartner BJ, Shine HD . Targeted transduction of CNS neurons with adenoviral vectors carrying neurotrophic factor genes confers neuroprotection that exceeds the transduced population. J Neurosci 1997; 17: 6504–6511.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  57. Martin KR, Quigley HA, Zack DJ, Levkovitch-Verbin H, Kielczewski J, Valenta D et al. Gene therapy with brain-derived neurotrophic factor as a protection: retinal ganglion cells in a rat glaucoma model. Invest Ophthalmol Vis Sci 2003; 44: 4357–4365.

    Article  PubMed  Google Scholar 

  58. Weibel D, Kreutzberg GW, Schwab ME . Brain-derived neurotrophic factor (BDNF) prevents lesion-induced axonal die-back in young rat optic nerve. Brain Res 1995; 679: 249–254.

    CAS  PubMed  Article  Google Scholar 

  59. Cohen-Cory S . BDNF modulates, but does not mediate, activity-dependent branching and remodeling of optic axon arbors in vivo. J Neurosci 1999; 19: 9996–10003.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  60. Buffo A, Holtmaat AJ, Savio T, Verbeek JS, Oberdick J, Oestreicher AB et al. Targeted overexpression of the neurite growth-associated protein B-50/GAP-43 in cerebellar Purkinje cells induces sprouting after axotomy but not axon regeneration into growth-permissive transplants. J Neurosci 1997; 17: 8778–8791.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  61. Park K, Luo JM, Hisheh S, Harvey AR, Cui Q . Cellular mechanisms associated with spontaneous and ciliary neurotrophic factor-cAMP-induced survival and axonal regeneration of adult retinal ganglion cells. J Neurosci 2004; 24: 10806–10815.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  62. Ip NY, Yancopoulos GD . The neurotrophins and CNTF: two families of collaborative neurotrophic factors. Annu Rev Neurosci 1996; 19: 491–515.

    CAS  PubMed  Article  Google Scholar 

  63. Wormald S, Hilton DJ . Inhibitors of cytokine signal transduction. J Biol Chem 2004; 279: 821–824.

    CAS  PubMed  Article  Google Scholar 

  64. Park K, Hisheh S, Turnley AM, Cui Q, Harvey AR . Suppressor of cytokine signaling (SOCS) mRNA expression in axotomized retina subjected to peripheral nerve graft and ciliary neurotrophic factor (CNTF). Proc Aus Neurosci Soc 2006; 17: 155.

    Google Scholar 

  65. Cayouette M, Behn D, Sendtner M, Lachapelle P, Gravel C . Intraocular gene transfer of ciliary neurotrophic factor prevents death and increases responsiveness of rod photoreceptors in the retinal degeneration slow mouse. J Neurosci 1998; 18: 9282–9293.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  66. 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.

    CAS  Article  PubMed  Google Scholar 

  67. Schlichtenbrede FC, MacNeil A, Bainbridge JW, Tschernutter M, Thrasher AJ, Smith AJ et al. 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 Therapy 2003; 10: 523–527.

    CAS  PubMed  Article  Google Scholar 

  68. Shen S, Wiemelt AP, McMorris FA, Barres BA . Retinal ganglion cells lose trophic responsiveness after axotomy. Neuron 1999; 23: 285–295.

    CAS  PubMed  Article  Google Scholar 

  69. Lu P, Yang H, Jones LL, Filbin MT, Tuszynski MH . Combinatorial therapy with neurotrophins and cAMP promotes axonal regeneration beyond sites of spinal cord injury. J Neurosci 2004; 24: 6402–6409.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. Klein RL, King MA, Hamby ME, Meyer EM . Dopaminergic cell loss induced by human A30P alpha-synuclein gene transfer to the rat substantia nigra. Hum Gene Ther 2002; 13: 605–612.

    CAS  Article  PubMed  Google Scholar 

  71. Ruitenberg M, Blits B, Dijkhuizen PA, te Beek ET, Bakker A, van Heerikhuize JJ et al. Adeno-associated viral vector-mediated gene transfer of brain-derived neurotrophic factor reverses atrophy of rubrospinal neurons following both acute and chronic spinal cord injury. Neurobiol Dis 2004; 15: 394–406.

    CAS  Article  PubMed  Google Scholar 

  72. Hermens WT, ter Brake O, Dijkhuizen PA, Sonnemans MA, Grimm D, Kleinschmidt JA et al. Purification of recombinant adeno-associated virus by iodixanol gradient ultracentrifugation allows rapid and reproducible preparation of vector stocks for gene transfer in the nervous system. Hum Gene Ther 1999; 10: 1885–1891.

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

This work was supported by NHMRC Grants (254507, 211924) to ARH and QC, the WA Neurotrauma Research Program, and an RD Wright NHMRC Fellowship to GWP. SGL received a UWA Postgraduate Award and further scholarship support from the Western Australian Institute for Medical Research. We thank Dr Kleinschmidt (Heidelberg) for the gift of the AAV helper plasmid pDG, and Dr Sendtner (Wurzburg) for the gift of the CNTF plasmid. Our thanks also to Erich Ehlert, William Hendricks and Simone Niclou (Netherlands Institute for Neuroscience) for technical support and assistance with plasmid cloning and viral production.

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Leaver, S., Cui, Q., Plant, G. et al. AAV-mediated expression of CNTF promotes long-term survival and regeneration of adult rat retinal ganglion cells. Gene Ther 13, 1328–1341 (2006). https://doi.org/10.1038/sj.gt.3302791

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Keywords

  • BDNF
  • growth associated proteins
  • optic nerve crush
  • peripheral nerve graft

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