Abstract
Purpose There has been recent interest in the potential use of gene therapy techniques to treat ocular disease. In this article, we consider the optic nerve diseases that are potentially most amenable to gene therapy.
Methods We discuss the recent success of gene transfer experiments in animal models of glaucoma, optic neuritis, Leber's hereditary optic neuropathy (LHON), and optic nerve transection, and we assess the possibility of using similar techniques to treat human disease in the future.
Results We have achieved highly efficient transfection of retinal ganglion cells in a rat model of glaucoma following a single intravitreal injection of adeno-associated virus (AAV). In our model, we have found that AAV-mediated gene therapy with brain-derived neurotrophic factor has a significant neuroprotective effect compared to saline or control virus injections. Guy and co-workers have successfully used AAV-mediated gene therapy to replace the defective mitochondrial enzyme subunit in cells derived from human patients with LHON. Gene therapy techniques have also shown promise in animal models of optic neuritis and optic nerve trauma.
Conclusions Human diseases with single-gene defects such as LHON may soon be treated successfully by gene therapy, assuming that vectors continue to improve and are well tolerated in the human eye. Other optic nerve diseases such as glaucoma that do not have a single-gene defect may also benefit from gene therapy to enhance RGC survival. In all cases, the risks of treatment will need to be balanced against the potential benefits.
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References
Knowles MR, Hohneker KW, Zhou Z, Olsen JC, Noah TL, Hu PC et al. A controlled study of adenoviral-vector-mediated gene transfer in the nasal epithelium of patients with cystic fibrosis. N Engl J Med 1995; 333(13): 823–831.
West J, Rodman DM . Gene therapy for pulmonary diseases. Chest 2001; 119(2): 613–617.
Griesenbach U, Ferrari S, Geddes DM, Alton EW . Gene therapy progress and prospects: cystic fibrosis. Gene Therapy 2002; 9(20): 1344–1350.
Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G, Gross F, Yvon E, Nusbaum P et al. Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science 2000; 288(5466): 669–672.
Hacein-Bey-Abina S, Le Deist F, Carlier F, Bouneaud C, Hue C, De Villartay JP et al. Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy. N Engl J Med 2002; 346(16): 1185–1193.
Hacein-Bey-Abina S, von Kalle C, Schmidt M, Le Deist F, Wulffraat N, McIntyre E et al. A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N Engl J Med 2003; 348(3): 255–256.
Kohn DB, Sadelain M, Glorioso JC . Occurrence of leukaemia following gene therapy of X-linked SCID. Nat Rev Cancer 2003; 3(7): 477–488.
Chtarto A, Bender HU, Hanemann CO, Kemp T, Lehtonen E, Levivier M et al. Tetracycline-inducible transgene expression mediated by a single AAV vector. Gene Therapy 2003; 10(1): 84–94.
Kafri T, van Praag H, Gage FH, Verma IM . Lentiviral vectors: regulated gene expression. Mol Ther 2000; 1(6): 516–521.
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(5): 591–594.
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(13): 6916–6921.
Jomary C, Vincent KA, Grist J, Neal MJ, Jones SE . Rescue of photoreceptor function by AAV-mediated gene transfer in a mouse model of inherited retinal degeneration. Gene Therapy 1997; 4(7): 683–690.
Lai YK, Rakoczy P, Constable I, Rolling F . Adeno-associated virus-mediated gene transfer into human retinal pigment epithelium cells. Aust N Z J Ophthalmol 1998; 26(Suppl 1): S77–S79.
Grant CA, Ponnazhagan S, Wang XS, Srivastava A, Li T . Evaluation of recombinant adeno-associated virus as a gene transfer vector for the retina. Curr Eye Res 1997; 16(9): 949–956.
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(2): 241–248.
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(1): 81–86.
Guy J, Qi X, Muzyczka N, Hauswirth WW . Reporter expression persists 1 year after adeno-associated virus-mediated gene transfer to the optic nerve. Arch Ophthalmol 1999; 117(7): 929–937.
Martin KR, Klein RL, Levkovitch-Verbin H, Valenta D, Baumrind LA, Pease ME et al. High efficiency transfection of rat retinal ganglion cells by a modified adeno-associated virus incorporating the woodchuck hepatitis post-transcriptional regulatory element. Invest Ophthalmol Vis Sci (ARVO Abstract) 2002.
Martin KR, Klein RL, Quigley HA . Gene delivery to the eye using adeno-associated viral vectors. Methods 2002; 28(2): 267–275.
Nakai H, Montini E, Fuess S, Storm TA, Grompe M, Kay MA . AAV serotype 2 vectors preferentially integrate into active genes in mice. Nat Genet 2003; 34(3): 297–302.
Dong JY, Fan PD, Frizzell RA . Quantitative analysis of the packaging capacity of recombinant adeno-associated virus. Hum Gene Ther 1996; 7(17): 2101–2112.
Hermonat PL, Quirk JG, Bishop BM, Han L . The packaging capacity of adeno-associated virus (AAV) and the potential for wild-type-plus AAV gene therapy vectors. FEBS Lett 1997; 407(1): 78–84.
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(11): 3622–3633.
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(5): 461–472.
Sarra GM, Stephens C, de Alwis M, Bainbridge JW, Smith AJ, Thrasher AJ et al. Gene replacement therapy in the retinal degeneration slow (rds) mouse: the effect on retinal degeneration following partial transduction of the retina. Hum Mol Genet 2001; 10(21): 2353–2361.
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(3): 306–310.
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(1): 92–95.
Chinnery PF, Johnson MA, Wardell TM, Singh-Kler R, Hayes C, Brown DT et al. The epidemiology of pathogenic mitochondrial DNA mutations. Ann Neurol 2000; 48(2): 188–193.
Guy J, Qi X, Pallotti F, Schon EA, Manfredi G, Carelli V et al. Rescue of a mitochondrial deficiency causing Leber Hereditary Optic Neuropathy. Ann Neurol 2002; 52(5): 534–542.
Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM et al. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 1988; 242(4884): 1427–1430.
Quigley HA . Number of people with glaucoma worldwide. Br J Ophthalmol 1996; 80(5): 389–393.
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 USA 1994; 91(5): 1632–1636.
Takano M, Horie H, Iijima Y, Dezawa M, Sawada H, Ishikawa Y . Brain-derived neurotrophic factor enhances neurite regeneration from retinal ganglion cells in aged human retina in vitro. Exp Eye Res 2002; 74(2): 319–323.
Watanabe M, Sawai H, Fukuda Y . Survival of axotomized retinal ganglion cells in adult mammals. Clin Neurosci 1997; 4(5): 233–239.
Pease ME, McKinnon SJ, Quigley HA, Kerrigan-Baumrind LA, Zack DJ . Obstructed axonal transport of BDNF and its receptor TrkB in experimental glaucoma. Invest Ophthalmol Vis Sci 2000; 41(3): 764–774.
Ko ML, Hu DN, Ritch R, Sharma SC, Chen CF . Patterns of retinal ganglion cell survival after brain-derived neurotrophic factor administration in hypertensive eyes of rats. Neurosci Lett 2001; 305(2): 139–142.
Ko ML, Hu DN, Ritch R, Sharma SC . The combined effect of brain-derived neurotrophic factor and a free radical scavenger in experimental glaucoma. Invest Ophthalmol Vis Sci 2000; 41(10): 2967–2971.
Martin K, Quigley H, DJZack, Levkovitch-Verbin H, Kielczewski J, Valenta D et al. Gene therapy with brain-derived neurotrophic factors as a protection for retinal ganglion cells in a rat model of glaucoma. Invest Ophthalmol Vis Sci 2003 (in press).
McKinnon SJ, Lehman DM, Tahzib NG, Ransom NL, Reitsamer HA, Liston P et al. Baculoviral IAP repeat-containing-4 protects optic nerve axons in a rat glaucoma model. Mol Ther 2002; 5(6): 780–787.
The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration. The AGIS Investigators. Am J Ophthalmol 2000; 130(4): 429–440.
Heijl A, Leske MC, Bengtsson B, Hyman L, Hussein M . Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol 2002; 120(10): 1268–1279.
The Collaborative Normal-Tension Glaucoma Study Group. Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures. Collaborative Normal-Tension Glaucoma Study Group [see comments] [published erratum appears in Am J Ophthalmol 1999; 127(1):120]. Am J Ophthalmol 1998; 126(4): 487–497.
Anand V, Chirmule N, Fersh M, Maguire AM, Bennett J . Additional transduction events after subretinal readministration of recombinant adeno-associated virus. Hum Gene Ther 2000; 11(3): 449–457.
Guy J, Qi X, Wang H, Hauswirth WW . Adenoviral gene therapy with catalase suppresses experimental optic neuritis. Arch Ophthalmol 1999; 117(11): 1533–1539.
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(10): 3977–3986.
Shen S, Wiemelt AP, McMorris FA, Barres BA . Retinal ganglion cells lose trophic responsiveness after axotomy. Neuron 1999; 23(2): 285–295.
Straten G, Schmeer C, Kretz A, Gerhardt E, Kugler S, Schulz JB et al. Potential synergistic protection of retinal ganglion cells from axotomy-induced apoptosis by adenoviral administration of glial cell line-derived neurotrophic factor and X-chromosome-linked inhibitor of apoptosis. Neurobiol Dis 2002; 11(1): 123–133.
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Financial support: The TFC Frost Trust, University College Oxford, NEI EY02120.
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Martin, K., Quigley, H. Gene therapy for optic nerve disease. Eye 18, 1049–1055 (2004). https://doi.org/10.1038/sj.eye.6701579
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DOI: https://doi.org/10.1038/sj.eye.6701579
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