Abstract
Gene transfer provides an exciting new approach for the treatment of retinal and choroidal diseases. Two areas of concern are the potential for vector-related toxicity and uncertainties associated with prolonged transgene expression. One way to address these concerns for transfer of genes encoding secreted proteins is to transduce cells on the outside of the eye, provided the gene product can gain access to the eye and have the desired effect. In this study, we investigated the feasibility of this approach. Periocular injection of an adenoviral vector encoding β-galactosidase (AdLacZ.10) resulted in LacZ-stained cells throughout the orbit and around the eye. Compared to periocular injection of 5 × 109 particles of control vector, periocular injection of 5 × 109 or 1 × 109 particles of an adenoviral vector expressing pigment epithelium-derived factor (PEDF) regulated by a CMV promoter (AdPEDF.11) resulted in significantly elevated intraocular levels of PEDF and suppression of choroidal neovascularization. Periocularly injected recombinant PEDF was also found to diffuse through the sclera into the eye. Although similar experiments are needed in an animal with a human-sized eye, these data suggest that periocular gene transfer deserves consideration for the treatment of choroidal diseases.
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References
Bennett J et al. Photoreceptor cell rescue in retinal degeneration (rd) mice by in vivo gene therapy. Nat Med 1996; 2: 649–654.
Kumar-Singh R, Farber DB . Encapsidated adenovirus mini-chromosome-mediated delivery of genes to the reina: application to the rescue of photoreceptor degeneration. Hum Mol Genet 1998; 7: 1893–1900.
Takahashi M, Miyoshi H, Verma IM, Gage FH . Rescue from photoreceptor degeneration in the rd mouse by human immunodeficiency virus vector-mediated gene transfer. J Virol 1999; 73: 7812–7816.
Acland GM et al. Gene therapy restores vision in a canine model of childhood blindness. Nat Genet 2001; 28: 92–95.
Cayouette M, Gravel C . Adenovirus-mediated gene transfer of ciliary neurotrophic factor can prevent photoreceptor degeneration in the retinal degeneration (rd) mouse. Hum Gene Ther 1997; 8: 423–430.
Cayouette M et al. 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.
Fong-Qi L 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.
Lau D et al. Retinal degeneration is slowed in transgenic rats by AAV-mediated delivery of FGF-2. Invest Ophthalmol Vis Sci 2000; 41: 3622–3633.
Mori K et al. Inhibition of choroidal neovascularization by intravenous injection of adenoviral vectors expressing secretable endostatin. Am J Pathol 2001; 159: 313–320.
Mori K et al. Pigment epithelium-derived factor inhibits retinal and choroidal neovascularization. J Cell Physiol 2001; 188: 253–263.
Lai C-C et al. Suppression of choroidal neovascularization by adeno-associated virus vector expressing angiostatin. Invest Ophthalmol Vis Sci 2001; 42: 2401–2407.
Honda M et al. Experimental subretinal neovascularization is inhibited by adenovirus-mediated soluble VEGF.flt-1 receptor gene transfection: a role of VEGF and possible treatment for SRN in age-related macular degeneration. Gene Ther 2000; 7: 978–985.
Lai C-M et al. Inhibition of angiogenesis by adenovirus-mediated sFlt-1 expression in a rat model of corneal neovascularization. Human Gene Ther 2001; 12: 1299–1310.
Bainbridge J et al. Inhibition of retinal neovascularization by gene transfer of soluble VEGF receptor sFlt-1. Gene Ther 2002; 9: 320–326.
Rakoczy PE et al. Recombinant adenovirus-mediated gene delivery into the rat retinal pigment epithelium in vivo. Austr NZ J Ophthalmol 1998; 26: S56–S58.
Anglade E, Csaky KG . Recombinant adenovirus-mediated gene transfer into the adult rat retina. Curr Eye Res 1998; 17: 316–321.
Mori K et al. Intraocular adenoviral vector-mediated gene transfer is increased in proliferative retinopathies. Invest Ophthalmol Vis Sci 2002; 43: 1610–1615.
Flannery JG et al. Efficient photoreceptor-targeted gene expression in vivo by recombinant adeno-associated virus. Proc Natl Acad Sci USA 1997; 94: 6916–6921.
Bennett J, Duan D, Engelhardt JF, Maguire AM . Real-time, noninvasive in vivo assessment of adeno-associated virus-mediated retinal transduction. Invest Ophthalmol Vis Sci 1997; 38: 2857–2863.
Ali RR et al. Adeno-associated virus gene transfer to mouse retina. Hum Gene Ther 1998; 9: 81–86.
Bennett J et al. Stable transgene expression in rod photoreceptors after recombinant adeno-associated virus-mediated gene transfer to monkey retina. Proc Natl Acad Sci USA 1999; 96: 9920–9925.
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: 929–937.
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.
Olsson JE et al. Transgenic mice with a rhodopsin mutation (Pro23His): a mouse model of autosomal dominant retinitis pigmentosa. Neuron 1992; 9: 815–830.
Sarra GM 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: 2353–2361.
Brough DE et al. A gene transfer vector-cell line system for complete functional complementation of adenovirus early regions E1 and E4. J Virol 1996; 70: 6497–6501.
Duh EJ et al. Pigment epithelium-derived factor suppresses ischemia-induced retinal neovascularization and VEGF-induced migration and growth. Invest Ophthalmol Vis Sci 2002; 43: 821–829.
Tobe T et al. Targeted disruption of the FGF2 gene does not prevent choroidal neovascularization in a murine model. Am J Pathol 1998; 153: 1641–1646.
Edelman JL, Castro MR . Quantitative image analysis of laser-induced choroidal neovascularization in rat. Exp Eye Res 2000; 71: 523–533.
Tobe T et al. Evolution of neovascularization in mice with overexpression of vascular endothelial growth factor in photoreceptors. Invest Ophthalmol Vis Sci 1998; 39: 180–188.
Smith LEH et al. Oxygen-induced retinopathy in the mouse. Invest Ophthalmol Vis Sci 1994; 35: 101–111.
Ando A et al. Nitric oxide is proangiogenic in retina and choroid. J Cell Physiol 2001; 191: 116–124.
Rasmussen HS et al. Safety of intravitreal delivery of adenovirus in cynomolgus monkeys. Invest Ophthalmol Vis Sci (suppl) 2002: 43: 1289.
Ambati J et al. Transscleral delivery of bioactive protein to the choroid and retina. Invest Ophthalmol Vis Sci 2000; 41: 1186–1191.
Musch DC et al. Treatment of cytomegalovirus retinitis with a sustained-release ganciclovir implant. The Ganciclovir Impant Study Group. N Engl J Med 1997; 337: 83–90.
Ambati J et al. Diffusion of high molecular weight compounds through sclera. Invest Ophthalmol Vis Sci 2000; 41: 1181–1185.
Acknowledgements
Supported by grants from Michael Panitch, the National Eye Institute (EY05951, EY12609, K08EYB420, and core grant P30EY1765), the Juvenile Diabetes Foundation (PG), Knights Templar (PG and AD), Research to Prevent Blindness (a Lew R Wasserman Merit Award (PAC), a Career Development Award (EJD), and an unrestricted grant), the BMA John William Clark Award (AD), GenVec, Inc., the Ruth and Milton Steinbech Foundation, and Dr and Mrs William Lake. PAC is the George S and Dolores Dore Eccles Professor of Ophthalmology and Neuroscience.
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Gehlbach, P., Demetriades, A., Yamamoto, S. et al. Periocular injection of an adenoviral vector encoding pigment epithelium-derived factor inhibits choroidal neovascularization. Gene Ther 10, 637–646 (2003). https://doi.org/10.1038/sj.gt.3301931
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DOI: https://doi.org/10.1038/sj.gt.3301931
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