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BA van Adel, C Kostic, N Déglon, AK Ball, Y Arsenijevic; Lentiviral-mediated Transfer of Ciliary Neurotrophic Factor Rescues Axotomized Retinal Ganglion Cells . Invest. Ophthalmol. Vis. Sci. 2002;43(13):1993.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Ciliary neurotrophic factor (CNTF) has recently been demonstrated to be one of the most promising trophic factors to improve both the survival and regeneration of injured RGCs (Weise et al., 2000). Adenoviral-mediated transfer of CNTF has been shown to dramatically increase the survival of axotomized RGCs 14 days post-injury (van Adel et al. 2000). However, the inability of adenoviral vectors to protect axotomized RGCs beyond 14 days is due to transient expression of the adenoviral vector transgene, and host immune responses. In comparison, lentiviral vectors have proven more efficient to deliver genes to the CNS and may hold more promise as a potential gene therapy approach to rescue injured RGCs. In this study, we used optic nerve transection as an in vivo animal model to test the efficacy of lentiviral-mediated gene transfer of ciliary neurotrophic factor (CNTF) to prevent RGC death at 21 days post-axotomy. Methods: The optic nerve was transected intraorbitally 2mm behind the eye, and RGCs were labeled by injecting Dextran-FITC into the proximal nerve ending. A replication-deficient, self-inactivating lentivirus encoding CNTF (PGK-CNTF) was injected intraocularly at the time of axotomy. For control experiments, no injection was made, or a control vector encoding for beta-galactosidase (PGK-lacZ), or PBS was injected into the eye. RGC densities were determined using confocal microscopy in flatmounts isolated from experimental and control groups surviving 14 and 21 days post-axotomy (dpa). Results: The percentage of surviving RGCs was drastically reduced after optic nerve transection to only 15 ± 2 and 8 ± 1 % at 14 and 21 dpa in untreated animals. In contrast, the percentage of surviving RGCs at 14 and 21 dpa in retinas treated with PGK-CNTF was 68 ± 6 and 31 ± 7 % respectively. This corresponded to a RGC rescue rate of 52 ± 5 and 25 ± 7 % at 14 and 21 dpa above control retinas treated with PGK-lacZ. This compares with a rescue rate of 18% above Ad.CNTF at 21 days post-axotomy. Conclusion: These results demonstrate that prolonged delivery of CNTF using lentiviral-mediated gene transfer to the retina is the most effective treatment in rescuing RGCs for an extended period of time. Therefore, continuous administration of CNTF could serve as a potential treatment for retinal disorders involving optic neuropathy and RGC injury such as in glaucoma.
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