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Kun Do Rhee, Dean Bok, Steven Nusinowitz, Kevin Chao, Xian-Jie Yang; CNTF-mediated Neuroprotection in a Mouse Model of Retinitis Pigmentosa Promotes Outer Segment Elongation and Requires Cytokine Receptor gp130 Initially in Müller Glial Cells. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1270.
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CNTF acts as a potent neural protective agent in a number of retinal degeneration models. Currently CNTF is used in clinical trials for age-related macular degeneration and retinitis pigmentosa. We have shown previously that in a mouse model of retinitis pigmentosa caused by a dominant mutation (P216L) in rds/peripherin, constitutive expression of CNTF by rAAV delays photoreceptor cell death, but alters retinal transcription profiles and suppresses the ERG. In this study, we examine the mechanism of CNTF-mediated neuroprotection.
A lentiviral vector (LV-hCNTF) was constructed to express the same secreted CNTF used in clinical trials. Subretinal delivery of LV-hCNTF was performed in rds mice at postnatal day 25. Deletions of cytokine receptor gp130 were carried out using Cre driver lines expressing the recombinase in Müller cells or rod photoreceptors. Morphological analyses, IHC, Western blot, ELISA, and ERG were used to characterize effects of LV-hCNTF in rds and gp130 conditional mutant retinas.
Subretinal delivery of LV-hCNTF results in expression of CNTF from the RPE. LV-hCNTF effectively preserves the ONL of rds without suppression of the ERG. In addition, CNTF improves the morphology and promotes elongation of the OS. ELISA indicates that the dosages of LV-hCNTF expression in vivo corresponded to the lower dose ranges used in human trials. Mice that lack gp130 in Müller glia show significantly reduced neuroprotection of photoreceptors by CNTF. Moreover, CNTF-triggered downstream signalling events were severely attenuated in the gp130 Müller mutant both in Müller glia and photoreceptor cells. Mice that lack gp130 in rod photoreceptors also show reduced neuroprotection, accompanied by diminished cytokine signalling only in the rod photoreceptors without affecting signalling in the rest of the retina.
These results indicate that neuroprotection by CNTF in the rds mutant is indirect. Exogenous CNTF initially activates Jak-STAT and ERK signalling in Müller glia, which subsequently secret cytokines that act upon photoreceptors through gp130 to promote photoreceptor survival. Results of these studies provide cellular mechanisms for CNTF-mediated neuroprotection in diseased neural retinas and suggest that low dosage of CNTF treatment could have therapeutic benefits.
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