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L. Zhao, Y. Song, Y. Liu, A.M. Laties, R. Wen; Long-term Rescue of Photoreceptors by Oncostatin M in Transgenic Rats with Rhodopsin Mutation S334ter . Invest. Ophthalmol. Vis. Sci. 2003;44(13):2846.
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Purpose: Oncostatin M (OSM) is a member of the IL-6 family of cytokines. It shares the receptor complex of LIFR/gp130 with other members of the family, including LIF, CNTF, and CT-1. In addition, it has its own high affinity receptor OSMR which forms an OSMR/gp130 receptor complex not shared by other members. We report here that repeated intravitreal injection of recombinant human OSM resulted in long-term rescue of photoreceptors in a line of transgenic rats (S334ter-3 rats) carrying a murine rhodopsin mutation S334ter. Methods: The cDNA encoding mature human OSM (aa 26-220) was PCR cloned and expressed in E. coli. Recombinant protein was purified on Ni+ columns under native conditions. Heterozygous S334ter-3 rats were used in all experiments. The left eye was injected with 2 µg of OSM protein (in 2 µl PBS) intravitreally every four days starting at PD9. The right eye was injected with 2 µl of PBS in the same fashion. Eyes were collected at PD20 or 50 and retinas were examined histologically to evaluate photoreceptor survival. For immunoblot analysis, retinas were collected 0.5, 1, 2, 6, 12, 24, and 48 hours after a single intravitreal injection of 2 µg of OSM protein (in 2 µl PBS) at PD9. Total protein from each retina was subjected to SDS-PAGE. Phosphorylated STAT3 was detected using phospho-STAT3 specific antibodies. Results: In untreated animals most photoreceptors die from PD8 through PD20. The peak of photoreceptor death occurs on PD11 and 12. In PBS injected control eyes at PD20, only one row of nuclei in the ONL in the superior retina and 1-2 rows in the inferior retina remain, similar to the untreated eye. In OSM treated eyes at PD20, there are 7-8 rows of nuclei in the ONL in both the superior and inferior retina. At PD50, the PBS injected eyes have 0-1 row of photoreceptor nuclei in the entire retina. The OSM treated eyes still retain 3-5 rows of nuclei in both the superior and inferior retina. Immunoblot analysis shows a remarkable increase in STAT3 phosphorylation after a single injection of OSM at PD9. Conclusions: Long-term rescue of photoreceptors is achieved by repeated intravitreal injection of recombinant human OSM protein. These results provide evidence that long-term rescue is achievable by sustained delivery of cytokines like OSM.
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