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Meredith S Gregory-Ksander, Andrew J Kocab, David N Zacks, Anitha krishnan; A small peptide inhibitor of the Fas receptor prevents axon degeneration and death of retinal ganglion cells in a microbead-induced mouse model of glaucoma.. Invest. Ophthalmol. Vis. Sci. 2018;59(9):6139.
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© ARVO (1962-2015); The Authors (2016-present)
Our laboratory demonstrated previously using genetically modified mice that Fas/FasL signaling is required for the death of RGCs and loss of axons in two different mouse models of glaucoma- chronic and inducible. Therefore, we hypothesized that specifically blocking the Fas receptor would serve as a novel neuroprotective approach in the treatment of glaucoma. To test this hypothesis, we examined the ability of a small peptide inhibitor of the Fas receptor (ONL1204) to protect RGCs and axons in a microbead-induced mouse model of glaucoma.
Intracameral injection of microbeads (control: saline-only) was used to elevate intraocular pressure (IOP) in WT C57BL/6 mice. IOP was monitored by rebound tonometry. Mice received an intravitreal injection of the small peptide inhibitor, ONL1204 (2μg/1μl) (control: vehicle only) at the same time as the microbead injection or 7 days after microbead injection. At 28 days post microbead injection, mice were euthanized and the ONH and retina were processed for: (i) qPCR, (ii) immunostaining, and (iii) RGC and axon counts.
Rebound tonometry demonstrated that treatment with ONL1204 had no effect on IOP elevation when compared to controls. However, treatment with ONL1204 at either the same time as microbead injection or 7 days after IOP elevation resulted in significant protection of RGCs and axons, as compared to controls. Moreover, confocal analysis and qPCR of the neural retina demonstrated that neuroprotection correlated with reduced microglia activation (Iba1 and CD11b staining in retinal wholemounts) and reduced expression of several factors that mediate glial activation and inflammation (TNFα, IL-6, MCP1, MIP1α, and MIP2).
These data demonstrate the effectiveness of targeting the Fas receptor in preventing axon degeneration and death of RGCs following elevated IOP, as well as, inhibiting glial activation and inflammation. More importantly, these results serve as proof-of-principal that the small peptide inhibitor of the Fas receptor, ONL1204, can provide robust neuroprotection in an inducible mouse model of glaucoma, even when administered after IOP elevation.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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