Abstract
Purpose :
Glaucoma is a progressive optic neuropathy characterized by retinal ganglion cell (RGC) degeneration and visual field loss. Dysregulation of iron homeostasis and oxidative stress have been implicated in the pathogenesis of glaucoma. EYS611 is a novel non-viral gene therapy delivering sustained intraocular concentration of human transferrin (Tf), an endogenous iron chelator. We previously demonstrated that EYS611 slowed disease progression in acute and chronic rat models of retinal degeneration supporting its development for retinitis pigmentosa and dry age-related macular degeneration. To evaluate whether EYS611 could be protective in glaucoma, we evaluated the effect of Tf in a rat model of ocular hypertension (OHT).
Methods :
OHT was induced by injection of magnetic microbeads into the anterior chamber of adult Brown Norway rats (n = 5/group). Animals then received four weekly intravitreal injections of Tf (240 µg/eye) or vehicle (BSS). Naïve rats served as normotensive internal controls and remained untreated. Intraocular pressure (IOP) was measured during the 4 week-experimental period. Pattern electroretinogram (pERG) was measured prior to OHT, then 2 and 4 weeks after OHT. RNA-binding protein with multiple splicing (RBPMS) immunolabeling of flat-mounted retinas was used for RGC quantification at 4 weeks.
Results :
IOP in rats with OHT was significantly increased over naïve controls by 48h and remained elevated for the entire 4-week experimental period. Both treated groups had lower pERG amplitude compared to naïve controls on weeks 2 and 4. Significantly lower RGC density (-49.7%) was reported in BSS-treated animals at week 4 in comparison to naïve animals (958 ± 146 cells/mm2 vs. 1927 ± 61 cells/mm2, p < 0.0001) whereas RGC density in Tf-treated rats was not statistically different from RGC density of naïve animals (p = 0.17). Tf administration preserved RGC by about 70% compared to BSS-treated animals with OHT (1628 ± 92 and vs. 958 ± 146 cells/mm2, p 0.0013).
Conclusions :
These results demonstrate the ability of Tf to protect RGCs exposed to elevated IOP, suggesting that iron chelation could benefit glaucoma patients. These proof-of-concept findings and previous data demonstrating sustained intraocular production of Tf following non-viral gene transfer strongly support the evaluation of EYS611 for long-term and effective neuroprotection in glaucoma.
This is a 2021 ARVO Annual Meeting abstract.