Abstract
Purpose :
We previously demonstrated in the DBA/2J mouse model of glaucoma that a single intravitreal injection of AAV2.sFasL at 2 months of age, prior to the elevation of intraocular pressure (IOP), provided long-term neuroprotection of RGCs and axons up to 15 months of age. These studies were performed to determine if sFasL treatment can provide similar neuroprotection if delivered after elevated IOP and neurodegeneration has already begun and whether treatment with sFasL alters microglia activity.
Methods :
DBA/2J (D2) mice received an intravitreal injection of AAV2.control or AAV2.sFasL at 7 or 9 months of age. D2 uninjected mice (elevated IOP and glaucoma) served as positive controls and D2-Gpnmb+ mice (no elevated IOP and no glaucoma) served as negative controls. Rebound tonometry was used to monitor IOP. Mice were euthanized at 9, 12, and 15 months of age; retina and optic nerves were processed for: (i) RGC counts (β-III tubulin and Brn3a), (ii) axon counts (PPD), and (iii) immunofluorescence (microglia, P2RY12).
Results :
Increased retinal expression of sFasL in AAV2.sFasL treated mice was confirmed by western blot and had no effect on IOP, pigment dispersion, or iris atrophy when compared to controls. As compared to non-glaucoma controls, the increase in IOP was similar between all D2 treatment groups, with no significant difference in cIOP prior to treatment or after treatment. D2 mice treated with AAV2.sFasL at 7 months of age, when IOP first increases, displayed significant protection of RGCs and axons out to 15 months of age when compared to AAV2.control and D2-uninjected control groups. Even when treated at 9 months of age, when 30% of D2 mice present with moderate disease (mild ≤ 5% axon loss, moderate 5-50% axon loss, severe ≥ 50% axon loss)treatment with AAV2.sFasL offered significant neuroprotection with only 12% of the AAV2.sFasL treated mice progressing to severe disease at 12 months of age, as compared to 40% of the AAV2-control mice and 50% of the D2-uninjected mice.
Conclusions :
These data demonstrate AAV2.sFasL treatment provides significant neuroprotection in a chronic mouse model of glaucoma, even when administered after optic nerve degeneration has already begun.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.