June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Post injury treatment with intravitreal AAV2-soluble Fas ligand restores retinal microglia homeostasis and rescues retinal ganglion cell function in a mouse model of glaucoma
Author Affiliations & Notes
  • Meredith S Gregory-Ksander
    Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, Massachusetts, United States
    Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
  • Anitha Krishnan
    Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, Massachusetts, United States
    Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
  • Maleeka Shrestha
    Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, Massachusetts, United States
    Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
  • Khoa Nguyen
    Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, Massachusetts, United States
    Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
  • Ann Marshak-Rotstein
    Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Meredith Gregory-Ksander ONL Therapeutics, Code C (Consultant/Contractor), ONL Therapeutics, Code P (Patent); Anitha Krishnan ONL Therapeutics, Code P (Patent); Maleeka Shrestha None; Khoa Nguyen None; Ann Marshak-Rotstein None
  • Footnotes
    Support  NIH Grant RO1EY021543; NIH Grant R21EY030276; Massachusetts Lions Eye Research Fund; NEI Core Grant P30EY003790
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 2583. doi:
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      Meredith S Gregory-Ksander, Anitha Krishnan, Maleeka Shrestha, Khoa Nguyen, Ann Marshak-Rotstein; Post injury treatment with intravitreal AAV2-soluble Fas ligand restores retinal microglia homeostasis and rescues retinal ganglion cell function in a mouse model of glaucoma. Invest. Ophthalmol. Vis. Sci. 2023;64(8):2583.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : In both chronic and inducible mouse models of glaucoma, we previously demonstrated that a decreased expression of soluble Fas ligand (sFasL) and increased expression of membrane FasL (mFasL) within the retina correlated with increased glial activation, axon degeneration, and death of retinal ganglion cells (RGCs). However, this was prevented if we restored the level of sFasL by a single intravitreal injection of AAV2.sFasL administered prior to elevation of intraocular pressure (IOP) (pre-treatment). In the current study, we are administering AAV2.sFasL 3 weeks after induction of elevated IOP (post-treatment) when significant loss of ganglion cell function has already occurred. We hypothesize that AAV2.sFasL post-treatment will promote RGC survival in part, through inhibition of microglia activation and restoration of the neuroprotective environment of the eye.

Methods : Intracameral injection of microbeads (control: saline) was used to elevate IOP in WT C57BL/6 mice. IOP and RGC function were monitored by rebound tonometry and pattern ERG (pERG), respectively. At 3 wks post microbead injection, pERG was performed in all mice and two groups of mice were euthanized (pre-treatment baseline). A third group of mice received intravitreal AAV2.sFasL or control AAV2 and pERG was performed monthly until final endpoint at 6 months post treatment. RGC survival (Brn3a staining) and microglia activation (measurement of the longest process length) were assessed in retinal whole mounts. Retinal expression of sFasL and mFasL was assessed by western blot.

Results : Pre-treatment baseline pERG (3 wks post microbeads) revealed a significant loss of RGC function as compared to saline controls, which coincided with a significant (i) increase in mFasL and loss of sFasL, and (ii) increase in microglia activation. At 6 months post AAV2.sFasL treatment, RGC function by pERG was significantly restored as compared to control mice and coincided with restoration of a homeostatic microglia phenotype. Microglia remained activated in control AAV2 treated mice at 6 months.

Conclusions : Post injury administration of AAV2.sFasL restores intraocular expression of sFasL and reverts activated microglia to a homeostatic phenotype, resetting the neuroprotective environment and restoring RGC function.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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