Effect of XIAP gene therapy in an experimental model of glaucoma

Abstract

Purpose : Loss of vision in glaucoma is primarily caused by the loss of retinal ganglion cells (RGCs) due to elevated intraocular pressure (IOP). X-linked inhibitor of apoptosis (XIAP) is a potent caspase inhibitor that has previously been shown to be protective in a variety of in vivo and in vitro models of retinal cell death. This study tested XIAP's ability to protect against RGC apoptosis and axon degeneration in a mouse model of glaucoma.

Methods : IOP elevation was induced with a unilateral intracameral injection of magnetic microbeads into the eyes of 16 mice. Beads-injected eyes also received an intravitreal injection of XIAP or GFP packaged in an adeno-associated virus (AAV). Control animals were given a unilateral injection of BSS intracamerally and AAV-XIAP or AAV-GFP intravitreally. Eyes were monitored weekly for three weeks following beads surgery for IOP elevation using a Tonopen, and changes in visual function were measured using electroretinography (ERG) and visual-evoked potentials (VEPs) at baseline and three weeks following beads surgery.

Results : Eyes injected with XIAP+beads and GFP+beads showed significant IOP elevation at each timepoint when compared to their baseline measurements and when compared to XIAP+BSS or GFP+BSS control eyes. The b-wave amplitudes of the ERG were diminished in both GFP-treated and XIAP-treated glaucoma animals at three weeks compared to baseline. Analysis of pattern-ERG (PERG) and VEP data showed that GFP-treated glaucomatous eyes had significantly reduced PERG component values as well as significantly reduced P1 values in the VEP data at three weeks compared to baseline; however, XIAP-treated glaucomatous eyes did not show a significant reduction in any component of the PERG or VEP.

Conclusions : Reductions in b-wave amplitude found in both XIAP- and GFP-treated glaucomatous eyes suggest damage to the inner nuclear layer by the microbead injection. The lack of protection of the b-wave by XIAP is not surprising given that the AAV does not penetrate the retina beyond the RGC layer. However, amplitude reductions in the PERG and VEP tests were unique to GFP-treated glaucoma animals and not found in XIAP-treated animals, suggesting that XIAP is preserving RGC function in glaucoma.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.