AAV-mediated expression of X-linked Inhibitor of Apoptosis protects photoreceptors in two canine models of early onset RP

Abstract

Purpose : Overexpression of X-linked Inhibitor of Apoptosis (XIAP) has been shown to protect photoreceptors in rodent models of retinal degeneration. Here we evaluated the neuroprotective effect of AAV-mediated subretinal delivery of XIAP in two canine models of early onset RP: the rcd1 (PDE6B mutation) and XLPRA2 (RPGR mutation) dogs.

Methods : Subretinal injections of an AAV2/5-CBA-XIAP-WPRE vector (vol: 60-150 µl; titer: 4.8 x10¹¹ vg/mL) were performed at early stage disease (~ 5.5 wks of age) in 6 rcd1 and 4 XLPRA2 eyes, and at mid-stage disease (11.1 wks of age) in 3 XLPRA2 eyes. ONL thickness was examined in the bleb areas by sdOCT and/or histology and compared to untreated areas of the same eye or to contralateral eyes that were sham-injected or uninjected. Photoreceptor function was assessed in XLPRA2 dogs by full-field ERGs.

Results : At 9 wks post-injection a significantly thicker ONL was observed by sdOCT in the treated area of all 6 rcd1 eyes injected with AAV-XIAP. Histology showed an ONL with a mean thickness of 4.5 (±0.8) rows of nuclei in the treated areas versus 2.7 (± 0.4) in untreated/ctrl areas. XLPRA2 dogs treated at early stage showed by sdOCT a significantly thicker ONL in the treated area both at 10 and 19 wks post injection; however rod-mediated ERG function was severely impaired in both AAV-XIAP and sham-injected eyes at 19 wks post injection. In XLPRA2 eyes injected with AAV-XIAP at mid-stage disease, photoreceptor loss was also reduced with treated areas showing thicker ONL by sdOCT than contralateral sham-injected eyes both at 8 and 13 wks post-injection. No rescue of rod-mediated ERG function was observed.

Conclusions : XIAP gene augmentation slows the course of photoreceptor death in two non-allelic canine models of RP. Increased survival of photoreceptors was not associated with improved rod function in the RPGR ciliopathy. These results suggest that AAV-XIAP gene therapy may provide a way of delaying loss of rods in RP and thus secondarily promoting cone survival and longer retention of cone-mediated vision.

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