X-Linked Inhibitor of Apoptosis Gene Therapy Protects Retinal Structure in a Feline Model of Retinal Detachment

Abstract

Purpose : Our laboratory has previously shown that delivery of the gene encoding X-linked Inhibitor of Apoptosis (XIAP), using an Adeno-Associated Viral (AAV) vector, can protect photoreceptor structure in a rat model of retinal detachment. Due to the miniature dimensions of the rat eye, we were unable to induce reattachment of the retina and therefore could not assess photoreceptor function. In the current study, we designed a large animal model of retinal detachment and natural re-attachment, treated with XIAP gene therapy, to assess the effects on photoreceptor structure and function.

Methods : One eye of 12 healthy wild-type felines received either AAV8.RK.XIAP or AAV8.RK.GFP, injected into the subretinal space (superior pole, along the plane of the optic nerve). Three weeks after viral delivery, a retinal detachment was created by administering a gas bubble (C₃F₈) into the same position. Eyes were monitored every three weeks with optical coherence tomography (OCT) and full-field flash electroretinography (ERG). At nine weeks post detachment, the treated eyes were removed for histological examination.

Results : A complete 3-port pars plana lensectomy (20G) and vitrectomy (25G) provided the stable and safe setting required to precisely inject AAV8.RK.XIAP or AAV8.RK.GFP into the subretinal space. Three weeks later, a C₃F₈ gas bubble was injected into the same area. The retinal detachment resolved spontaneously within 6 weeks, as seen by OCT. Three animals were removed from the study due to a complete retinal detachment (2 GFP animals and 1 XIAP animal). ERG data suggests that XIAP protects photoreceptor function at 9 weeks post-detachment, but significance was not reached (p=0.159) due to the small number of animals tested. Histological sections at the plane and lateral to the optic nerve showed significant preservation of the photoreceptor layer in AAV8.RK.XIAP animals compared to AAV8.RK.GFP control animals (4 out of 5 animals). Immunohistochemistry identified XIAP-infected photoreceptors within areas of retinal detachment.

Conclusions : The results show that XIAP protects photoreceptor structure and may preserve function at later time-points. These studies provide important proof-of-principle data for anti-apoptotic gene therapy efficacy.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

 

Feline sections along the plane of the optic nerve. XIAP treatment preserves the outer nuclear layer.