Effects on XIAP Retinal Detachment-Induced Photoreceptor Apoptosis

Retinal detachment involves a separation of the neural retina from the underlying retinal pigment epithelium (RPE). It is a common form of retinal injury and a significant cause of visual loss,1,2 especially if it involves the macula. The incidence of retinal detachment is approximately 1 in 10,000 people per year, with a lifetime prevalence of 1 in 300.3 Risk increases dramatically when factors such as trauma, myopia, cataract surgery, previous retinal detachment, or family history are considered.4 Retinal detachment may also be associated with ocular disorders such as age-related macular degeneration (AMD), diabetic retinopathy, retinopathy of prematurity, retinoschisis, and central serous retinopathy among others. Rhegmatogenous detachment is the most common type; it involves a retinal tear that allows vitreal fluid to leak into the subretinal space and to detach the retina from the underlying RPE. In tractional detachment, fibrovascular tissue caused by injury, inflammation, or neovascularization pulls the neurosensory retina away from the RPE. Exudative retinal detachment results from subretinal fluid accumulation in the absence of a retinal tear. Recovery of vision after retinal separation from the RPE depends on the nature, severity, and duration of the detachment. The primary retinal cell types affected by detachment are the photoreceptors. These cells undergo characteristic changes such as shortening of the outer segments, retraction of rod terminals from the outer plexiform layer,5 and opsin redistribution.6 In addition, synapses of second-order neurons are remodeled and retinal glial cells proliferate.7 Some of these changes are significant obstacles to recovery but may be reversible after reattachment of the retina.8 However, the primary cause of visual loss is most likely photoreceptor death by apoptosis.1,9 In animal studies, apoptosis is initiated within 24 hours after retinal detachment and peaks at 3 days.2,8 Apoptosis most often involves the activation of cysteine proteases, called caspases, which are involved in the proteolytic digestion of the cell and its contents. Retinal detachment causes cell death through the activation of caspases 3, 7, and 9.2 X-linked inhibitor of apoptosis (XIAP) is a key member of the inhibitors of apoptosis (IAP) gene family. Members of this family all share at least one baculoviral IAP repeat (BIR) domain, so named because it was first discovered in baculoviruses. XIAP has three BIR domains, which, in combination with the linker regions between them, are involved in binding to and suppressing the activity of caspases 3, 7, and 9.10 XIAP also contains a carboxyl-terminal RING zinc finger domain that has E3 ubiquitin ligase activity. This domain determines the fate of XIAP or the cell, or both, depending on the severity of the cellular insult. Under conditions of severe cellular stress, XIAP will undergo auto-ubiquitination and degrade, allowing the apoptotic cascade to culminate in the death of the cell. Under lower apoptotic stress, XIAP will promote the ubiquitination and degradation of the caspases, leading to cell survival through the suppression of apoptosis.10 In disease models, XIAP has been shown to confer protection in forebrain ischemia,11 in methyl-phenyl-tetrahydropyridine–induced Parkinson disease,12,13 and in cisplatin-induced ototoxicity.14–16 In gene therapy studies in the eye, XIAP protects ganglion cells after axotomy of the optic nerve,17,18 increased intraocular pressure,19 and retinal ischemia.20 It also protects photoreceptors from chemotoxic insult21,22 and in genetic models of retinitis pigmentosa.23 The present study examines the protective effects of XIAP delivered through an adenoassociated virus (AAV) vector on retinal detachment–induced photoreceptor apoptosis. XIAP is an ideal therapeutic agent because it suppresses caspases 3, 7, and 9, whose activation has previously been shown to be responsible for apoptotic cell death in animal studies of retinal detachment.2