Age-related macular degeneration (AMD) is the leading cause of central vision loss and blindness in the elderly. It is characterized by a progressive loss of photoreceptors in the macula due to damage to the retinal pigment epithelium (RPE). Clinically, it is manifested by drusen deposition between the RPE and underlying choroid and accumulation of lipofuscin in the RPE. End-stage disease is characterized by geographic atrophy (dry AMD) or choroidal neovascularization (wet AMD). The NLRP3 inflammasome has recently been implicated in the disease pathology. Here we review the current knowledge on the involvement of this multiprotein complex and its effector cytokines interleukin-1β (IL-1β) and IL-18 in AMD progression. We also describe cell death mechanisms that have been proposed to underlie RPE degeneration in AMD and discuss the role of autophagy in the regulation of disease progression.

PURPOSE. Age-related macular degeneration is the most common form of central retinal blindness in the elderly. Of the two end stages of disease, neovascular AMD-although the minority formis the most severe. Current therapies are highly successful at controlling progression of neovascular lesions; however, a significant number of patients remain refractory to treatment and the development of alternative and additive therapies to anti-VEGFs is essential.METHODS. In order to address the translational potential of interleukin (IL)-18 for use in neovascular AMD, we initiated a nonhuman primate tolerability and efficacy study for the use of intravitreally (IVT) administered clinical grade human IL-18 (SB-485232). Cynomolgus monkeys were injected IVT with increasing doses of human IL-18 (two each at 1000, 3000, and 10,000 ng per eye). In tandem, 21 monkeys were administered nine laser burns in each eye prior to receiving IL-18 as an IVT injection at a range of doses. Fundus fluorescein angiography (FFA) was performed on days 8, 15, and 22 post injection and the development of neovascular lesions was assessed.RESULTS. We show intravitreal, mature, recombinant human IL-18 is safe and can reduce choroidal neovascular lesion development in cynomolgus monkeys.CONCLUSIONS. Based on our data comparing human IL-18 to current anti-VEGF-based therapy, clinical deployment of IL-18 for neovascular AMD has the potential to lead to a new adjuvant immunotherapy-based treatment for this severe form of central blindness.

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This novel CH partially protects mice against obesity-induced hyperglycemia coincident with attenuated IL-1β secretion and improved insulin signaling.

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