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AssigneeUniversity of Virginia Patent Foundation
InventorsJayakrishna Ambati, Nagaraj Kerur
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It is disclosed herein that RPE degeneration in human cell culture and in mouse models is driven by a non-canonical inflammasome pathway that results in activation of caspase-4 (also known as caspase-11 in mouse) and caspase-1, and requires cyclic GMP-AMP synthase (cGAS)-dependent interferon-β (IFN-β) production and gasdermin D-dependent interleukin-18 (IL-18) secretion. Reduction of DICER1 or accumulation of Alu RNA triggers cytosolic escape of mitochondrial DNA, which engages cGAS. Collectively, these data highlight an unexpected role for cGAS in responding to mobile element transcripts, reveal cGAS-driven interferon signaling as a conduit for mitochondrial damage-induced NLRP3 activation, and expand the immune sensing repertoire of cGAS and caspase-4 to non-infectious human disease. Coupled with the unexpected result that caspase-4, gasdermin D, IFN-β, and cGAS are elevated in the RPE of human eyes with geographic atrophy, these findings also identify new targets for a major cause of blindness.
A method for preventing or treating age-related macular degeneration in a subject in need thereof by targeting at least one of the alternative, non-canonical inflammasome signaling molecules, protein complex, or signal transduction pathways in retinal pigment epithelium (RPE), the method comprising administering to the subject a pharmaceutical composition comprising a pharmaceutically-acceptable carrier, an effective amount of an inhibitor of noncanonical-inflammasome activation in RPE, and optionally an additional therapeutic agent, thereby preventing or treating age-related macular degeneration.
A method for preventing or inhibiting Alu RNA-induced retinal pigment epithelium (RPE) cell degeneration by targeting at least one of the alternative, non-canonical inflammasome signaling molecules or protein complex, the method comprising contacting said RPE cell with an inhibitor of at least one molecule or complex selected from the group consisting of cGAS, Caspase-4, STING, PPIF, MPTP, Gasdermin D, IFN-β, and IFNAR.
A method for inhibiting a non-canonical inflammasome signaling molecule, protein complex, or pathway in an RPE cell, the method comprising contacting said RPE cell with an inhibitor of at least one a non-canonical inflammasome molecule or protein complex, the method comprising contacting said RPE cell with an inhibitor of at least one molecule or complex selected from the group consisting of cGAS, Caspase-4, STING, PPIF, MPTP, GSDMD, IFN-β, and IFNAR.
A method of determining whether a subject should be treated for age-related macular degeneration, said method comprising measuring the levels of at least one of Caspase-4, cGAS, and Gasdermin D in RPE of said subject, wherein an increase in the levels of one or more of Caspase-4, cGAS, and Gasdermin D compared to control levels is an indication that the subject should be treated for said age-related macular degeneration by administering an effective amount of an inhibitor of at least one of the alternative, non-canonical inflammasome signaling molecules or protein complex in RPE.
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