Abstract: 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-? (IFN-?) 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-?, 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.

Abstract: Provided are method for treating age-related macular degeneration (AGE), and/or preventing the occurrence or progression thereof in a subject in need thereof. In some embodiments, the methods include administering to the subject in need thereof a composition that has an effective amount of an inhibitor of reverse transcriptase (RTase) activity. Also provided are methods for protecting retinal pigmented epithelium (RPE) cells, retinal photoreceptor cells, and/or choroidal cells; methods for treating geographic atrophy of the eye, and/or for preventing occurrence or progression thereof; and pharmaceutical compositions for treating AGE and/or GA and/or for preventing the occurrence or progression thereof; and/or for protecting RPE cells, retinal photoreceptor cells, and/or choroidal cells.

Abstract: 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-? (IFN-?) 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-?, 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.