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Shinichi Fukuda, Junichi Fukuhara, Younghee Kim, Benjamin Fowler, Tetsuhiro Yasuma, Reo Yasuma, Takako Fukuhara, Nagaraj Kerur, Bradley D Gelfand, Jayakrishna Ambati; Nucleoside reverse transcriptase inhibitors are anti-inflammatory and inhibit poly I:C-induced retinal pigment epithelium degeneration. Invest. Ophthalmol. Vis. Sci. 2016;57(12):6551.
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© ARVO (1962-2015); The Authors (2016-present)
Age-related macular degeneration (AMD) is the leading cause of legal blindness among people aged over 60 years especially in developed countries. Double stranded RNAs including Alu RNA and Poly I:C are toxic to RPE cells. We recently demonstrated that Alu RNA-induced RPE toxicity, which is mediated by the NLRP3 inflammasome, is prevented by nucleoside reverse transcriptase inhibitors (NRTI), a widely used class of drugs to treat HIV. We and others have previously reported that poly I:C (pIC), a synthetic high-molecular weight dsRNA induces retinal degeneration with large areas of RPE cell loss and apoptosis of adjacent photoreceptors. Since pIC is also known to activate NLRP3 inflammasome, we hypothesized that NRTIs could block pIC-driven inflammasome activation and RPE cytotoxicity in cell culture and a mouse model of RPE degeneration.
For the mouse model of dry AMD, RPE degeneration was induced by subretinal injection of pIC. Twice daily intraperitoneal administration of NRTI lamivudine (3TC) (75 mg/kg/day) in wild-type male C57BL6/J mice was performed for one week after pIC administration. RPE degeneration was assessed by fundus photography and ZO-1 staining of RPE flat mounts. For cell culture, primary human RPE cells were maintained in DMEM supplemented with 10% FBS and antibiotics. Transfection of pIC was achieved by supplementing the culture medium for 24 hr. Cells were treated with NRTI lamivudine (3TC). NLRP3 inflammasome activation was monitored by western blot for Caspase-1.
NRTI lamivudine (3TC) blocked RPE cell death and inflammasome activation induced by pIC. Intraperitoneal administration of the NRTI lamivudine, at a dose equivalent to what is administered in humans, prevented RPE degeneration in the pIC-induced mouse model of dry AMD.
We have identified that, the novel anti-inflammatory activity of NRTIs can be exploited to prevent the RPE toxicity in a mouse model of dry AMD. Therefore the FDA approved NRTI compounds can be ideally repurposed for therapeutic use in dry AMD.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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