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Junichi Fukuhara, Younghee Kim, Tetsuhiro Yasuma, Reo Yasuma, Benjamin Fowler, Shinichi Fukuda, Takako Fukuhara, Nagaraj Kerur, Bradley D Gelfand, Jayakrishna Ambati; Nucleoside reverse transcriptase inhibitors prevent iron-induced retinal pigment epithelium cell death. Invest. Ophthalmol. Vis. Sci. 2016;57(12):5005.
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NLRP3 inflammasome activation induces retinal pigment epithelium (RPE) cell death in dry age-related macular degeneration (AMD), a devastating and currently untreatable blindness. Nucleoside reverse transcriptase inhibitors (NRTIs) are widely used to treat HIV and hepatitis B. Recently we demonstrated that NRTIs are effective in Alu RNA induced RPE cell death in mouse and cell models by inhibiting the NLRP3 inflammasome. Retinal iron overload is also implicated in AMD, and induces NLRP3 inflammasome-mediated RPE cell death. Therefore, we hypothesized that NRTIs prevent inflammasome activation and RPE cell death in cell culture and animal models of iron overload.
In wild-type male C57BL6/J mice, RPE degeneration was induced by subretinal injection of Fe (III) ammonium citrate. The NRTI lamivudine (3TC) was administered twice daily by intraperitoneal administration (75 mg/kg/day) for one week after Fe (III) ammonium citrate administration. RPE degeneration was assessed by fundus photography and ZO-1 staining of RPE flat mounts. Separately, primary human RPE cells were exposed to iron overload by supplementing the culture medium with Fe(III) ammonium citrate for 96 h in combination with NRTIs lamivudine (3TC), stavudine (d4T) or zidovudine (AZT). NLRP3 inflammasome activation was monitored by western blotting for Caspase-1.
Results: Multiple NRTIs blocked RPE cell death and inflammasome activation induced by Fe (III) ammonium citrate. Intraperitoneal administration of the NRTI lamivudine, at a similar equivalent dose typically administered in humans, prevented RPE degeneration in the Fe (III)-induced mouse model of dry AMD. NRTIs prevented activation of Caspase-1 by iron overload in primary human RPE cells.
NRTIs prevent RPE cell death and Caspase-1 activation in models of iron overload. The tested NRTI compounds have been FDA-approved and widely used clinically for decades. Therefore, NRTIs are ideal drug repurposing candidates for treatment of 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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