Journal
SCIENCE
Volume 346, Issue 6212, Pages 1000-1003Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1261754
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Funding
- NIH [DP1GM114862, R01EY018350, R01EY018836, R01EY020672, R01EY022238, R01EY024068, T32HL091812, UL1RR033173, K99EY024336]
- Doris Duke Distinguished Clinical Scientist Award
- Burroughs Wellcome Fund Clinical Scientist Award in Translational Research
- Ellison Medical Foundation Senior Scholar in Aging Award
- Foundation Fighting Blindness Individual Investigator Research Award
- Harrington Discovery Institute Scholar-Innovator Award
- Dr. E. Vernon Smith and Eloise C. Smith Macular Degeneration Endowed Chair
- Research to Prevent Blindness departmental unrestricted grant
- Programme for Advanced Medical Education - Fundacao Calouste Gulbenkian
- Programme for Advanced Medical Education - Fundacao Champalimaud
- Programme for Advanced Medical Education - Ministerio da Saude
- Programme for Advanced Medical Education - Fundacao para a Ciencia e Tecnologia, Portugal
- Bayer Global Ophthalmology Research Award
- Alcon Japan Research award
- Beckman Initiative for Macular Research
- American Heart Association
- International Retinal Research Foundation (IRRF)
- Fight for Sight postdoctoral award
- Loris and David Rich Postdoctoral Scholar Award (IRRF)
- Center for Cancer Research, National Cancer Institute
- Biotechnology and Biological Sciences Research Council (BBSRC) grant [BB/J017345/1]
- NIH grants [P30EY003040, R01EY001545]
- Arnold and Mabel Beckman Foundation
- Alberta Innovates Health Solutions Graduate Studentship
- BBSRC
- BBSRC [BB/J017345/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/J017345/1] Funding Source: researchfish
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Nucleoside reverse transcriptase inhibitors (NRTIs) are mainstay therapeutics for HIV that block retrovirus replication. Alu (an endogenous retroelement that also requires reverse transcriptase for its life cycle)-derived RNAs activate P2X7 and the NLRP3 inflammasome to cause cell death of the retinal pigment epithelium in geographic atrophy, a type of age-related macular degeneration. We found that NRTIs inhibit P2X7-mediated NLRP3 inflammasome activation independent of reverse transcriptase inhibition. Multiple approved and clinically relevant NRTIs prevented caspase-1 activation, the effector of the NLRP3 inflammasome, induced by Alu RNA. NRTIs were efficacious in mouse models of geographic atrophy, choroidal neovascularization, graft-versus-host disease, and sterile liver inflammation. Our findings suggest that NRTIs are ripe for drug repurposing in P2X7-driven diseases.
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