Researchers are exploring whether these ubiquitous fluorinated molecules might worsen infections or hamper vaccine effectiveness.
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Edited by Jeremy Nathans, Johns Hopkins University School of Medicine, Baltimore, MD, and approved December 19, 2019 (received for review July 8, 2019)
Significance
DICER1 processes micro-RNAs into their bioactive forms and metabolizes RNAs from short interspersed nuclear element genetic repeats, principally Alu RNAs in humans. DICER1 deficiency is implicated in retinal pigmented epithelium (RPE) degeneration in atrophic age-related macular degeneration (AMD). Here, we report that three independent mouse models of DICER1 deficiency develop RPE degeneration and aberrant choroidal and retinal neovascularization (CRNV), both hallmarks of advanced AMD. These pathologies were dependent on inflammatory caspases 1 and 11 and the signaling adaptor MyD88. We observed reduced DICER1 abundance in a separate model of spontaneous CRNV and developed an adenoassociated vector-mediated DICER1 delivery construct, which reduced the severity of established spontaneous CRNV. Thus, persistent deficiency in DICER1 results in RPE degeneration and CRNV.
Abstract
Degeneration of the retinal pigmented epithelium (RPE) and aberrant blood vessel growth in the eye are advanced-stage processes in blinding diseases such as age-related macular degeneration (AMD), which affect hundreds of millions of people worldwide. Loss of the RNase DICER1, an essential factor in micro-RNA biogenesis, is implicated in RPE atrophy. However, the functional implications of DICER1 loss in choroidal and retinal neovascularization are unknown. Here, we report that two independent hypomorphic mouse strains, as well as a separate model of postnatal RPE-specific DICER1 ablation, all presented with spontaneous RPE degeneration and choroidal and retinal neovascularization. DICER1 hypomorphic mice lacking critical inflammasome components or the innate immune adaptor MyD88 developed less severe RPE atrophy and pathological neovascularization. DICER1 abundance was also reduced in retinas of the JR5558 mouse model of spontaneous choroidal neovascularization. Finally, adenoassociated vector-mediated gene delivery of a truncated DICER1 variant (OptiDicer) reduced spontaneous choroidal neovascularization in JR5558 mice. Collectively, these findings significantly expand the repertoire of DICER1 in preserving retinal homeostasis by preventing both RPE degeneration and pathological neovascularization.
Footnotes
↵1C.B.W. and H.U. contributed equally to this work.
- ↵2To whom correspondence may be addressed. Email: gelfand{at}virginia.edu.
↵3Present address: OliX Pharmaceuticals, Inc., Suwon-Si, Gyeonggi-do 16226, Korea.
↵4Present address: Vistar Eye Center, Roanoke, VA 24019.
Author contributions: C.B.W., H.U., Y.K., T.Y., R.Y., S.H., R.D.M., I.A., F.P., Y.N., S.N., S.F., R.A., B.J.F., A.B.-C., N.K., B.K.A., J.A., and B.D.G. designed research; C.B.W., H.U., Y.K., T.Y., R.Y., S.H., R.D.M., I.A., F.P., Y.N., S.N., S.F., R.A., A.B.-C., B.K.A., and B.D.G. performed research; H.U., P.G., I.H., B.C., B.K.A., and B.D.G. contributed new reagents/analytic tools; C.B.W., H.U., Y.K., T.Y., R.Y., S.H., R.D.M., I.A., F.P., Y.N., S.N., S.F., R.A., B.J.F., A.B.-C., N.K., B.K.A., J.A., and B.D.G. analyzed data; and C.B.W., H.U., B.K.A., J.A., and B.D.G. wrote the paper.
Competing interest statement: J.A. is a co-founder of iVeena Holdings, iVeena Delivery Systems, and Inflammasome Therapeutics, and has been a consultant for Allergan, Biogen, Boehringer-Ingelheim, Immunovant, Janssen, Olix Pharmaceuticals, Retinal Solutions, and Saksin LifeSciences unrelated to this work. B.K.A. is a co-founder of iVeena Holdings, iVeena Delivery Systems, and Inflammasome Therapeutics, and has been a consultant to Alcon, Genentech, and Johnson & Johnson unrelated to this work. H.U., S.F., B.J.F., N.K., B.K.A., J.A., and B.D.G. are named as inventors on patent applications related to the intellectual property described in this manuscript that have been filed by the University of Virginia, the University of Kentucky, or the University of Utah.
This article is a PNAS Direct Submission.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1909761117/-/DCSupplemental.
- Copyright © 2020 the Author(s). Published by PNAS.
This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
Chronic Dicer1 deficiency promotes atrophic and neovascular outer retinal pathologies in mice
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