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.
|Number of pages||9|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - Feb 4 2020|
Bibliographical noteFunding Information:
ACKNOWLEDGMENTS. We thank G. Pattison, K. Langberg, D. Robertson, X. Zhou, K. Atwood, and H. Hall for their technical assistance. These studies were supported by NIH Grant R01EY028027 and American Heart Association Grant 13SDG16770008 (B.D.G.); J.A. was supported by NIH Grants DP1GM114862, R01EY022238, R01EY024068, R01EY028027, and R01EY029799; John Templeton Foundation Grant 60763; and the DuPont Guerry, III, Professorship; N.K. by NIH Grants K99EY024336 and R00EY024336; R.D.M. by NIH Grant T32 HL007284; B.K.A. and H.U. by NIH Grants R01EY017950 and R01EY017182; and B.C. by NIH Grant R01EY019943. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
© 2020 National Academy of Sciences. All rights reserved.
- Choroidal neovascularization
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