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PU-91 drug rescues human age-related macular degeneration RPE cells; implications for AMD therapeutics.

Authors
  • Nashine, Sonali1
  • Subramaniam, Sudhakar R2
  • Chwa, Marilyn1
  • Nesburn, Anthony1, 3
  • Kuppermann, Baruch D1
  • Federoff, Howard2
  • Kenney, M Cristina1, 4
  • 1 Department of Ophthalmology, Gavin Herbert Eye Institute, University of California Irvine, Irvine, CA 92697, USA.
  • 2 Department of Neurology, University of California Irvine, Irvine, CA 92697, USA.
  • 3 Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • 4 Department of Pathology and Laboratory Medicine, University of California Irvine, Irvine, CA 92697, USA.
Type
Published Article
Journal
Aging
Publisher
"Impact Journals, LLC "
Publication Date
Sep 02, 2019
Volume
11
Issue
17
Pages
6691–6713
Identifiers
DOI: 10.18632/aging.102179
PMID: 31477635
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Since mitochondrial dysfunction is implicated in the pathogenesis of AMD, this study is based on the premise that repurposing of mitochondria-stabilizing FDA-approved drugs such as PU-91, might rescue AMD RPE cells from AMD mitochondria-induced damage. The PU-91 drug upregulates PGC-1α which is a critical regulator of mitochondrial biogenesis. Herein, we tested the therapeutic potential of PU-91 drug and examined the additive effects of treatment with PU-91 and esterase inhibitors i.e., EI-12 and EI-78, using the in vitro transmitochondrial AMD cell model. This model was created by fusing platelets obtained from AMD patients with Rho0 i.e., mitochondria-deficient, ARPE-19 cell lines. The resulting AMD RPE cell lines have identical nuclei but differ in their mitochondrial DNA content, which is derived from individual AMD patients. Briefly, we report significant improvement in cell survival, mitochondrial health, and antioxidant potential in PU-91-treated AMD RPE cells compared to their untreated counterparts. In conclusion, this study identifies PU 91 as a therapeutic candidate drug for AMD and repurposing of PU-91 will be a smoother transition from lab bench to clinic since the pharmacological profiles of PU-91 have been examined already.

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