June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Stress resilience-enhancing drugs preserve tissue structure and function in degenerating retina via phosphodiesterase inhibition
Author Affiliations & Notes
  • Jennings Luu
    Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States
    Department of Ophthalmology, University of California Irvine School of Medicine, Irvine, California, United States
  • Aicha Saadane
    Department of Ophthalmology, University of California Irvine School of Medicine, Irvine, California, United States
  • Henri Leinonen
    Health Sciences, Ita-Suomen yliopisto Farmasian laitos, Kuopio, Pohjois-Savo, Finland
    Department of Ophthalmology, University of California Irvine School of Medicine, Irvine, California, United States
  • Elliot Choi
    Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States
    Department of Ophthalmology, University of California Irvine School of Medicine, Irvine, California, United States
  • Fangyuan Gao
    Department of Ophthalmology, University of California Irvine School of Medicine, Irvine, California, United States
  • Dominik Lewandowski
    Department of Ophthalmology, University of California Irvine School of Medicine, Irvine, California, United States
  • Maximilian Halabi
    Department of Ophthalmology, University of California Irvine School of Medicine, Irvine, California, United States
  • Arum Wu
    Department of Ophthalmology, University of California Irvine School of Medicine, Irvine, California, United States
  • Zhiqian Dong
    Department of Ophthalmology, University of California Irvine School of Medicine, Irvine, California, United States
  • Grazyna Palczewska
    Department of Ophthalmology, University of California Irvine School of Medicine, Irvine, California, United States
  • Robert Mullins
    Department of Ophthalmology and Visual Sciences, The University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, Iowa, United States
  • Neal S Peachey
    Department of Ophthalmic Research, Cleveland Clinic Cole Eye Institute, Cleveland, Ohio, United States
    Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, United States
  • Philip David Kiser
    Department of Ophthalmology, University of California Irvine School of Medicine, Irvine, California, United States
    Research Service, VA Long Beach Healthcare System, Long Beach, California, United States
  • Marcin Tabaka
    International Centre for Translational Eye Research, Polska Akademia Nauk, Warszawa, Mazowieckie, Poland
  • Timothy S Kern
    Department of Ophthalmology, University of California Irvine School of Medicine, Irvine, California, United States
  • Krzysztof Palczewski
    Department of Ophthalmology, University of California Irvine School of Medicine, Irvine, California, United States
    Department of Physiology & Biophysics, University of California Irvine School of Medicine, Irvine, California, United States
  • Footnotes
    Commercial Relationships   Jennings Luu None; Aicha Saadane None; Henri Leinonen None; Elliot Choi None; Fangyuan Gao None; Dominik Lewandowski None; Maximilian Halabi None; Arum Wu None; Zhiqian Dong None; Grazyna Palczewska None; Robert Mullins None; Neal Peachey None; Philip Kiser None; Marcin Tabaka None; Timothy Kern None; Krzysztof Palczewski None
  • Footnotes
    Support  NIH Grant F30EY031566
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 2417. doi:
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      Jennings Luu, Aicha Saadane, Henri Leinonen, Elliot Choi, Fangyuan Gao, Dominik Lewandowski, Maximilian Halabi, Arum Wu, Zhiqian Dong, Grazyna Palczewska, Robert Mullins, Neal S Peachey, Philip David Kiser, Marcin Tabaka, Timothy S Kern, Krzysztof Palczewski; Stress resilience-enhancing drugs preserve tissue structure and function in degenerating retina via phosphodiesterase inhibition. Invest. Ophthalmol. Vis. Sci. 2023;64(8):2417.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Despite decades of research, therapeutic options for millions of patients suffering from age-related macular degeneration (AMD), diabetic retinopathy (DR), and retinitis pigmentosa (RP) remain limited, especially for earlier stages of pathogenesis when the opportunity to preserve retinal structure and visual function is greatest. To address this urgent, unmet medical need, we employed a systems pharmacology platform for therapeutic development. Based on the premise that cyclic nucleotide phosphodiesterases (PDEs) function as integrative signaling nodes that could be therapeutically targeted, we set out to investigate the effects of selective PDE-inhibitor (PDEi) therapy on the hallmarks of age-related and inherited retinal diseases.

Methods : We conducted in vitro studies utilizing the human-derived ARPE-19 cell line, as well as in vivo studies employing several murine models; namely, the photosensitive Abca4-/-Rdh8-/- mouse, which exhibits epigenetic and pathological hallmarks of human AMD, the streptozotocin model of DR, and the rd10 model of RP. By comparing PDEi-treated groups to vehicle-treated controls, retinal phenotypes were characterized using optical coherence tomography (OCT), scanning laser ophthalmoscopy (SLO), immunohistochemistry (IHC), and electroretinography (ERG). Integrative single-cell transcriptomics, proteomics, and phosphoproteomics were also performed to delineate pertinent molecular mechanisms.

Results : Across various models of retinopathy, OCT, SLO, and/or IHC analyses demonstrated structural preservation and ERG analyses revealed functional improvement with PDEi therapy. For instance, rd10 mice reared on a diet infused with Rolipram, a selective inhibitor of PDE4, exhibited an approximate two-fold improvement in retinal function relative to controls (n = 4, *P = 0.0308), consistent with a reduction in Fas-mediated apoptosis and overall improvement in photoreceptor viability as determined by IHC (Fig. 1).

Conclusions : Our results demonstrate that selective PDE inhibition stabilized the transcriptome, proteome, and phosphoproteome, thereby preserving retinal structure and function across human and animal models of retinopathy. Taken together, these findings exemplify a systems pharmacology approach to drug discovery and development, revealing a new class of therapeutics with potential clinical utility in the most common causes of blindness.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

 

 

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