Stress resilience-enhancing drugs preserve tissue structure and function in degenerating retina via phosphodiesterase inhibition

Jennings C Luu; Aicha Saadane; Henri Leinonen; Elliot H Choi; Fangyuan Gao; Dominik Lewandowski; Maximilian Halabi; Christopher L Sander; Arum Wu; Jacob M Wang; Rupesh Singh; Songqi Gao; Emma M Lessieur; Zhiqian Dong; Grazyna Palczewska; Robert F Mullins; Neal S Peachey; Philip D Kiser; Marcin Tabaka; Timothy S Kern; Krzysztof Palczewski

doi:10.1073/pnas.2221045120

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Stress resilience-enhancing drugs preserve tissue structure and function in degenerating retina via phosphodiesterase inhibition

Journal article

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Stress resilience-enhancing drugs preserve tissue structure and function in degenerating retina via phosphodiesterase inhibition

Jennings C Luu, Aicha Saadane, Henri Leinonen, Elliot H Choi, Fangyuan Gao, Dominik Lewandowski, Maximilian Halabi, Christopher L Sander, Arum Wu, Jacob M Wang, …

Proceedings of the National Academy of Sciences - PNAS, Vol.120(19), e2221045120

05/09/2023

DOI: 10.1073/pnas.2221045120

PMCID: PMC10175720

PMID: 37126699

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Abstract

Chronic, progressive retinal diseases, such as age-related macular degeneration (AMD), diabetic retinopathy, and retinitis pigmentosa, arise from genetic and environmental perturbations of cellular and tissue homeostasis. These disruptions accumulate with repeated exposures to stress over time, leading to progressive visual impairment and, in many cases, legal blindness. Despite decades of research, therapeutic options for the millions of patients suffering from these disorders remain severely limited, especially for treating earlier stages of pathogenesis when the opportunity to preserve the retinal structure and visual function is greatest. To address this urgent, unmet medical need, we employed a systems pharmacology platform for therapeutic development. Through integrative single-cell transcriptomics, proteomics, and phosphoproteomics, we identified universal molecular mechanisms across distinct models of age-related and inherited retinal degenerations, characterized by impaired physiological resilience to stress. Here, we report that selective, targeted pharmacological inhibition of cyclic nucleotide phosphodiesterases (PDEs), which serve as critical regulatory nodes that modulate intracellular second messenger signaling pathways, stabilized the transcriptome, proteome, and phosphoproteome through downstream activation of protective mechanisms coupled with synergistic inhibition of degenerative processes. This therapeutic intervention enhanced resilience to acute and chronic forms of stress in the degenerating retina, thus preserving tissue structure and function across various models of age-related and inherited retinal disease. 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 treatment or prevention of the most common causes of blindness.

Diabetic Retinopathy - metabolism

Humans

Macular Degeneration - pathology

Retina - metabolism

Retinal Degeneration - metabolism

Retinitis Pigmentosa - metabolism

Details

Title: Subtitle: Stress resilience-enhancing drugs preserve tissue structure and function in degenerating retina via phosphodiesterase inhibition
Creators: Jennings C Luu - University of California, Irvine
Aicha Saadane - University of California, Irvine
Henri Leinonen - University of California, Irvine
Elliot H Choi - University of California, Irvine
Fangyuan Gao - University of California, Irvine
Dominik Lewandowski - University of California, Irvine
Maximilian Halabi - University of California, Irvine
Christopher L Sander - University of California, Irvine
Arum Wu - University of California, Irvine
Jacob M Wang - Cleveland Eye Clinic
Rupesh Singh - Cleveland Eye Clinic
Songqi Gao - Case Western Reserve University
Emma M Lessieur - University of California, Irvine
Zhiqian Dong - University of California, Irvine
Grazyna Palczewska - University of California, Irvine
Robert F Mullins - University of Iowa
Neal S Peachey - Cleveland Clinic
Philip D Kiser - University of California, Irvine
Marcin Tabaka - Polish Academy of Sciences
Timothy S Kern - University of California, Irvine
Krzysztof Palczewski - University of California, Irvine
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.120(19), e2221045120
DOI: 10.1073/pnas.2221045120
PMID: 37126699
PMCID: PMC10175720
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Grant note: R24 EY027283 / NEI NIH HHS I01 BX004939 / BLRD VA T32 GM007250 / NIGMS NIH HHS R01 EY009339 / NEI NIH HHS P30 EY025585 / NEI NIH HHS F30 EY031566 / NEI NIH HHS R01 EY030873 / NEI NIH HHS P30 EY034070 / NEI NIH HHS R01 EY022938 / NEI NIH HHS IK6 BX003604 / BLRD VA IK6 BX005233 / BLRD VA
Language: English
Date published: 05/09/2023
Academic Unit: The University of Iowa Institute for Vision Research; Ophthalmology and Visual Sciences
Record Identifier: 9984400756502771

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