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

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

Authors :
Luu, Jennings C.
Saadane, Aicha
Leinonen, Henri
Choi, Elliot H.
Fangyuan Gao
Lewandowski, Dominik
Halabi, Maximilian
Sander, Christopher L.
Wu, Arum
Wang, Jacob M.
Singh, Rupesh
Songqi Gao
Lessieur, Emma M.
Zhiqian Dong
Palczewska, Grazyna
Mullins, Robert F.
Peachey, Neal S.
Kiser, Philip D.
Tabaka, Marcin
Kern, Timothy S.
Source :
Proceedings of the National Academy of Sciences of the United States of America; 5/9/2023, Vol. 120 Issue 19, p1-12, 30p
Publication Year :
2023

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 resil-ience 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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00278424
Volume :
120
Issue :
19
Database :
Complementary Index
Journal :
Proceedings of the National Academy of Sciences of the United States of America
Publication Type :
Academic Journal
Accession number :
174724951
Full Text :
https://doi.org/10.1073/pnas.2221045120