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

生物 色素性视网膜炎 视网膜变性 视网膜 黄斑变性 生物信息学 转录组 神经科学 医学 遗传学 基因 基因表达 眼科
作者
Jennings Luu,Aicha Saadane,Henri Leinonen,Elliot H. Choi,Fangyuan Gao,Dominik Lewandowski,Maximilian Halabi,Christian 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
出处
期刊:Proceedings of the National Academy of Sciences of the United States of America [National Academy of Sciences]
卷期号:120 (19)
标识
DOI:10.1073/pnas.2221045120
摘要

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.
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