Systems pharmacology identifies drug targets for Stargardt disease–associated retinal degeneration
Yu Chen, … , Akiko Maeda, Krzysztof Palczewski
Yu Chen, … , Akiko Maeda, Krzysztof Palczewski
Published November 15, 2013
Citation Information: J Clin Invest. 2013;123(12):5119-5134. https://doi.org/10.1172/JCI69076.
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Research Article Genetics

Systems pharmacology identifies drug targets for Stargardt disease–associated retinal degeneration

Abstract

A systems pharmacological approach that capitalizes on the characterization of intracellular signaling networks can transform our understanding of human diseases and lead to therapy development. Here, we applied this strategy to identify pharmacological targets for the treatment of Stargardt disease, a severe juvenile form of macular degeneration. Diverse GPCRs have previously been implicated in neuronal cell survival, and crosstalk between GPCR signaling pathways represents an unexplored avenue for pharmacological intervention. We focused on this receptor family for potential therapeutic interventions in macular disease. Complete transcriptomes of mouse and human samples were analyzed to assess the expression of GPCRs in the retina. Focusing on adrenergic (AR) and serotonin (5-HT) receptors, we found that adrenoceptor α 2C (Adra2c) and serotonin receptor 2a (Htr2a) were the most highly expressed. Using a mouse model of Stargardt disease, we found that pharmacological interventions that targeted both GPCR signaling pathways and adenylate cyclases (ACs) improved photoreceptor cell survival, preserved photoreceptor function, and attenuated the accumulation of pathological fluorescent deposits in the retina. These findings demonstrate a strategy for the identification of new drug candidates and FDA-approved drugs for the treatment of monogenic and complex diseases.

Authors

Yu Chen, Grazyna Palczewska, Debarshi Mustafi, Marcin Golczak, Zhiqian Dong, Osamu Sawada, Tadao Maeda, Akiko Maeda, Krzysztof Palczewski

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Figure 9

ROS generation in photoreceptors of Abca4–/–Rdh8–/– mice after bright light exposure is decreased by either DOX, GUB, or SQ pretreatment.

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ROS generation in photoreceptors of Abca4–/–Rdh8–/– mice after bright li...
Dark-adapted pigmented 4- to 5-week-old Abca4–/–Rdh8–/– mice were treated with the ROS probe DHE 1 hour prior to light exposure at 10,000 lux for 30 minutes. Either vehicle control (DMSO), DOX, GUB, or SQ were also administered by i.p. injection 30 minutes prior to light exposure. The dose of each compound was as follows: DOX,10 mg/kg; GUB, 2.0 mg/kg; SQ, 0.5 mg/kg. Dark-adapted Abca4–/–Rdh8–/– mice not exposed to light were included for DHE probe treatment as well (no light). Retinas were harvested 3 hours after illumination. ROS signals were obtained with the identical exposure setup under a fluorescence microscope (right panel of each image set). DAPI staining was performed as well to visualize cell nuclei and gross retinal structure (left panel of each image set). Recorded ROS fluorescence intensity in arbitrary units averaged from various areas was further analyzed and summarized for group comparisons (means ± SEM). *P < 0.05 compared with DMSO control. Scale bars: 50 μm.