Systems pharmacology identifies drug targets for Stargardt disease–associated retinal degeneration
Yu Chen, Grazyna Palczewska, Debarshi Mustafi, Marcin Golczak, Zhiqian Dong, Osamu Sawada, Tadao Maeda, Akiko Maeda, Krzysztof Palczewski
Yu Chen, Grazyna Palczewska, Debarshi Mustafi, Marcin Golczak, Zhiqian Dong, Osamu Sawada, Tadao Maeda, Akiko Maeda, Krzysztof Palczewski
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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 3

Multiple pharmacological antagonists of Gs-coupled GPCRs protect Abca4–/–Rdh8–/– mouse retinas from light-induced damage.

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Multiple pharmacological antagonists of Gs-coupled GPCRs protect Abca4–/...
RS, a 5-HT4R antagonist; SGS and RO, selective 5-HT6R antagonists; SB, and LY, 5-HT7R antagonists; and the DMSO vehicle control were each administered to 4- to 5-week-old Abca4–/–Rdh8–/– mice by i.p. injection 30 minutes prior to white light exposure at 10,000 lux for 30 minutes. (A) The effect of each treatment was examined by OCT imaging 7 days after light exposure. Representative OCT images featured a disrupted photoreceptor structure only in the DMSO control, as indicated by the asterisk. (B) Statistically analyzed OCT scores (means ± SEM; *P < 0.01 compared with DMSO control). (C) SLO imaging was performed 8 days after light exposure. Representative retinal autofluorescence images show protection by all agents except DMSO. (D) Numbers of retinal autofluorescent spots were counted and statistically analyzed (means ± SEM; *P < 0.01 compared with DMSO control). Scale bars: 50 μm.