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 4

The selective AC inhibitor SQ protects Abca4–/–Rdh8–/– mouse retinas against bright light–induced damage in a dose-dependent fashion.

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The selective AC inhibitor SQ protects Abca4–/–Rdh8–/– mouse retinas aga...
Increasing doses of SQ were 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. Doses were: SQ1: 0.083 mg/kg; SQ2: 0.125 mg/kg; SQ3: 0.25 mg/kg; and SQ4: 0.5 mg/kg. (A) The effect of SQ pretreatment was assessed by OCT imaging 7 days after light exposure. OCT images indicate damaged photoreceptor structures in DMSO-treated and a dose-dependent preservation of photoreceptor morphology in SQ-treated mice (asterisks identify damaged ONL). (B) Statistical analysis of OCT scores (means ± SEM; #P < 0.05 and *P < 0.01 compared with DMSO control). (C) Retinal autofluorescence was examined by SLO imaging 8 days after light exposure. Representative retinal autofluorescent images reveal numbers and densities of bright spots that correlated with retinal damage. (D) Statistical analysis of the numbers of SLO autofluorescence spots (means ± SEM; *P < 0.01 compared with DMSO control). Scale bars: 50 μm.