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 8

DOX, GUB, and SQ each prevent light-induced retinal degeneration in WT mice.

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DOX, GUB, and SQ each prevent light-induced retinal degeneration in WT m...
The α1-AR antagonist DOX, the α2-AR agonist GUB, or the AC inhibitor SQ was given to 4-week-old WT BALB/c mice by i.p. injection 30 minutes prior to white light exposure at 10,000 lux for 1 hour. BALB/c mice were used to reduce absorption of light by the RPE pigment. Doses of each compound were as follows: DOX, 10 mg/kg; GUB, 2.0 mg/kg; and SQ, 0.5 mg/kg. Effects of these compounds were evaluated by spectral domain optical coherence tomography (SD-OCT) imaging 7 days after light exposure. Representative images of SD-OCT 500 μm away from the optic nerve head in the superior retina are shown in the left panels. Asterisks indicate damaged photoreceptor structures evident only in DMSO-treated control mice. Retinal cross-sectional images of plastic sections (middle panels) were obtained from areas similar to those used for the OCT images. Retinal autofluorescence also was examined by SLO 7 days after light exposure (right panels). Numbers (means ± SEM) of bright spots are indicated at the right bottom of the SLO images. Scale bars: 50 μm.