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 10

Detection and quantification of DOX, GUB, and SQ in mouse eye.

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Detection and quantification of DOX, GUB, and SQ in mouse eye. (A) HPLC ...
(A) HPLC separation of SQ (peak 1), clenbuterol (IS) (peak 2), and GUB (peak 3). (B–D) MS and MS2 patterns for SQ, clenbuterol, and GUB, respectively. Characteristic fragmentation profiles were used to design the selected reaction monitoring-based detection and quantification method. (E) Elution profile of PRA (IS) (peak 1) and DOX (peak 2). (F and G) MS and MS2 fragmentation pattern for PRA and DOX. (H) Relationship between ion intensities and molar ratio for drug/internal standard pairs (DOX/PRA [black triangles] and overlapping black and white circles for GUB/clenbuterol and SQ/clenbuterol, respectively), which were used for IS-based drug quantification. (I–K) Representative chromatograms of the eye extract indicating the presence of DOX, GUB, and SQ, respectively. Black chromatograms correspond to ion intensities of SRM transitions characteristic for the tested drugs. Gray lines represent ion intensities for the ISs. Letters “T” and “C” discriminate between samples obtained from drug-treated mice (T) and control, nontreated animals (C).