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 2

Agonists of the α2-AR, a Gi-coupled GPCR, protect Abca4–/–Rdh8–/– mouse retinas from bright light–induced degeneration.

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Agonists of the α2-AR, a Gi-coupled GPCR, protect Abca4–/–Rdh8–/– mouse ...
The α2-AR agonists LOF, GUB, and GUF 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. DMSO was used as a vehicle control. (A) OCT imaging was performed to evaluate the effect of each treatment 7 days after light exposure. Asterisk indicates a markedly damaged photoreceptor structure in vehicle-treated control animals. (B) Statistical analysis of OCT scores (means ± SEM; *P < 0.01 compared to DMSO control). (C) SLO imaging was performed to detect autofluorescence 8 days after light exposure. Representative retinal autofluorescence images correlated positively with retinal damage. (D) SLO autofluorescence spot counts were further analyzed for statistical significance (means ± SEM; *P < 0.01 compared to DMSO control). Retinal autofluorescence images correlated positively with retinal damage revealed by OCT imaging. Scale bars indicate 50 μm.