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 7

Therapeutics targeting Gq-, Gs-, and Gi-coupled GPCRs and AC preserve retinal function in 4- to 5-week-old Abca4–/–Rdh8–/– mice.

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Therapeutics targeting Gq-, Gs-, and Gi-coupled GPCRs and AC preserve re...
Abca4–/–Rdh8–/– mice were exposed to 10,000 lux light for 30 minutes after pretreatment with the pharmacological agents DOX (10 mg/kg BW), LOF (2 mg/kg BW), LY (10 mg/kg BW), RO (30 mg/kg BW), RS (20 mg/kg BW), and SQ (0.5 mg/kg BW). ERGs were recorded to evaluate the effects of these agents on retinal function 2 weeks after light exposure. (A) ERG responses were compared between mice not exposed to intense light (No light), vehicle only (DMSO), and tested agents under both scotopic and photopic conditions. Amplitudes of B waves at 1.6 log cd × s/m2 under scotopic and photopic conditions are shown (B). Tested compounds showed significant protective effects when compared with DMSO-treated mice, which displayed significantly impaired retinal function as indicated by decreased ERG amplitudes. *P < 0.05 compared with DMSO control. Bars indicate SDs. n = 4–6 eyes per group.