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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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 11

GPCR-targeted therapeutics prevent formation of large fluorescent granules in the RPE of 6- to 7-week-old Abca4–/–Rdh8–/– mice after exposure to bright light.

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GPCR-targeted therapeutics prevent formation of large fluorescent granul...
(A) Representative TPM images of the RPE 10 days after exposure to bright light. Upper left panel, unexposed to light (No light) control; upper right panel, exposed to bright light (Bleached) and DMSO-treated control; lower left panel, pretreated with PRA; lower right panel, pretreated with GUB. Cross sections shown at the right edge and at the bottom of each en face RPE image reveal that fluorescent granules, most pronounced in the bleached DMSO-treated control, extend across the whole thickness of the RPE and into the outer retina-photoreceptor space. Scale bars: 25 μm. (B) Emission spectra after excitation with 730 nm light (left panel) and after excitation with 850 nm light (right panel). The spectra from light-exposed, DMSO-treated control are notably red-shifted for both excitation wavelengths.