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.
View: Text | PDF
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

×

Figure 1

Antagonists of the α1-AR, a Gq-coupled GPCR, protect Abca4–/–Rdh8–/– mouse retinas from bright light–induced degeneration.

Options: View larger image (or click on image) Download as PowerPoint
Antagonists of the α1-AR, a Gq-coupled GPCR, protect Abca4–/–Rdh8–/– mou...
(A) Schematic protocol for pharmacological treatment. All pharmacological compounds tested were administered via i.p. injection to 4- to 5-week-old Abca4–/–Rdh8–/– mice 30 minutes prior to white light exposure at 10,000 lux for 30 minutes. After light exposure, mice were kept in the dark for 7 to 14 days before functional and morphological examination by ERG, OCT, SLO, and IHC. (B) α1-AR antagonists, including DOX, PRA, and TAM, or DMSO vehicle were administered to Abca4–/–Rdh8–/– mice 30 minutes prior to white light exposure. OCT imaging was performed 7 days later to evaluate retinal morphology, and representative OCT images are shown. Asterisk indicates severely disrupted photoreceptor structures in vehicle-treated animals. ONL, outer nuclear layer; INL inner nuclear layer. (C) OCT scores from different treatment groups were subjected to statistical analysis (means ± SEM; *P < 0.01 compared with DMSO control). (D) SLO imaging was performed 8 days after light exposure, and retinal autofluorescence images are shown. (E) Numbers of retinal autofluorescence (AF) spots were counted and subjected to statistical analysis (means ± SEM; *P < 0.01 compared with DMSO control). Scale bars: 50 μm.