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Systems Pharmacology Identifies Drug Targets for Stargardt Disease

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Systems Pharmacology Identifies Drug Targets for Stargardt Disease Research article Systems pharmacology identifies drug targets for Stargardt disease–associated retinal degeneration Yu Chen,1 Grazyna Palczewska,2 Debarshi Mustafi,1 Marcin Golczak,1 Zhiqian Dong,2 Osamu Sawada,3 Tadao Maeda,3 Akiko Maeda,1,3 and Krzysztof Palczewski1 1Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA. 2Polgenix, Inc., Cleveland, Ohio, USA. 3Department of Ophthalmology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA. A systems pharmacological approach that capitalizes on the characterization of intracellular signaling net- works 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 interven- tion. 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 accumula- tion of pathological fluorescent deposits in the retina. These findings demonstrate a strategy for the identifi- cation of new drug candidates and FDA-approved drugs for the treatment of monogenic and complex diseases. Introduction through the optic nerve but is accessible to various biochemical Decades of scientific advances have identified a large number of and electrophysiological analyses (23–25). Retinal degeneration monogenic inherited (1–3) and complex genetic traits (4–7) that, and pathological changes can be monitored by three key non- along with environmental insults to organs and tissues with fully invasive imaging techniques: scanning laser ophthalmoscopy delineated specific genetic backgrounds (8–10), can drive disease (SLO) (26), optical coherence tomography (OCT) (27, 28), and progression in humans. In addition to identifying causes of these two-photon microscopy (TPM) (29–33). diseases, such as DNA sequence variants, it has been demonstrated Stargardt disease, the most common juvenile form of retinal that the activation of specific metabolic and signaling pathways macular degeneration, is associated with more than 800 muta- can accelerate disease pathology (11, 12). Characterization of these tions in the ABCA4 gene (34). ABCA4 is an ATP-binding cassette pathways has also instigated ideas of potentially treating certain transporter that shuttles all- trans-retinal (atRAL) from the internal human conditions by either blocking or activating them (e.g., refs. membranes of retinal outer segment discs to the cytoplasm, where 11, 13), but in most cases, possible links between such pathways it is reduced to retinol by retinol dehydrogenases (RDHs) (35). and human disease are unclear or unexplored. Moreover, some of Although the Abca4–/– mouse model fails to mimic the human dis- these pathways at first glance appear unrelated. In recent years, ease phenotype (36, 37), simultaneous removal of RDH8, the next new concepts of quantitative systems pharmacology have emerged enzyme in this retinoid pathway (37, 38), results in double-knock- that integrate systems biology and pharmacology (14–18). In out Abca4–/–Rdh8–/– mice that exhibit many phenotypic changes the present genomic era, the process of integration has further found in patients with Stargardt disease. Here, the retinal pathol- advanced with massive sequencing data obtained from tissue- ogy can be traced to the cytotoxic effect of atRAL (31). Exposure of specific transcriptomes by next-generation sequencing that simul- Abca4–/–Rdh8–/– mice to bright light consistently increased atRAL taneously provides quantitative identification of all transduction levels in the retina, which induced rapid NADPH oxidase–medi- cascades (19, 20). This connection can improve our understanding ated overproduction of intracellular ROS through a cascade impli- 2+ of drug action from diverse classes of pharmaceuticals. Moreover, cating GPCR and PLC/IP3/Ca signaling (39). systems pharmacology promises to identify new uses of existing Despite delineating the genetic contributions that give rise to drugs for combined therapies. Stargardt disease, lack of understanding the precise pathways that The vertebrate retina is exceptionally suited for systems phar- drive this disease has resulted in inadequate therapeutics for this macology because of its isolation from other organs and easy disorder. With the hypothesis that activation and/or inhibition of diagnostic access. Nurtured by a rich choroid coat situated key GPCRs in the retina can affect disease progression, we used between the photoreceptors/retinal pigment epithelium (RPE) a systems pharmacological approach with Abca4–/–Rdh8–/– mice and sclera (21, 22), the retina connects with the brain only that specifically targeted signal transduction by several different GPCRs and their interconnected mechanisms to identify novel Conflict of interest: The authors have declared that no conflict of interest exists. therapeutic strategies for treating blinding retinal disorders such Citation for this article: J Clin Invest. 2013;123(12):5119–5134. doi:10.1172/JCI69076. as Stargardt disease and age-related macular degeneration (AMD). The Journal of Clinical Investigation http://www.jci.org Volume 123 Number 12 December 2013 5119 research article Table 1 Results Expression of ARs, 5-HT receptors, and ACs in the eye and retina of C57BL/6J Expression of GPCRs and GPCR signaling genes in human mice, the eye of photoreceptor-degenerated Rho –/– mice, the retina of a human and mouse retinas. Expression analysis of retinal GPCRs donor eye, and macular tissue from monkey (Macaca fasicularis)A by immunocytochemistry was unreliable for reasons that include poor specificity and low affinity of anti- Gene B6 mouse B6 mouse Rho–/– mouse Human Monkey bodies (data not shown) as well as low GPCR expres- eye retina eye retina macula sion. Therefore, we turned to quantitative transcrip- tome analysis of human and mouse retinas without ACs specific cellular localization. Adcy1 17.53 37.50 9.72 68.60 81.26 Overall, we conducted gene ontology analysis in 14.41 21.70 22.96 5.78 11.42 Adcy2 Mus musculus and found 1,766 unique gene prod- Adcy3 5.59 5.09 1.57 5.70 21.21 ucts categorized as having GPCR activity. The same Adcy4 1.34 0.54 2.52 1.18 0.48 Adcy5 7.19 11.15 11.14 8.00 12.79 mouse transcripts were also recognized in the retinal Adcy6 17.68 49.98 11.41 9.99 7.25 transcriptome from Homo sapiens. Of these 1,766, we Adcy7 4.95 0.75 0.60 1.14 2.46 found that 165 genes displayed expression of at least Adcy8 2.13 3.80 2.76 3.73 8.94 1 fragment per kilobase of exon per million mapped Adcy9 3.05 3.99 3.53 4.64 ND reads (FPKM), equivalent to 1 transcript per cell, in Adcy10 0.02 0.03 0.01 0.01 0.33 C57BL/6J mouse eye or retina, with 6 genes below ARs the 1-FPKM threshold in mouse eye, but above the Adra1a 0.45 0.26 0.63 0.20 1.35 1-FPKM threshold in mouse retina (Supplemental Adra1b 1.60 1.62 2.35 1.12 6.61 Table 1; supplemental material available online with Adra1d 1.72 3.83 4.26 0.08 3.97 this article; doi:10.1172/JCI69076DS1). Expression of Adra2a 4.60 9.91 6.14 0.25 0.67 these 165 genes from human retina is also displayed Adra2b 0.20 0.29 0.20 0.02 0.06 as decreasing FPKM values starting from rhodopsin Adra2c 8.96 7.17 19.28 2.38 4.30 (RHO), the most highly expressed gene in mouse eye. 5-HT receptors The most highly expressed human GPCR was rhodop- Htr1a 0.17 0.28 0.13 0.15 0.16 sin, followed by retinal G protein receptor (RGR) and Htr1b 1.80 3.99 1.05 0.80 8.22 the cone pigments OPN1SW and OPN1MW. Htr1d 1.49 2.58 1.91 0.00 0.07 We performed a more detailed analysis of adeny- Htr1f 0.03 0.04 0.03 0.44 0.06 late cyclases (ACs), α1-adrenergic receptors (α1-ARs), Htr2a 0.67 0.72 0.68 1.30 0.67 α2-ARs, and serotonin receptors (5-HTRs) to detect Htr2b 0.50 0.43 0.30 0.39 0.86 potential pathways that could be affected by a sys- Htr2c 0.56 0.73 0.52 0.02 0.27 tems pharmacological approach. Reaction-quenching Htr4 0.02 0.01 0.01 0.43 0.05 Htr5a 0.43 0.59 0.48 0.00 2.17 molecules, such as arrestins and GPCR kinases, were Htr6 0.19 0.36 0.29 0.00 0.29 also investigated (Table 1). Expression values for these Htr7 0.31 0.31 0.41 0.01 0.59 genes in mouse and human retinas highlighted those Arrestins pathways that should be most susceptible to pharma- cological treatment as well as those targets that would Sag 1220.54 1805.26 301.99 3562.22 2248.35 best translate from mouse models to human patients. Arrb1 18.38 18.10 9.42 8.21 18.22 Arrb2 8.86 14.99 11.92 17.92 21.68 For example, among isoforms of the α1-ARs and Arr3 50.73 128.48 32.62 270.16 680.86 α2-ARs, the human retina expressed α2C-AR at the highest level (Table 1), and among 5-HTRs, 5-HT2AR GPCR kinases had the highest expression.
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