Systems pharmacology identifies drug targets for Stargardt disease-associated retinal degeneration.
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.
Yu
Y
Chen
Grazyna
G
Palczewska
Debarshi
D
Mustafi
Marcin
M
Golczak
Zhiqian
Z
Dong
Osamu
O
Sawada
Tadao
T
Maeda
Akiko
A
Maeda
Krzysztof
K
Palczewski
D018528:ATP-Binding Cassette Transporters / Q000172:deficiency / Q000235:genetics; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000067956:Adenylyl Cyclase Inhibitors; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D000429:Alcohol Oxidoreductases / Q000172:deficiency / Q000235:genetics; D000818:Animals; D002470:Cell Survival; D004195:Disease Models, Animal; D017292:Doxazosin / Q000494:pharmacology / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D006143:Guanabenz / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008027:Light / Q000009:adverse effects; D008252:Macaca fascicularis; D008268:Macular Degeneration / Q000151:congenital* / Q000188:drug therapy / Q000235:genetics / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects* / Q000473:pathology / Q000502:physiology / Q000528:radiation effects; D017382:Reactive Oxygen Species; D044402:Receptor, Serotonin, 5-HT2A / Q000096:biosynthesis* / Q000235:genetics; D018341:Receptors, Adrenergic, alpha-2 / Q000096:biosynthesis* / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis / Q000235:genetics; D012702:Serotonin Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction; D000080362:Stargardt Disease
D018528:ATP-Binding Cassette Transporters; D000225:Adenine; D000067956:Adenylyl Cyclase Inhibitors; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D000429:Alcohol Oxidoreductases; D017292:Doxazosin; D006143:Guanabenz; D009419:Nerve Tissue Proteins; D017382:Reactive Oxygen Species; D044402:Receptor, Serotonin, 5-HT2A; D018341:Receptors, Adrenergic, alpha-2; D043562:Receptors, G-Protein-Coupled; D012702:Serotonin Antagonists; C056475:ABCA4 protein, human; C547774:ADRA2C protein, human; C512841:Abca4 protein, mouse; C547775:Adra2c protein, mouse; C017759:9-(tetrahydro-2-furyl)-adenine; C525880:HSD17B6 protein, mouse