{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T07:30:37Z","timestamp":1792654237807,"version":"4.5.0"},"reference-count":99,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2019,6,14]],"date-time":"2019-06-14T00:00:00Z","timestamp":1560470400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010665","name":"H2020 Marie Sk\u0142odowska-Curie Actions","doi-asserted-by":"publisher","award":["765441"],"award-info":[{"award-number":["765441"]}],"id":[{"id":"10.13039\/100010665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["PA1751\/7-1, 8-1"],"award-info":[{"award-number":["PA1751\/7-1, 8-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Photoreceptor physiology and pathophysiology is intricately linked to guanosine-3\u2019,5\u2019-cyclic monophosphate (cGMP)-signaling. Here, we discuss the importance of cGMP-signaling for the pathogenesis of hereditary retinal degeneration. Excessive accumulation of cGMP in photoreceptors is a common denominator in cell death caused by a variety of different gene mutations. The cGMP-dependent cell death pathway may be targeted for the treatment of inherited photoreceptor degeneration, using specifically designed and formulated inhibitory cGMP analogues. Moreover, cGMP-signaling and its down-stream targets may be exploited for the development of novel biomarkers that could facilitate monitoring of disease progression and reveal the response to treatment in future clinical trials. We then briefly present the importance of appropriate formulations for delivery to the retina, both for drug and biomarker applications. Finally, the review touches on important aspects of future clinical translation, highlighting the need for interdisciplinary cooperation of researchers from a diverse range of fields.<\/jats:p>","DOI":"10.3390\/genes10060453","type":"journal-article","created":{"date-parts":[[2019,6,14]],"date-time":"2019-06-14T11:19:58Z","timestamp":1560511198000},"page":"453","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["The cGMP Pathway and Inherited Photoreceptor Degeneration: Targets, Compounds, and Biomarkers"],"prefix":"10.3390","volume":"10","author":[{"given":"Arianna","family":"Tolone","sequence":"first","affiliation":[{"name":"Institute for Ophthalmic Research, University of T\u00fcbingen, Elfriede-Aulhorn-Strasse 5-7, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soumaya","family":"Belhadj","sequence":"additional","affiliation":[{"name":"Institute for Ophthalmic Research, University of T\u00fcbingen, Elfriede-Aulhorn-Strasse 5-7, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Rentsch","sequence":"additional","affiliation":[{"name":"Biolog Life Science Institute, 28199 Bremen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8185-3392","authenticated-orcid":false,"given":"Frank","family":"Schwede","sequence":"additional","affiliation":[{"name":"Biolog Life Science Institute, 28199 Bremen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"Paquet-Durand","sequence":"additional","affiliation":[{"name":"Institute for Ophthalmic Research, University of T\u00fcbingen, Elfriede-Aulhorn-Strasse 5-7, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,6,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.preteyeres.2014.06.003","article-title":"Functional architecture of the retina: Development and disease","volume":"42","author":"Hoon","year":"2014","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.preteyeres.2018.03.005","article-title":"Non-syndromic retinitis pigmentosa","volume":"66","author":"Verbakel","year":"2018","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"260","DOI":"10.2174\/138920211795860071","article-title":"Good epidemiologic practice in retinitis pigmentosa: From phenotyping to biobanking","volume":"12","author":"Chizzolini","year":"2011","journal-title":"Curr. Genom."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.tig.2004.12.001","article-title":"Light in retinitis pigmentosa","volume":"21","author":"Kennan","year":"2005","journal-title":"Trends Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/1750-1172-2-7","article-title":"Cone rod dystrophies","volume":"2","author":"Hamel","year":"2007","journal-title":"Orphanet. J. Rare. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"598","DOI":"10.2174\/156652412800620048","article-title":"Neuroprotective Strategies for the Treatment of Inherited Photoreceptor Degeneration","volume":"12","author":"Trifunovic","year":"2012","journal-title":"Curr. Mol. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1002\/cne.21144","article-title":"Retinal organization in the retinal degeneration 10 (rd10) mutant mouse: A morphological and ERG study","volume":"500","author":"Gargini","year":"2007","journal-title":"J. Comp. Neurol."},{"key":"ref_8","first-page":"489","article-title":"Differential effect of the rd mutation on rods and cones in the mouse retina","volume":"17","author":"LaVail","year":"1978","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1146\/annurev.ne.09.030186.000511","article-title":"Cyclic GMP cascade of vision","volume":"9","author":"Stryer","year":"1986","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1126\/science.186.4162.449","article-title":"Cyclic guanosine monophosphate: Elevation in degenerating photoreceptor cells of the C3H mouse retina","volume":"186","author":"Farber","year":"1974","journal-title":"Science"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Arango-Gonzalez, B., Trifunovic, D., Sahaboglu, A., Kranz, K., Michalakis, S., Farinelli, P., Koch, S., Koch, F., Cottet, S., and Janssen Bienhold, U. (2014). Identification of a common non-apoptotic cell death mechanism in hereditary retinal degeneration. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0112142"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1152\/jn.00683.2018","article-title":"Temporal resolution of single-photon responses in primate rod photoreceptors and limits imposed by cellular noise","volume":"121","author":"Field","year":"2019","journal-title":"J. Neurophysiol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Michalakis, S., Becirovic, E., and Biel, M. (2018). Retinal Cyclic Nucleotide-Gated Channels: From Pathophysiology to Therapy. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19030749"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.preteyeres.2018.06.001","article-title":"Regulation of calcium homeostasis in the outer segments of rod and cone photoreceptors","volume":"67","author":"Vinberg","year":"2018","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_15","unstructured":"Kulkarni, M., Trifunovic, D., Schubert, T., Euler, T., and Paquet-Durand, F. (2016). Calcium dynamics change in degenerating cone photoreceptors. Hum. Mol. Genet., ddw219."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1126\/science.193183","article-title":"Cyclic GMP accumulation causes degeneration of photoreceptor cells: Simulation of an inherited disease","volume":"196","author":"Lolley","year":"1977","journal-title":"Science"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1038\/ng0693-130","article-title":"Recessive mutations in the gene encoding the beta-subunit of rod phosphodiesterase in patients with retinitis pigmentosa","volume":"4","author":"McLaughlin","year":"1993","journal-title":"Nat. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1038\/ng1295-468","article-title":"Autosomal recessive retinitis pigmentosa caused by mutations in the alpha subunit of rod cGMP phosphodiesterase","volume":"11","author":"Huang","year":"1995","journal-title":"Nat. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1093\/hmg\/ddq539","article-title":"A key role for cyclic nucleotide gated (CNG) channels in cGMP-related retinitis pigmentosa","volume":"20","author":"Beck","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"13897","DOI":"10.1073\/pnas.0404197101","article-title":"Leber congenital amaurosis linked to AIPL1: A mouse model reveals destabilization of cGMP phosphodiesterase","volume":"101","author":"Ramamurthy","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2990","DOI":"10.1523\/JNEUROSCI.2985-17.2018","article-title":"GUCY2D Cone-Rod Dystrophy-6 Is a \u201cPhototransduction Disease\u201d Triggered by Abnormal Calcium Feedback on Retinal Membrane Guanylyl Cyclase 1","volume":"38","author":"Sato","year":"2018","journal-title":"J. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1111\/j.1471-4159.2008.05822.x","article-title":"PKG activity causes photoreceptor cell death in two retinitis pigmentosa models","volume":"108","author":"Hauck","year":"2009","journal-title":"J. Neurochem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.preteyeres.2016.05.003","article-title":"Molecular basis for photoreceptor outer segment architecture","volume":"55","author":"Goldberg","year":"2016","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_24","unstructured":"De la Rosa, E.J., and Cotter, T.G. (2019). Modulation of cGMP-signaling to prevent retinal degeneration. Therapies for Retinal Degeneration: Targeting Common Processes, Royal Society of Chemistry."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1038\/sj.embor.7400627","article-title":"cGMP signaling: From bench to bedside. Conference on cGMP generators, effectors and therapeutic implications","volume":"7","author":"Feil","year":"2006","journal-title":"EMBO Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1126\/science.175.4023.757","article-title":"Cyclic nucleotide phosphodiesterase: High activity in a mammalian photoreceptor","volume":"175","author":"Pannbacker","year":"1972","journal-title":"Science"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Lim, S., Roseman, G., Peshenko, I., Manchala, G., Cudia, D., Dizhoor, A.M., Millhauser, G., and Ames, J.B. (2018). Retinal guanylyl cyclase activating protein 1 forms a functional dimer. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0193947"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"24504","DOI":"10.1074\/jbc.M116.755553","article-title":"The R838S Mutation in Retinal Guanylyl Cyclase 1 (RetGC1) Alters Calcium Sensitivity of cGMP Synthesis in the Retina and Causes Blindness in Transgenic Mice","volume":"291","author":"Dizhoor","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Makino, C.L., Wen, X.H., Olshevskaya, E.V., Peshenko, I.V., Savchenko, A.B., and Dizhoor, A.M. (2012). Enzymatic relay mechanism stimulates cyclic GMP synthesis in rod photoresponse: Biochemical and physiological study in guanylyl cyclase activating protein 1 knockout mice. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0047637"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1023\/A:1014248208584","article-title":"Factors that affect regulation of cGMP synthesis in vertebrate photoreceptors and their genetic link to human retinal degeneration","volume":"230","author":"Olshevskaya","year":"2002","journal-title":"Mol. Cell. Biochem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1111\/j.1749-6632.1999.tb07837.x","article-title":"Calcium overload triggers rod photoreceptor apoptotic cell death in chemical-induced and inherited retinal degenerations","volume":"893","author":"Fox","year":"1999","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1038\/13508","article-title":"Retinitis pigmentosa: Rod photoreceptor rescue by a calcium-channel blocker in the rd mouse","volume":"5","author":"Frasson","year":"1999","journal-title":"Nat. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.exer.2007.09.008","article-title":"Systemic administration of nilvadipine delays photoreceptor degeneration of heterozygous retinal degeneration slow (rds) mouse","volume":"86","author":"Takeuchi","year":"2008","journal-title":"Exp. Eye Res."},{"key":"ref_34","first-page":"42","article-title":"Calcium channel blocker D-cis-diltiazem does not slow retinal degeneration in the PDE6B mutant rcd1 canine model of retinitis pigmentosa","volume":"7","author":"Aleman","year":"2001","journal-title":"Mol. Vis."},{"key":"ref_35","first-page":"1912","article-title":"Absence of photoreceptor rescue with D-cis-diltiazem in the rd mouse","volume":"43","author":"Pawlyk","year":"2002","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1007\/978-1-4419-1399-9_56","article-title":"Do calcium channel blockers rescue dying photoreceptors in the Pde6b (rd1) mouse?","volume":"664","author":"Barabas","year":"2010","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1152\/physrev.00015.2005","article-title":"Function of cGMP-dependent protein kinases as revealed by gene deletion","volume":"86","author":"Hofmann","year":"2006","journal-title":"Physiol. Rev."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Hofmann, F., Bernhard, D., Lukowski, R., and Weinmeister, P. (2009). cGMP regulated protein kinases (cGK). Handb. Exp. Pharmacol., 137\u2013162.","DOI":"10.1007\/978-3-540-68964-5_8"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1002\/1873-3468.12228","article-title":"Intracellular calcium signaling regulates glomerular filtration barrier permeability: The role of the PKGIalpha-dependent pathway","volume":"590","author":"Piwkowska","year":"2016","journal-title":"FEBS Lett."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1016\/j.neuroscience.2005.06.051","article-title":"Distribution of cGMP-dependent protein kinase type I and its isoforms in the mouse brain and retina","volume":"135","author":"Feil","year":"2005","journal-title":"Neuroscience"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3478","DOI":"10.2174\/0929867321666140601201337","article-title":"Novel in situ activity assays for the quantitative molecular analysis of neurodegenerative processes in the retina","volume":"21","author":"Ekstrom","year":"2014","journal-title":"Curr. Med. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3045","DOI":"10.1093\/emboj\/17.11.3045","article-title":"Defective smooth muscle regulation in cGMP kinase I-deficient mice","volume":"17","author":"Pfeifer","year":"1998","journal-title":"EMBO J."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1161\/CIRCRESAHA.107.154351","article-title":"Rescue of cGMP kinase I knockout mice by smooth muscle specific expression of either isozyme","volume":"101","author":"Weber","year":"2007","journal-title":"Circ. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1038\/nm.2634","article-title":"cGMP-Prkg1 signaling and Pde5 inhibition shelter cochlear hair cells and hearing function","volume":"18","author":"Jaumann","year":"2012","journal-title":"Nat. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1016\/S0960-9822(03)00252-5","article-title":"cGMP-dependent protein kinase II modulates mPer1 and mPer2 gene induction and influences phase shifts of the circadian clock","volume":"13","author":"Oster","year":"2003","journal-title":"Curr. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3360","DOI":"10.1111\/j.1742-4658.2011.08260.x","article-title":"Cyclic GMP induced apoptosis via protein kinase G in oestrogen receptor-positive and -negative breast cancer cell lines","volume":"278","author":"Fallahian","year":"2011","journal-title":"FEBS J."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1517\/14728222.12.3.367","article-title":"Protein kinase G as a therapeutic target for the treatment of metastatic colorectal cancer","volume":"12","author":"Browning","year":"2008","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1158\/1541-7786.MCR-09-0178","article-title":"Protein kinase G type Ialpha activity in human ovarian cancer cells significantly contributes to enhanced Src activation and DNA synthesis\/cell proliferation","volume":"8","author":"Leung","year":"2010","journal-title":"Mol. Cancer Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"21542","DOI":"10.1074\/jbc.M213174200","article-title":"Nitric oxide triggers the toxicity due to glutathione depletion in midbrain cultures through 12-lipoxygenase","volume":"278","author":"Canals","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1002\/jnr.20971","article-title":"Involvement of the nitric oxide\/protein kinase G pathway in polychlorinated biphenyl-induced cell death in SH-SY 5Y neuroblastoma cells","volume":"84","author":"Canzoniero","year":"2006","journal-title":"J. Neurosci. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2299","DOI":"10.1093\/hmg\/ddx121","article-title":"Two pathways of rod photoreceptor cell death induced by elevated cGMP","volume":"26","author":"Wang","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"14772","DOI":"10.1073\/pnas.97.26.14772","article-title":"Highly specific, membrane-permeant peptide blockers of cGMP-dependent protein kinase Ialpha inhibit NO-induced cerebral dilation","volume":"97","author":"Dostmann","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"269","DOI":"10.3390\/ph6020269","article-title":"cGMP-Dependent Protein Kinase Inhibitors in Health and Disease","volume":"6","author":"Wolfertstetter","year":"2013","journal-title":"Pharmaceuticals (Basel)"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Falk, J., Drinjakovic, J., Leung, K.M., Dwivedy, A., Regan, A.G., Piper, M., and Holt, C.E. (2007). Electroporation of cDNA\/Morpholinos to targeted areas of embryonic CNS in Xenopus. BMC. Dev. Biol., 7.","DOI":"10.1186\/1471-213X-7-107"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1007\/s10585-012-9464-6","article-title":"Insidious role of nitric oxide in migration\/invasion of colon cancer cells by upregulating MMP-2\/9 via activation of cGMP-PKG-ERK signaling pathways","volume":"29","author":"Babykutty","year":"2012","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"33536","DOI":"10.1074\/jbc.M005670200","article-title":"KT5823 inhibits cGMP-dependent protein kinase activity in vitro but not in intact human platelets and rat mesangial cells","volume":"275","author":"Burkhardt","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1146\/annurev.pa.32.040192.002113","article-title":"Pharmacology of protein kinase inhibitors","volume":"32","author":"Hidaka","year":"1992","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1111\/j.1476-5381.2012.02044.x","article-title":"The oligopeptide DT-2 is a specific PKG I inhibitor only in vitro, not in living cells","volume":"167","author":"Gambaryan","year":"2012","journal-title":"Br. J. Pharmacol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/S0968-0004(97)01086-4","article-title":"Distinct and specific functions of cGMP-dependent protein kinases","volume":"22","author":"Lohmann","year":"1997","journal-title":"Trends Biochem. Sci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/S0163-7258(00)00051-6","article-title":"Cyclic nucleotide analogs as biochemical tools and prospective drugs","volume":"87","author":"Schwede","year":"2000","journal-title":"Pharmacol. Ther."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.ejmech.2017.09.053","article-title":"New dimeric cGMP analogues reduce proliferation in three colon cancer cell lines","volume":"141","author":"Hoffmann","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"5301","DOI":"10.18632\/oncotarget.23685","article-title":"New cGMP analogues restrain proliferation and migration of melanoma cells","volume":"9","author":"Vighi","year":"2018","journal-title":"Oncotarget"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"31929","DOI":"10.1074\/jbc.272.50.31929","article-title":"Progressive cyclic nucleotide-induced conformational changes in the cGMP-dependent protein kinase studied by small angle X-ray scattering in solution","volume":"272","author":"Zhao","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"8813","DOI":"10.1073\/pnas.82.24.8813","article-title":"Interaction of hydrolysis-resistant analogs of cyclic GMP with the phosphodiesterase and light-sensitive channel of retinal rod outer segments","volume":"82","author":"Zimmerman","year":"1985","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"E2997","DOI":"10.1073\/pnas.1718792115","article-title":"Combination of cGMP analogue and drug delivery system provides functional protection in hereditary retinal degeneration","volume":"115","author":"Vighi","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3110","DOI":"10.1111\/j.1476-5381.1995.tb15112.x","article-title":"Inhibition of cyclic GMP-dependent protein kinase-mediated effects by (Rp)-8-bromo-PET-cyclic GMPS","volume":"116","author":"Butt","year":"1995","journal-title":"Br. J. Pharmacol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/0922-4106(94)90095-7","article-title":"(Rp)-8-pCPT-cGMPS, a novel cGMP-dependent protein kinase inhibitor","volume":"269","author":"Butt","year":"1994","journal-title":"Eur. J. Pharmacol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.pharmthera.2017.02.009","article-title":"Retinal biomarkers provide \"insight\" into cortical pharmacology and disease","volume":"175","author":"Nguyen","year":"2017","journal-title":"Pharmacol. Ther."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.1093\/brain\/awx088","article-title":"Real-time imaging of single neuronal cell apoptosis in patients with glaucoma","volume":"140","author":"Cordeiro","year":"2017","journal-title":"Brain"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1989","DOI":"10.1021\/bc3003309","article-title":"Biomarkers and molecular probes for cell death imaging and targeted therapeutics","volume":"23","author":"Smith","year":"2012","journal-title":"Bioconjug. Chem."},{"key":"ref_71","unstructured":"Camara, M.-F.d.l., Salom, D., Sequedo, M.D., Hervas, D., Marin-Lambies, C., Aller, E., Jaijo, T., Diaz-Llopis, M., Millan, J.M., and Rodrigo, R. (2013). Altered antioxidant-oxidant status in the aqueous humor and peripheral blood of patients with retinitis pigmentosa. PLoS ONE, 8."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"6048","DOI":"10.1167\/iovs.16-19861","article-title":"Increased Plasma cGMP in a Family With Autosomal Recessive Retinitis Pigmentosa Due to Homozygous Mutations in the PDE6A Gene","volume":"57","author":"Kjellstrom","year":"2016","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1016\/j.exer.2005.01.018","article-title":"Retinal degeneration and local oxygen metabolism","volume":"80","author":"Yu","year":"2005","journal-title":"Exp. Eye Res."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1146\/annurev.ne.19.030196.001155","article-title":"Neuronal intermediate filaments","volume":"19","author":"Lee","year":"1996","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1601","DOI":"10.1007\/s00702-009-0316-8","article-title":"A novel biomarker for retinal degeneration: Vitreous body neurofilament proteins","volume":"116","author":"Petzold","year":"2009","journal-title":"J. Neural. Transm. (Vienna)"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"e3","DOI":"10.1038\/cddis.2009.3","article-title":"Imaging multiple phases of neurodegeneration: A novel approach to assessing cell death in vivo","volume":"1","author":"Cordeiro","year":"2010","journal-title":"Cell Death. Dis."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1038\/s41418-017-0012-4","article-title":"Molecular mechanisms of cell death: Recommendations of the Nomenclature Committee on Cell Death 2018","volume":"25","author":"Galluzzi","year":"2018","journal-title":"Cell Death Differ."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1007\/s12035-008-8045-9","article-title":"Photoreceptor cell death mechanisms in inherited retinal degeneration","volume":"38","author":"Kustermann","year":"2008","journal-title":"Mol. Neurobiol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"20880","DOI":"10.1074\/jbc.M115.641159","article-title":"cGMP\/Protein Kinase G Signaling Suppresses Inositol 1,4,5-Trisphosphate Receptor Phosphorylation and Promotes Endoplasmic Reticulum Stress in Photoreceptors of Cyclic Nucleotide-gated Channel-deficient Mice","volume":"290","author":"Ma","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_80","first-page":"1","article-title":"Excessive HDAC activation is critical for neurodegeneration in the rd1 mouse","volume":"1","author":"Alavi","year":"2010","journal-title":"Cell Death Dis."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1002\/jnr.21151","article-title":"Calpain activity in retinal degeneration","volume":"85","author":"Johnson","year":"2007","journal-title":"J. Neurosci. Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"e1558","DOI":"10.1038\/cddis.2014.512","article-title":"DNA methylation and differential gene regulation in photoreceptor cell death","volume":"5","author":"Farinelli","year":"2014","journal-title":"Cell Death Dis."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"10311","DOI":"10.1523\/JNEUROSCI.1514-07.2007","article-title":"Excessive activation of poly(ADP-ribose) polymerase contributes to inherited photoreceptor degeneration in the retinal degeneration 1 mouse","volume":"27","author":"Silva","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"39537","DOI":"10.1038\/srep39537","article-title":"Olaparib significantly delays photoreceptor loss in a model for hereditary retinal degeneration","volume":"6","author":"Sahaboglu","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1517\/17425247.2010.490554","article-title":"Systemic delivery of therapeutics to neuronal tissues: A barrier modulation approach","volume":"7","author":"Campbell","year":"2010","journal-title":"Expert. Opin. Drug Deliv."},{"key":"ref_86","unstructured":"Yeh, S., Kurup, S.K., Wang, R.C., Foster, C.S., Noronha, G., Nguyen, Q.D., Do, D.V., and Team, D.S. (2018). Suprachoroidal Injection of Triamcinolone Acetonide, CLS-TA, for macular edema due to noninfectious uveitis: A Randomized, Phase 2 Study (DOGWOOD). Retina."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"4155","DOI":"10.1167\/iovs.17-22402","article-title":"Subretinal Injection for Gene Therapy Does Not Cause Clinically Significant Outer Nuclear Layer Thinning in Normal Primate Foveae","volume":"58","author":"Ochakovski","year":"2017","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1111\/aos.12803","article-title":"Topical dexamethasone gamma-cyclodextrin nanoparticle eye drops increase visual acuity and decrease macular thickness in diabetic macular oedema","volume":"93","author":"Ohira","year":"2015","journal-title":"Acta Ophthalmol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1159\/000431143","article-title":"Routes for Drug Delivery to the Eye and Retina: Intravitreal Injections","volume":"55","author":"Meyer","year":"2016","journal-title":"Dev. Ophthalmol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1016\/S0140-6736(13)62117-0","article-title":"Retinal gene therapy in patients with choroideremia: Initial findings from a phase 1\/2 clinical trial","volume":"383","author":"MacLaren","year":"2014","journal-title":"Lancet"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.cell.2018.03.021","article-title":"Gene Therapy for Retinal Degeneration","volume":"173","author":"Apte","year":"2018","journal-title":"Cell"},{"key":"ref_92","first-page":"CD005139","article-title":"Anti-vascular endothelial growth factor for neovascular age-related macular degeneration","volume":"3","author":"Solomon","year":"2019","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Himawan, E., Ekstr\u00f6m, P., Buzgo, M., Gaillard, P., Stefansson, E., Marigo, V., Loftsson, T., and Paquet-Durand, F. (2019). Drug delivery to retinal photoreceptors. Drug Discov. Today, in press.","DOI":"10.1016\/j.drudis.2019.03.004"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.preteyeres.2016.12.001","article-title":"Pharmacokinetic aspects of retinal drug delivery","volume":"57","author":"Rimpela","year":"2017","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1910","DOI":"10.1167\/iovs.17-22494","article-title":"Humoral Immune Response After Intravitreal But Not After Subretinal AAV8 in Primates and Patients","volume":"59","author":"Reichel","year":"2018","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1136\/bjophthalmol-2015-307707","article-title":"Incidence and clinical features of post-injection endophthalmitis according to diagnosis","volume":"100","author":"Rayess","year":"2015","journal-title":"Br. J. Ophthalmol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1016\/0024-3205(83)90915-3","article-title":"Transport and metabolism of N6- and C8-substituted analogs of adenosine 3\u2019,5\u2019-cyclic monophosphate and adenosine 3\u20195\u2019-cyclic phosphorothioate by the isolated perfused rat kidney","volume":"32","author":"Coulson","year":"1983","journal-title":"Life Sci."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.ddtec.2016.09.003","article-title":"Glutathione conjugation dose-dependently increases brain-specific liposomal drug delivery in vitro and in vivo","volume":"20","author":"Maussang","year":"2016","journal-title":"Drug Discov. Today Technol."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Williams, M.L., Coleman, J.E., Haire, S.E., Aleman, T.S., Cideciyan, A.V., Sokal, I., Palczewski, K., Jacobson, S.G., and Semple-Rowland, S.L. (2006). Lentiviral expression of retinal guanylate cyclase-1 (RetGC1) restores vision in an avian model of childhood blindness. PLoS Med., 3.","DOI":"10.1371\/journal.pmed.0030201"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/10\/6\/453\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:58:29Z","timestamp":1760187509000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/10\/6\/453"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,6,14]]},"references-count":99,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2019,6]]}},"alternative-id":["genes10060453"],"URL":"https:\/\/doi.org\/10.3390\/genes10060453","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,6,14]]}}}