{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T09:09:38Z","timestamp":1790932178518,"version":"4.1.0"},"reference-count":20,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2009,8,7]],"date-time":"2009-08-07T00:00:00Z","timestamp":1249603200000},"content-version":"vor","delay-in-days":6,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2009,8]]},"abstract":"<jats:sec><jats:label\/><jats:p> <jats:bold>WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT<\/jats:bold> <\/jats:p><jats:p>\u2022\u2003Corneal proliferative angiogenesis is an orphan disease leading to cornea loss.<\/jats:p><jats:p>\u2022\u2003Today's therapeutic approach is not clearly established, although essentially based on topical corticosteroids.<\/jats:p><jats:p>\u2022\u2003There is therefore a need for new therapeutic alternatives specifically targeting angiogenesis.<\/jats:p><jats:p> <jats:bold>WHAT THIS PAPER ADDS<\/jats:bold> <\/jats:p><jats:p>\u2022\u2003Preclinical data demonstrated the efficacy of GS\u2010101, an antisense oligonucleotide inhibiting insulin receptor substrate\u20101 expression, at inhibiting experimental corneal angiogenesis.<\/jats:p><jats:p>\u2022\u2003This study demonstrates the excellent safety and tolerability profile of GS\u2010101 applied as eye drops three times daily in this \u2018first\u2010in\u2010man\u2019 study.<\/jats:p><jats:p>\u2022\u2003Upon validation in human of its immediate benefit, GS\u2010101 would offer an alternative to antivascular endothelial growth factor therapies in the treatment of corneal angiogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>AIMS<\/jats:title><jats:p>GS\u2010101 (GeneSignal, Epalinges, Switzerland) is an antisense oligonucleotide that inhibits the expression of the scaffold protein insulin receptor substrate\u20101 (IRS\u20101). Inhibition of IRS\u20101 results in the prevention of neovascular growth and was shown to prevent the angiogenic process in preclinical <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> experiments. There is therefore a strong therapeutic rational for targeting angiogenesis in pathological neovascularization. We aimed to investigate the safety, tolerability and bioavailability of GS\u2010101 eye drops.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>This was a Phase I open\u2010label study. The investigation was performed in two steps. Local ocular tolerability was first assessed with the application of one single low dose in one eye. After no signs of intolerance were observed in the subjects, the dose escalation phase of the study was initiated, and the remaining subjects received three times daily escalating doses of GS\u2010101 in one eye for 14 days.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>The 14 healthy volunteers tolerated well 14 days' continued use of escalating doses of GS\u2010101 from 43 to 430\u2003\u00b5g per day. Other than itching, experienced also in the control eye by one subject and determined to be unrelated to the study treatment, no signs of intolerance were observed.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>The tolerability profile obtained from this study suggests that GS\u2010101 is safe for human use. Further clinical evaluations in diseases related to abnormal angiogenesis are being targeted. In particular, the neovascularization\u2010related orphan indications of corneal graft rejection, retinopathy of pre\u2010maturity and neovascular glaucoma are currently under Phase II clinical investigation and are showing promising results.<\/jats:p><\/jats:sec>","DOI":"10.1111\/j.1365-2125.2009.03450.x","type":"journal-article","created":{"date-parts":[[2009,5,6]],"date-time":"2009-05-06T09:21:32Z","timestamp":1241601692000},"page":"169-173","source":"Crossref","is-referenced-by-count":12,"title":["Tolerability and safety of GS\u2010101 eye drops, an antisense oligonucleotide to insulin receptor substrate\u20101: a \u2018first in man\u2019 Phase I investigation"],"prefix":"10.1111","volume":"68","author":[{"given":"Hermann","family":"Kain","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Goldblum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard","family":"Geudelin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Thorin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Beglinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2009,8,7]]},"reference":[{"key":"e_1_2_7_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/1097-4652(200009)184:3<301::AID-JCP3>3.0.CO;2-H"},{"key":"e_1_2_7_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm0195-27"},{"key":"e_1_2_7_4_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-4362.1998.00275.x"},{"key":"e_1_2_7_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/386671a0"},{"key":"e_1_2_7_6_2","doi-asserted-by":"publisher","DOI":"10.1210\/endo.140.5.6724"},{"key":"e_1_2_7_7_2","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1042\/bj20020137","article-title":"The type 2 vascular endothelial growth factor receptor recruits insulin receptor substrate\u20101 in its signalling pathway","volume":"368","author":"Senthil D","year":"2002","journal-title":"Biochem J"},{"key":"e_1_2_7_8_2","doi-asserted-by":"crossref","first-page":"5082","DOI":"10.1128\/MCB.21.15.5082-5093.2001","article-title":"Identification of insulin receptor substrate 1 (IRS\u20101) and IRS\u20102 as signaling intermediates in the alpha6beta4 integrin\u2010dependent activation of phosphoinositide 3\u2010OH kinase and promotion of invasion","volume":"21","author":"Shaw LM","year":"2001","journal-title":"Mol Cell Biol"},{"key":"e_1_2_7_9_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.7527156"},{"key":"e_1_2_7_10_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00514.2001"},{"key":"e_1_2_7_11_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000105902.89459.09"},{"key":"e_1_2_7_12_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M000805200"},{"key":"e_1_2_7_13_2","first-page":"119","article-title":"The IRS\u2010signaling system: a network of docking proteins that mediate insulin and cytokine action","volume":"53","author":"White MF","year":"1998","journal-title":"Recent Prog Horm Res"},{"key":"e_1_2_7_14_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M303314200"},{"key":"e_1_2_7_15_2","doi-asserted-by":"publisher","DOI":"10.1097\/00003226-200304000-00021"},{"key":"e_1_2_7_16_2","doi-asserted-by":"publisher","DOI":"10.1097\/00003226-200007000-00025"},{"key":"e_1_2_7_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/eye.2008.86"},{"key":"e_1_2_7_18_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.108.147496"},{"key":"e_1_2_7_19_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.05-0105"},{"key":"e_1_2_7_20_2","doi-asserted-by":"publisher","DOI":"10.1006\/abio.2002.5576"},{"key":"e_1_2_7_21_2","doi-asserted-by":"crossref","unstructured":"CursiefenC BockF KruseFE BorderieV WilhelmF SchirraF SeitzB MellerD Frueh EpsteinB ThielM.GS\u2010101 eye drops an antisense oligonucleotide against IRS\u20101 inhibit and regress corneal neovascularization: interim results of a multicentre double\u2010blind randomized phase II clinical study.Ophthalmology2009; 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