title: Phase I clinical trial of SYL040012, a small interfering RNA targeting β-adrenergic receptor 2, for lowering intraocular pressure.
abstract: The objective of this study was to evaluate ocular tolerance, safety, and effect on intraocular pressure (IOP) of a topically administered small interfering RNA; SYL040012, on healthy volunteers. The study was an open-label, controlled, single-center study comprised of two intervals that enrolled 30 healthy subjects having IOP below 21 mmHg. SYL040012 was administered to one eye as a single dose to six subjects during interval 1. During interval 2 two different doses of SYL040012 were administered to one eye on a daily basis to two separate groups of 12 subjects each, over a period of 7 days. The contralateral eye was evaluated but not administered and served as control for the tolerance study. SYL040012 was well tolerated locally. No local or systemic adverse events related to the product developed in response to any of the doses studied. SYL040012 was not detected in plasma at any time point. Administration of SYL040012 over a period of 7 days reduced IOP values in 15 out of 24 healthy subjects regardless of the dose used. IOP decrease was statistically significant in response to one of the doses tested and responsiveness to SYL040012 seemed to be greater in individuals with higher baseline IOP.
authors.affiliation: Department of Opthalmology, Facultad de Medicina, Universidad de Navarra, Pamplona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Moreno-Montañés
authors.affiliation: Department of Pharmacology and Clinical Investigational Unit, Facultad de Medicina, Universidad de Navarra, Pamplona, Spain.
authors.forename: Belén
authors.initials: B
authors.lastname: Sádaba
authors.affiliation: Sylentis, Madrid, Spain.
authors.forename: Verónica
authors.initials: V
authors.lastname: Ruz
authors.affiliation: Department of Opthalmology, Facultad de Medicina, Universidad de Navarra, Pamplona, Spain.
authors.forename: Almudena
authors.initials: A
authors.lastname: Gómez-Guiu
authors.affiliation: Department of Pharmacology and Clinical Investigational Unit, Facultad de Medicina, Universidad de Navarra, Pamplona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Zarranz
authors.affiliation: Sylentis, Madrid, Spain.
authors.forename: María Victoria
authors.initials: MV
authors.lastname: González
authors.affiliation: Sylentis, Madrid, Spain.
authors.forename: Covadonga
authors.initials: C
authors.lastname: Pañeda
authors.affiliation: Sylentis, Madrid, Spain.
authors.forename: Ana Isabel
authors.initials: AI
authors.lastname: Jimenez
mesh_terms: D000293:Adolescent; D000328:Adult; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007429:Intraocular Pressure / Q000235:genetics*; D008297:Male; D009883:Ophthalmic Solutions / Q000008:administration & dosage; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics*; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics* / Q000378:metabolism; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D009883:Ophthalmic Solutions; D034741:RNA, Small Interfering; D018343:Receptors, Adrenergic, beta-2
references.citation: Scand J Clin Lab Invest. 2007;67(2):237-45
references.pmid: 17366003
references.citation: Cell Death Dis. 2011 Jun 16;2:e173
references.pmid: 21677688
references.citation: Br J Clin Pharmacol. 2009 Aug;68(2):169-73
references.pmid: 19694734
references.citation: PLoS One. 2011;6(10):e26466
references.pmid: 22039495
references.citation: Ophthalmic Res. 2012;47(4):171-88
references.pmid: 22123077
references.citation: J Glaucoma. 2011 Apr-May;20(4):234-9
references.pmid: 21682002
references.citation: Curr Opin Pharmacol. 2013 Feb;13(1):50-5
references.pmid: 23069477
references.citation: Adv Genet. 2005;54:117-42
references.pmid: 16096010
references.citation: Jpn J Ophthalmol. 1998 Sep-Oct;42(5):417-23
references.pmid: 9822975
references.citation: Mol Ther. 2006 Apr;13(4):644-70
references.pmid: 16481219
references.citation: Biochem Pharmacol. 2006 Feb 28;71(5):702-10
references.pmid: 16376306
references.citation: Surv Ophthalmol. 2008 Nov;53 Suppl1:S3-10
references.pmid: 19038621
references.citation: Eye (Lond). 2012 Aug;26(8):1099-105
references.pmid: 22627477
references.citation: Methods Find Exp Clin Pharmacol. 2007 Dec;29(10):665-71
references.pmid: 18200329
references.citation: Indian J Ophthalmol. 2011 Jan;59 Suppl:S88-92
references.pmid: 21150040
references.citation: Nature. 2001 May 24;411(6836):494-8
references.pmid: 11373684
references.citation: Graefes Arch Clin Exp Ophthalmol. 2005 Dec;243(12):1221-7
references.pmid: 16003515
references.citation: Proc Natl Acad Sci U S A. 2010 May 11;107(19):8800-5
references.pmid: 20421463
references.citation: Cell. 2000 Mar 31;101(1):25-33
references.pmid: 10778853
references.citation: Nature. 1998 Feb 19;391(6669):806-11
references.pmid: 9486653
references.citation: Drugs Aging. 2011 Apr 1;28(4):267-82
references.pmid: 21428462
references.citation: Mol Ther. 2013 May;21(5):973-85
references.pmid: 23439496
references.citation: Cardiol Rev. 2008 Mar-Apr;16(2):95-108
references.pmid: 18281912