title: In vitro and in vivo efficacy of SYL040012, a novel siRNA compound for treatment of glaucoma.
abstract: Glaucoma is a progressive ocular syndrome characterized by degeneration of the optic nerve and irreversible visual field loss. Elevated intraocular pressure (IOP) is the main risk factor for glaucoma. Increased IOP is the result of an imbalance between synthesis and outflow of aqueous humor (AH). Blocking β2 adrenergic receptor (ADRB2) has shown to reduce IOP by decreasing production of AH at the ciliary body (CB). SYL040012 is a siRNA designed to specifically silence ADRB2 currently under development for glaucoma treatment. Here, we show that SYL040012 specifically reduces ADRB2 expression in cell cultures and eye tissues. The compound enters the eye shortly after administration in eye drops and is rapidly distributed among structures of the anterior segment of the eye. In addition, SYL040012 is actively taken up by cells of the CB but not by cells of systemic organs such as the lungs, where inhibition of ADRB2 could cause undesirable side effects. Moreover, SYL040012 reduces IOP in normotensive and hypertensive animal models and the effect appears to be long lasting and extremely well tolerated both locally and systemically.
authors.affiliation: Department of R&D, Sylentis, Madrid, Spain.
authors.forename: Tamara
authors.initials: T
authors.lastname: Martínez
authors.affiliation: Department of R&D, Sylentis, Madrid, Spain.
authors.forename: Maria Victoria
authors.initials: MV
authors.lastname: González
authors.affiliation: Axolabs GmbH, Kulmbach, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Roehl
authors.affiliation: Department of R&D, Sylentis, Madrid, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Wright
authors.affiliation: Department of R&D, Sylentis, Madrid, Spain.
authors.forename: Covadonga
authors.initials: C
authors.lastname: Pañeda
authors.affiliation: Department of R&D, Sylentis, Madrid, Spain.
authors.forename: Ana Isabel
authors.initials: AI
authors.lastname: Jiménez
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D005123:Eye / Q000378:metabolism; D005260:Female; D020868:Gene Silencing; D005901:Glaucoma / Q000235:genetics* / Q000628:therapy*; D006801:Humans; D007429:Intraocular Pressure / Q000235:genetics; D008252:Macaca fascicularis; D008297:Male; D020871:RNA Stability; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011817:Rabbits; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics* / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D034741:RNA, Small Interfering; D018343:Receptors, Adrenergic, beta-2
references.citation: J Pharmacol Exp Ther. 1985 Jan;232(1):119-26
references.pmid: 2856938
references.citation: Nature. 2004 Nov 11;432(7014):173-8
references.pmid: 15538359
references.citation: Scand J Clin Lab Invest. 2007;67(2):237-45
references.pmid: 17366003
references.citation: Per Med. 2008;5(4):377-385
references.pmid: 19266054
references.citation: Cell. 2001 Nov 2;107(3):309-21
references.pmid: 11701122
references.citation: J Ocul Pharmacol. 1993 Winter;9(4):373-84
references.pmid: 7906296
references.citation: EMBO J. 1998 May 1;17(9):2637-50
references.pmid: 9564046
references.citation: J Glaucoma. 2011 Apr-May;20(4):234-9
references.pmid: 21682002
references.citation: BMJ. 2004 Jan 10;328(7431):97-9
references.pmid: 14715605
references.citation: Adv Drug Deliv Rev. 2007 Mar 30;59(2-3):75-86
references.pmid: 17449137
references.citation: Biol Pharm Bull. 2005 Jan;28(1):65-8
references.pmid: 15635165
references.citation: J Pharmacol Methods. 1990 Sep;24(2):79-88
references.pmid: 2232818
references.citation: Adv Genet. 2005;54:117-42
references.pmid: 16096010
references.citation: Am J Ophthalmol. 2011 Sep;152(3):340-344.e2
references.pmid: 21855671
references.citation: Br J Ophthalmol. 1982 Dec;66(12):788-92
references.pmid: 6293532
references.citation: Mol Ther. 2006 Apr;13(4):644-70
references.pmid: 16481219
references.citation: Gen Pharmacol. 1999 Feb;32(2):201-5
references.pmid: 10188620
references.citation: Mol Vis. 2003 May 30;9:210-6
references.pmid: 12789138
references.citation: Adv Drug Deliv Rev. 2006 Nov 15;58(11):1131-5
references.pmid: 17097758
references.citation: Am J Ophthalmol. 2011 Oct;152(4):515-22
references.pmid: 21961848
references.citation: Surv Ophthalmol. 1997 Feb;41 Suppl 2:S105-10
references.pmid: 9154285
references.citation: Invest Ophthalmol Vis Sci. 1997 Mar;38(3):627-34
references.pmid: 9071216
references.citation: Lancet. 2011 Apr 16;377(9774):1367-77
references.pmid: 21453963
references.citation: Nature. 2008 Apr 3;452(7187):591-7
references.pmid: 18368052
references.citation: Invest Ophthalmol. 1976 Sep;15(9):781-4
references.pmid: 961721
references.citation: Mol Ther. 2012 Jan;20(1):101-8
references.pmid: 21988875
references.citation: Methods Find Exp Clin Pharmacol. 2007 Dec;29(10):665-71
references.pmid: 18200329
references.citation: BioDrugs. 2009;23(5):305-32
references.pmid: 19754220
references.citation: Am J Ophthalmol. 2010 Jul;150(1):33-39.e2
references.pmid: 20609706
references.citation: Nucleic Acid Ther. 2013 Feb;23(1):21-8
references.pmid: 23289535
references.citation: Cell Death Dis. 2011 Jun 16;2:e173
references.pmid: 21677688
references.citation: Invest Ophthalmol Vis Sci. 1989 Apr;30(4):684-9
references.pmid: 2703309
references.citation: J Drug Target. 1998;6(4):309-13
references.pmid: 9894698
references.citation: Oligonucleotides. 2008 Dec;18(4):345-54
references.pmid: 18844576
references.citation: Bull World Health Organ. 2004 Nov;82(11):887-8
references.pmid: 15640929
references.citation: Invest Ophthalmol Vis Sci. 1987 Mar;28(3):420-30
references.pmid: 3030954
references.citation: Invest Ophthalmol Vis Sci. 1987 Aug;28(8):1436-41
references.pmid: 3038771
references.citation: Cell. 2000 Mar 31;101(1):25-33
references.pmid: 10778853
references.citation: Invest Ophthalmol Vis Sci. 2009 Feb;50(2):779-86
references.pmid: 18757511
references.citation: Gene Ther. 2006 Mar;13(6):559-62
references.pmid: 16195702
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
references.citation: Gene Ther. 2006 Feb;13(3):225-34
references.pmid: 16195704
references.citation: Arch Ophthalmol. 2002 Jun;120(6):701-13; discussion 829-30
references.pmid: 12049574
references.citation: J Ocul Pharmacol. 1990 Summer;6(2):143-9
references.pmid: 2168462
references.citation: Arch Ophthalmol. 2002 Oct;120(10):1268-79
references.pmid: 12365904
references.citation: Invest Ophthalmol Vis Sci. 1985 Apr;26(4):584-7
references.pmid: 3884542
references.citation: Open Ophthalmol J. 2010 Sep 03;4:52-9
references.pmid: 21293732
references.citation: Nature. 2006 May 25;441(7092):537-41
references.pmid: 16724069