title: Visualization of conventional outflow tissue responses to netarsudil in living mouse eyes.
abstract: Visual impairment due to glaucoma currently impacts 70 million people worldwide. While disease progression can be slowed or stopped with effective lowering of intraocular pressure, current medical treatments are often inadequate. Fortunately, three new classes of therapeutics that target the diseased conventional outflow tissue responsible for ocular hypertension are in the final stages of human testing. The rho kinase inhibitors have proven particularly efficacious and additive to current therapies. Unfortunately, non-contact technology that monitors the health of outflow tissue and its response to conventional outflow therapy is not available clinically. Using optical coherence tomographic (OCT) imaging and novel segmentation software, we present the first demonstration of drug effects on conventional outflow tissues in living eyes. Topical netarsudil (formerly AR-13324), a rho kinase/ norepinephrine transporter inhibitor, affected both proximal (trabecular meshwork and Schlemm's Canal) and distal portions (intrascleral vessels) of the mouse conventional outflow tract. Hence, increased perfusion of outflow tissues was reliably resolved by OCT as widening of the trabecular meshwork and significant increases in cross-sectional area of Schlemm's canal following netarsudil treatment. These changes occurred in conjunction with increased outflow facility, increased speckle variance intensity of outflow vessels, increased tracer deposition in conventional outflow tissues and decreased intraocular pressure. This is the first report using live imaging to show real-time drug effects on conventional outflow tissues and specifically the mechanism of action of netarsudil in mouse eyes. Advancements here pave the way for development of a clinic-friendly OCT platform for monitoring glaucoma therapy.
authors.affiliation: Department of Ophthalmology, Duke University, Durham, NC 27710, USA.
authors.forename: Guorong
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC 27710, USA.
authors.forename: Dibyendu
authors.initials: D
authors.lastname: Mukherjee
authors.affiliation: Department of Ophthalmology, Duke University, Durham, NC 27710, USA.
authors.forename: Iris
authors.initials: I
authors.lastname: Navarro
authors.affiliation: Department of Ophthalmology, Duke University, Durham, NC 27710, USA.
authors.forename: Nicole E
authors.initials: NE
authors.lastname: Ashpole
authors.affiliation: Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Sherwood
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC 27710, USA.
authors.forename: Jinlong
authors.initials: J
authors.lastname: Chang
authors.affiliation: Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom.
authors.forename: Darryl R
authors.initials: DR
authors.lastname: Overby
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC 27710, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Yuan
authors.affiliation: Department of Ophthalmology, Duke University, Durham, NC 27710, USA.
authors.forename: Pedro
authors.initials: P
authors.lastname: Gonzalez
authors.affiliation: Aerie Pharmaceuticals, Inc., Durham, NC 27713, USA.
authors.forename: Casey C
authors.initials: CC
authors.lastname: Kopczynski
authors.affiliation: Department of Ophthalmology, Duke University, Durham, NC 27710, USA; Department of Biomedical Engineering, Duke University, Durham, NC 27710, USA.
authors.forename: Sina
authors.initials: S
authors.lastname: Farsiu
authors.affiliation: Department of Ophthalmology, Duke University, Durham, NC 27710, USA; Department of Biomedical Engineering, Duke University, Durham, NC 27710, USA. Electronic address: dan.stamer@duke.edu.
authors.forename: W Daniel
authors.initials: WD
authors.lastname: Stamer
mesh_terms: D000818:Animals; D001082:Aqueous Humor / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D001565:Benzoates / Q000008:administration & dosage / Q000494:pharmacology*; D005123:Eye / Q000187:drug effects* / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D007429:Intraocular Pressure / Q000187:drug effects; D051379:Mice; D009799:Ocular Physiological Phenomena / Q000187:drug effects*; D041623:Tomography, Optical Coherence; D014129:Trabecular Meshwork / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D015091:beta-Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D001565:Benzoates; D005456:Fluorescent Dyes; D015091:beta-Alanine; C000603944:netarsudil
keywords: Conventional outflow; Netarsudil (PubChem CID: 66599893); Ocular hypertension; Rho kinase inhibitor; Schlemm’s canal; Trabecular meshwork