%0 Journal Article
%A Bastia, Elena
%A Toris, Carol B.
%A Brambilla, Stefania
%A Galli, Corinna
%A Almirante, Nicoletta
%A Bergamini, Michael V. W.
%A Masini, Emanuela
%A Sgambellone, Silvia
%A Unser, Andrea M.
%A Ahmed, Feryan
%A Torrejon, Karen Y.
%A Navratil, Tomas
%A Impagnatiello, Francesco
%T NCX 667, a Novel Nitric Oxide Donor, Lowers Intraocular Pressure in Rabbits, Dogs, and Non-Human Primates and Enhances TGFβ2-Induced Outflow in HTM/HSC Constructs
%B Investigative Ophthalmology & Visual Science
%D 2021
%R 10.1167/iovs.62.3.17
%J Investigative Ophthalmology & Visual Science
%V 62
%N 3
%P 17-17
%@ 1552-5783
%X    NCX 667, a novel nitric oxide (NO) donor with an isomannide core, was characterized for its IOP-lowering ability in animal models of ocular hypertension and glaucoma. Bioengineered human trabecular meshwork/Schlemm's canal (HTM/HSC) constructs were used to explore the mode of action.    Ocular normotensive New Zealand white (NZW) rabbits (ONT-rabbits), spontaneously ocular hypertensive pigmented Dutch-belted rabbits (sOHT-rabbits), hypertonic saline (5%)–induced transient ocular hypertensive NZW rabbits (tOHT-rabbits), ocular normotensive Beagle dogs (ONT-dogs), and laser-induced ocular hypertensive cynomolgus monkeys (OHT-monkeys) were used. NCX 667 or vehicle (30 µL) was instilled in a crossover, masked fashion and intraocular pressure (IOP) measured before dosing (baseline) and for several hours thereafter. The ONT-rabbits were used for cyclic guanosine monophosphate (cGMP) determination in ocular tissues after ocular dosing with NCX 667. Transforming growth factor-beta2 (TGFβ2) (2.5 ng/mL, six days)–treated HTM/HSC constructs were used to address changes in outflow facility.    NCX 667 resulted in robust and dose-dependent IOP decrease in all models used. Maximal IOP-lowering efficacy at 1% was −4.1 ± 0.6, −12.2 ± 2.7, −10.5 ± 2.0, −5.3 ± 0.8, and −6.6 ± 1.9 mmHg, respectively, in ONT-dogs, sOHT-rabbits, tOHT-rabbits, ONT-rabbits, and OHT-monkeys. In ONT-rabbits NCX 667 (1%) increased cGMP in aqueous humor (AH) but not in retina and iris/ciliary body. NCX 667 concentration-dependently increased outflow facility in TGFβ2-treated HTM/HSC constructs (outflow facility, 0.10 ± 0.06 and 0.30 ± 0.10 µL/min/mmHg/mm2, respectively, in vehicle- and NCX 667–treated constructs).    NCX 667 leads to robust IOP lowering in several animal models. Evidence in HTM/HSC constructs indicate that the IOP reduction likely results from NO-mediated increase of the conventional outflow pathway. Other mechanisms including changes in AH production and episcleral vein pressure may not be excluded at this time.  
%[ 4/21/2021
%U https://doi.org/10.1167/iovs.62.3.17