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

Elena Bastia, Carol B. Toris, Stefania Brambilla, Corinna Galli, Nicoletta Almirante, Michael V.W. Bergamini, Emanuela Masini, Silvia Sgambellone, Andrea M. Unser, Feryan Ahmed, Karen Y. Torrejon, Tomas Navratil, Francesco Impagnatiello

Research output: Contribution to journalArticlepeer-review

Abstract

PURPOSE. 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. METHODS. 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. RESULTS. 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). CONCLUSIONS. 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.

Original languageEnglish (US)
Article number17
JournalInvestigative Ophthalmology and Visual Science
Volume62
Issue number3
DOIs
StatePublished - Mar 2021

Keywords

  • Conventional outflow
  • Glaucoma
  • IOP
  • Nitric oxide

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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