Bastia Elena, Toris Carol B, Brambilla Stefania, Galli Corinna, Almirante Nicoletta, Bergamini Michael V W, Masini Emanuela, Sgambellone Silvia, Unser Andrea M, Ahmed Feryan, Torrejon Karen Y, Navratil Tomas, Impagnatiello Francesco
Nicox Research Institute, Milan, Italy.
University of Nebraska Medical Center, Omaha, Nebraska, United States.
Invest Ophthalmol Vis Sci. 2021 Mar 1;62(3):17. doi: 10.1167/iovs.62.3.17.
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.
NCX 667是一种具有异甘露醇核心的新型一氧化氮（NO）供体，在高眼压和青光眼动物模型中对其降低眼压的能力进行了表征。使用生物工程化的人小梁网/施莱姆管（HTM/HSC）构建体来探索其作用模式。
使用眼压正常的新西兰白兔（ONT-兔）、自发性高眼压的荷兰带兔（sOHT-兔）、高渗盐水（5%）诱导的短暂性高眼压新西兰白兔（tOHT-兔）、眼压正常的比格犬（ONT-犬）以及激光诱导的高眼压食蟹猴（OHT-猴）。以交叉、盲法方式滴注NCX 667或赋形剂（30 μL），并在给药前（基线）及此后数小时测量眼压（IOP）。ONT-兔用于在眼内给予NCX 667后测定眼组织中的环磷酸鸟苷（cGMP）。使用转化生长因子-β2（TGFβ2）（2.5 ng/mL，六天）处理的HTM/HSC构建体来研究流出易度的变化。
在所有使用的模型中，NCX 667均导致眼压显著且剂量依赖性降低。在ONT-犬、sOHT-兔、tOHT-兔、ONT-兔和OHT-猴中，1%浓度的NCX 667最大降眼压功效分别为-4.1±0.6、-12.2±2.7、-10.5±2.0、-5.3±0.8和-6.6±1.9 mmHg。在ONT-兔中，NCX 667（1%）可增加房水中的cGMP，但视网膜和虹膜/睫状体中的cGMP未增加。NCX 667浓度依赖性地增加了TGFβ2处理的HTM/HSC构建体的流出易度（在赋形剂处理和NCX 667处理的构建体中，流出易度分别为0.10±0.06和0.30±0.10 μL/min/mmHg/mm2）。
NCX 667在多种动物模型中均能显著降低眼压。HTM/HSC构建体中的证据表明，眼压降低可能是由于NO介导的传统流出途径增加所致。目前不排除其他机制，包括房水生成和巩膜静脉压的变化。
