Development of a Novel Intraocular-Pressure-Lowering Therapy Targeting ATX

Abstract

Elevated intraocular pressure (IOP) is the major cause of glaucoma, which is the second leading cause of blindness. However, current glaucoma treatments cannot completely regulate IOP and progression of glaucoma. Our group recently found that autotaxin (ATX) activity in human aqueous humor (AH) was positively correlated with increased IOP in various subtypes of glaucoma. To develop new IOP-lowering treatments, we generated a novel ATX inhibitor as an ophthalmic drug by high-throughput screening, followed by inhibitor optimization. Administration of the optimized ATX inhibitor (Aiprenon) reduced IOP in laser-treated mice exhibiting elevated IOP and higher level of ATX activity in AH and normal mice in vivo. The stimulation of ATX induced outflow resistance in the trabecular pathway; however, administration of Aiprenon recovered the outflow resistance in vitro. The in vitro experiments implied that the IOP-lowering effect of Aiprenon could be correlated with the altered cellular behavior of trabecular meshwork (TM) and Schlemm's canal endothelial (SC) cells. Overall, our findings showed that ATX had major impact in regulating IOP as a target molecule, and potent ATX inhibitors such as Aiprenon could be a promising therapeutic approach for lowering IOP.

Alteration in Lysophospholipids and Converting Enzymes in Glaucomatous Optic Nerves

“…Our findings are inconsistent with aberration in the LPA-ATX pathway in the glaucomatous ON, unlike that observed in the anterior eye chamber/trabecular meshwork. 44,45,[49][50][51] Aside from the ATX-LPA pathway, there are numerous metabolic mechanisms that are responsible for the synthesis and breakdown of LPLs. We evaluated several pathways that interconnect the metabolism of LPA, LPE, and LPC ( Supplementary Fig.…”

“…Our findings are inconsistent with aberration in the LPA-ATX pathway in the glaucomatous ON, unlike that observed in the anterior eye chamber/trabecular meshwork. 44 , 45 , 49 – 51 …”

Synthesis, Characterization, and in vivo Evaluation of a Novel Potent Autotaxin-Inhibitor

“…As previously shown, IOP stayed within the normal range in the EAG model ( Laspas et al, 2011 ; Joachim et al, 2013 ). Other studies demonstrated that topically or intracamerally administrated ATX-inhibitors acutely decreased the IOP in healthy rabbits as well as in mice with elevated pressure due to laser peripheral iridotomy ( Iyer et al, 2012 ; Nagano et al, 2019 ). In contrast, ATX-i ( 13 ), which was administered via the oral route, did not lower IOP in both models.…”

Loss of P2Y1 receptors triggers glaucoma‐like pathology in mice

“…Such an imbalance of ATP and ADP may cause dysregulation in IOP‐regulating purinergic signalling and pathological IOP elevation. Normalization of the imbalance by pharmacological blockade of ENPP2 successfully reduces IOP to basal levels in animal models (Nagano et al, 2019). Thus, our present finding is not just an artefact in the mouse model but is related to pathogenic mechanisms in human glaucoma patients.…”