Development of a novel intraocular-pressure-lowering therapy targeting ATX

Norimichi Nagano, Megumi Honjo, Mitsuyasu Kawaguchi, Hiroshi Nishimasu, Osamu Nureki, Kuniyuki Kano, Junken Aoki, Toru Komatsu, Takayoshi Okabe, Hirotatsu Kojima, Tetsuo Nagano, Makoto Aihara

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)1926-1935
Number of pages10
JournalBiological and Pharmaceutical Bulletin
Volume42
Issue number11
DOIs
Publication statusPublished - 2019

Keywords

  • Autotaxin
  • High-throughput screening
  • Intraocular pressure
  • Ocular hypertension

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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