Pluripotent epigenetic regulator OBP-801 maintains filtering blebs in glaucoma filtration surgery model

Abstract

Inhibition of fibrosis is indispensable for maintaining filtering blebs after glaucoma filtration surgery (GFS). The purpose of this study was to investigate the ability of a pluripotent epigenetic regulator OBP-801 (OBP) to ameliorate extracellular matrix formation in a rabbit model of GFS. Rabbits that underwent GFS were treated with OBP. The gene expression profiles and intraocular pressure (IOP) were monitored until 30 postoperative days. The bleb tissues were evaluated for tissue fibrosis at 30 postoperative days. In in vitro models, OBP interfered the functions of diverse genes during the wound-healing process. In in vivo GFS models, the expressions of TGF-β3, MMP-2, TIMP-2 and 3, LOX, COL1A and SERPINH1 were significantly inhibited at 30 postoperative days in the OBP group compared with those in the vehicle control group. OBP treatment involving subconjunctival injection or eye drops showed no adverse effects, and reduced levels of α-SMA and collagen deposition at the surgical wound site. OBP maintained the long-lived bleb without scar formation, and IOP was lower at 30 postoperative days compared with the vehicle control group. These findings suggest that OBP is an effective and useful candidate low-molecular-weight agent for improving wound healing and surgical outcomes in a rabbit model of GFS.

Evaluation of matrix metalloproteinases and tissue inhibitors of metalloproteinases in aqueous humor of dogs with versus without naturally occurring primary angle-closure glaucoma

“…14,49,[121][122][123][124] Targeting alterations in MMPs and TIMPs may additionally lead to better success rates for glaucoma filtration surgeries in these later-stage patients, because filtering blebs are continuously bathed in aqueous humor and because MMP-to-TIMP ratio imbalances in aqueous humor likely influence bleb fibrosis and eventual failure. 14,54,125 Nevertheless, evaluation of MMPs and TIMPs in eyes with early-stage cPACG or in contralateral unaffected eyes prior to the onset of disease will be a critical next step in understanding the implications of the findings of the present study. Invasive sampling of at-risk but currently unaffected contralateral eyes carries risks for patients and should not be undertaken lightly but will be necessary to expand our knowledge of the pathogenesis of cPACG.…”

Relative ability of aqueous humor from dogs with and without primary angle‐closure glaucoma and ADAMTS10 open‐angle glaucoma to catalyze or inhibit collagenolysis

“…For example, elucidating changes in AH in later stages of disease could lead to improved outcomes for glaucoma filtration surgeries in later-stage patients, since failure of filtering blebs may be linked to constant exposure to profibrotic mediators like TIMPs in glaucomatous AH. 13,41,71,72 Eyes with ADAMTS10-OAG, on the other hand, were sampled relatively early in the course of disease (mean IOP in the group was 19.7 mmHg, as compared to 54.9 mmHg for dogs with CPACG). These dogs, along with heterozygote and wild-type counterpart Beagles, were markedly younger than the pet dogs with and without CPACG sampled for the other arm of the study.…”

“…Regardless of their cause, findings of the current study may provide justification for sampling of dogs in earlier stages of disease and may also contribute to the development of new therapies for dogs with CPACG in later stages of disease. For example, elucidating changes in AH in later stages of disease could lead to improved outcomes for glaucoma filtration surgeries in later‐stage patients, since failure of filtering blebs may be linked to constant exposure to profibrotic mediators like TIMPs in glaucomatous AH 13,41,71,72 …”