Integrin α5β1 Inhibition by CLT-28643 Reduces Postoperative Wound Healing in a Mouse Model of Glaucoma Filtration Surgery

PURPOSE. To evaluate the therapeutic potential of the small molecule integrin alpha 5 beta 1 inhibitor, CLT-28643, to improve the filtering surgery outcome in a mouse model. Different dose regimens and administration routes of the inhibitor were compared with mitomycin C (MMC), the gold standard in clin ical practice. METHODS. The efficacy of CLT-28643 on surgical outcome was studied in a mouse model for filtering surgery (n = 40 eyes from 20 mice per group). Single and repeated subconjunctival (SCJ) injections (1 or 2 mu g) and topical eye drops (10 mu g) of the integrin inhibitor were compared with 2-minute administration of MMC 0.02%. Bleb size, survival, and signs of toxicity were examined until 28 days after surgery. Immunohistochemical analysis of angiogenesis, inflammation, collagen deposition, and integrin alpha 5 beta 1 expression were performed on postoperative days 3, 8, 14, and 28. A masked observer performed all the assessments. RESULTS. Immunostaining showed that integrin alpha 5 beta 1 was highly expressed in the bleb at early time-points after surgery and that CLT-28643 inhibited this upregulation. Efficacy was shown to be dose-dependent for the integrin inhibitor CLT-28643 for bleb area and survival, and the wound healing process. While 2-mu g single injection of CLT-28643 improved bleb characteristics in a similar way as 10-mu g administered by eye drops and MMC, repeated injections of 2 mu g showed superior efficacy compared to MMC, with no corneal toxicity. CONCLUSIONS. Administration of the integrin alpha 5 beta 1 inhibitor CLT-28643 has therapeutic potential as an adjunct to glaucoma surgery, possibly with a superior efficacy and tolerability compared with MMC when used at the optimal dose.