Glaucoma is a leading cause of blindness in the United States. One of the major risk factors of glaucoma is an elevated intraocular pressure (IOP), and the goal of glaucoma therapy is to lower IOP to safe levels. Glaucoma filtration surgery (GFS) is a procedure frequently performed in glaucoma patients and has been reported to produce the largest and most sustained decrease in IOP. For successful IOP reduction, maintaining filtering blebs, which consist of the subconjunctival space where aqueous humor is drained into after GFS, is a key. Ocular scarring that scars and closes the subconjunctival space of filtering blebs leads to bleb and surgery failure. As subconjunctival anti-scarring treatments, antimetabolites, generally 5-fluorouracil (5-FU) and mitomycin-C (MMC), are commonly used to reduce post-operative scarring at the site of GFS and enhance the long-term success of GFS. While the use of antimetabolites benefits a number of patients, they do so by causing widespread cell death and are associated with severe and potentially blinding complications, such as late onset infection, endophthalmitis. The incidence of severe/blinding complications after GFS is extremely higher, e.g. endophthalmitis, 7.5% after GFS, than that after other ocular surgeries, e.g. 0.028-0.15% after cataract surgery (Wykoff et al, 2010; Freeman et al, 2010). In order to resolve these problems, other anti-scarring approaches are needed. TGF-2 has emerged as a key mediator of the fibrotic response to wounding and has been shown to be important in conditions in subconjunctival scarring, a complication of filtration surgery in glaucoma. Efficacy of antibody and antisense/siRNAs for TGF-2 or its receptors has been investigated in ocular scarring of GFS. However, in a phase III clinical trial, there was no difference between the antibody and a placebo in preventing the failure of primary trabeculectomy in human glaucoma eyes. In addition, clinical usage of antisense/siRNAs is still questionable. By contrast, it is practical to use chemical compounds, such as chemical inhibitors, because of their structural stability. Receptors and kinases are also generally believed to be effective targets for selectively blocking signaling pathways in a variety of biological systems. Recently, inhibitors of activin receptor-like kinase 5 (ALK-5, also called TGF-2 receptor type I) have been described to be effective suppressors of TGF-2 activity. In our previous experiments, the ALK-5 inhibitor SB-505124 induced a marked reduction in downstream proteins of TGF-2 in vitro. In addition, in an in vivo rabbit GFS model, it was shown that SB-505124 extended the period of filtering bleb survival. Toxicity of SB-505124 in GFS was shown to be substantially lower than that of MMC. On the other hand, while the bleb survival was improved by SB-505124, the survival period of GFS with SB-505124 was still shorter compared to that of MMC in our data. It is speculated that maintaining an appropriate concentration of SB-505124 in the filtering bleb is required for extending the period of bleb survival. Therefore, investigation of a controlled drug delivery for GFS needs to be conducted. Recently, controlled drug delivery systems using gel as a depot have been developed, which allow for easier administration and reduced irritation/inflammatory response. Among them, the thermoreversible gel has significant advantages, which include being biocompatible, non-irritable, easy for application and having a longer period of drug release. Novel PEG-PCL-PLA-PCL-PEG pentablock thermoreversible gel was recently developed in the laboratory of our Co-Investigator, and the gel has been successfully applied as an ocular sustained release system. The pentablock thermoreversible gel seems the best choice for ocular application including GFS because of its stable and longer drug release properties compared to other gels. We will use this novel and promising drug delivery system, PEG-PCL-PLA-PCL-PEG thermoreversible gel, in this project, and the data obtained in this proposed project will be significant for the future works of drug delivery in filtering blebs. The overall goal of our research is to establish and investigate the suppression of ocular scarring in an in vivo rabbit GFS model without using any antimetabolites. In a rabbit GFS model, aggressive scarring produces early bleb failure, generally within 4 to 7 days after GFS, unless the blebs are treated with antimetabolites, such as MMC, with which the period of bleb survival in a rabbit is extended to 30 days. To achieve our goal, we aim to use an activin receptor-like kinase 5 (ALK-5) inhibitor, SB-505124, which selectively inhibits the transforming growth factor-2 (TGF-2) pathway. In aim 1, the in vivo therapeutically effective concentration of ALK-5 inhibitor SB-505124 in filtering bleb will be determined in a rabbit GFS model. The result is directly relevant to aim 2 to establish and optimize controlled drug delivery system for GFS. In aim 2, the controlled drug delivery system, which maintains the therapeutically effective concentration of SB-505124 in the filtering bleb to allow bleb survival for 30 days, will be established and optimized. The controlled release of the ALK-5 inhibitor SB-505124 from thermoreversible gel will be examined both in vitro and in vivo. The efficacy and toxicity of the gel containing the inhibitor in the in vivo rabbit GFS model will be investigated by both clinical and bench-top examinations. The in vitro and in vivo results will be valuable for glaucoma therapy as well as in treatments for other ocular disorders related to scarring, such as proliferative vitreoretinopathy.
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