Cationic nano-copolymers mediated IKKβ targeting siRNA to modulate wound healing in a monkey model of glaucoma filtration surgery

PURPOSE: To investigate the efficacy and safety of cationic nano-copolymers CS-g-(PEI-b-mPEG) mediated IκB kinase beta (IKKβ) targeting siRNA in modulating wound healing in a monkey model of glaucoma filtration surgery. METHODS: The IKKβ targeting siRNAs were chemically synthesized and screened in cultured monkey Tenon’s fibroblasts in vitro. Fourteen monkeys underwent trabeculectomy and were randomly allocated to one of three treatment regimens: subconjunctival injection of either CS-g-(PEI-b-mPEG)/IKKβ-siRNA (six eyes, 50nM, at the time of surgery and 7 days post surgery) or phosphate buffered saline (four eyes), or treated with mitomycin C (MMC; four eyes, 0.2 mg/ml). Bleb survival and characteristics, and intraocular pressure, were evaluated over a 60-day period. Histology of the surgical eyes was performed to evaluate ocular scarring and fibrosis in each group. RESULTS: Subconjunctival injection of CS-g-(PEI-b-mPEG)/IKKβ-siRNA was well tolerated in this model. Both siRNA and MMC significantly prolonged bleb survival compared with the PBS group (the medians for survival days were 45.5, 60, and 29.5 in the siRNA, MMC, and PBS groups, respectively, p<0.01). Higher blebs were observed in the siRNA group than in the PBS group (p<0.01), while the MMC group showed the highest blebs among three groups (p<0.01). The surgical eyes in both the siRNA and MMC groups had significantly larger bleb area compared with the PBS group (p<0.01), but there was no significant difference between the siRNA and MMC groups (p=0.214). There were no significant differences in IOP readings among the three groups on the designated days after surgery (all p>0.05). The histologic examination demonstrated that the eyes treated with siRNA showed a marked reduction in subconjunctival scar tissue compared with the eyes in the PBS group. The conjunctival epithelium appeared healthy without the acellularity that was present in the MMC group. CONCLUSIONS: Subconjunctival injection of cationic nano-copolymers mediated IKKβ targeting siRNA is associated with improved surgical outcome in a monkey model of trabeculectomy. This novel approach may potentially be a more controlled alternative as an anti-scarring agent in glaucoma filtration surgery.