Modulation of transforming growth factor beta (TGF beta) and conjunctival scarring after glaucoma filtration surgery
The conjunctival wound healing response remains the major barrier to achieving long term intraocular pressure control after glaucoma filtration surgery (GFS). Current anti-scarring agents improve the outcome of surgery but act by causing widespread cell death and can be associated with potentially blinding complications. In addition, some individuals still fail surgery. A more physiological and targeted approach to wound healing control and scarring prevention is required. Of all the growth factors, TGF beta has been shown to play a pivotal role in wound healing throughout the body, and has been identified as a potent stimulant of the scarring process in the eye. Modulation of TGF beta has been highlighted as a possible mechanism by which ocular scarring may be reduced. This thesis has investigated the role of TGF p modulation as a potential anti-scarring strategy in glaucoma surgery. In vitro, I have demonstrated that the anti-TGF beta2 monoclonal antibody, CAT-152, inhibits Tenon's fibroblast collagen production and myofibroblast transformation at physiological concentrations. It appears that these are the key histological changes associated with bleb failure following experimental GFS. In vivo, subconjunctival administration of CAT-152, given at the time of surgery and in the immediate post-operative period, successfully improves surgical outcome, reduces subconjunctival fibrosis and is safe and well tolerated. Isolated post-operative administration of subconjunctival CAT-152 can prevent late bleb failure and prolonged dosing with CAT-152 appears to modulate the long-term scarring response after GFS. In addition, the anti-scarring effects of CAT-152 have compared favourably to one of the gold standard anti-scarring agents in clinical use. Finally, I have shown that antisense oligonucleotides directed against TGF beta may also have a role in the prevention of conjunctival scarring. In summary, the work supports the hypothesis that TGF beta modulation may represent a novel potential anti-scarring strategy in glaucoma surgery.