Glaucoma is an ocular disease that causes distinctive progressive changes in the optic nerve head, visual field loss or both1. Glaucoma can be divided into two groups; primary and secondary which are further subdivided into different groups [Fig 1]. Raised intraocular pressure (IOP) is the major risk factor for the development of primary glaucoma2. The IOP rises when the aqueous humour is not drained properly due to a blockage or reduced outflow through the trabecular meshwork. The common form of treatment for glaucoma is glaucoma filtration surgery (trabeculotomy) 3.
The procedure works by providing an alternative channel for the drainage of aqueous humor which collects in the subconjunctivital space as a bleb. A bleb is a “good kind” of blister that forms in the eye which contains the aqueous humor which is absorbed by the capillaries and lymphatics or evaporates across the conjunctiva1. Although this procedure seems sensible, it is after the surgery the major complications occur. The outcome of the filtration surgery is determined by the wound healing response at the wound site4. After surgery fibroblasts in the conjunctiva start producing fibrin; scar tissue.
This scar blocks movement of the aqueous around the wound site resulting in a non-draining bleb1. This essay discusses the wound healing response and the use of anti-scarring agents with reference to glaucoma filtration surgery. Figure 1: Classification of the glaucomas1. The main cells that are involved in subconjunctivital scarring are fibroblasts. Intraoperative use of anti proliferative agents has increased the success rate of glaucoma filtration surgery5. 5–Fluorouracil and mitomycin C (MMC) are clinically approved to be used during the procedure5.
5-FU acts a potent antimetabolite by inhibiting thymidylate synthetase and cell division6. It is applied during surgery using a sponge soaked with 5-FU1. It can also be applied after surgery as injections. The application of 5-FU being a plus point can also be a failure. 5-FU produces a bleb with thin bleb skin which is prone to leak predisposing the patient to hypotony, blebitis and endopthalmitis1. The postoperative application of 5-FU also leads to epithelial keraptopathy, which is a non-inflammatory disease of the cornea7.
MMC is also an antimetabolite that kills fibroblasts1. This can only be applied using a sponge intraoperatively. As with 5-FU this also cause complications after surgery. The usage of MMC causes a very a thin avascular blebs creating a greater risk of hypotony and blebitis1. Despite these techniques bleb failure happens after surgery hence a metabolite that increases the chances of success and also not posing a great risk of adverse reactions is needed. A greater understanding of the scarring process led to the culprit; transforming growth factor (TGF-? ).
TGF-?is a growth factor found throughout the body which is involved in the process of scarring. The human TGF-? is found in three isoforms throughout the body; TGF-? 1, TGF-? 2 and TGF-? 3. These growth factors induce transformation of fibroblastic cells in monolayer culture and hence named after their function8. Several in vitro assays of these three isoforms were used to compare the wound healing response and all these techniques were based on Human Tenon’s capsule fibroblast (HTF) as these are believed to be the key cells involved subconjunctivital scarring4.
The results showed that all three of these isoforms are involved in HTF proliferation, collagen contraction and migration5. In an age-matched control test performed on patients undergoing cataract surgery showed higher levels of TGF- ? 2 in the aqueous than in normal eyes4. Out of these three growth factors TGF-? 2 is the most prominent in the eye and is involved in wound healing response and pathogenesis of cataract and conjunctivital scarring5. Elevated levels of TGF-? 2 are found in glaucomatous eyes compared with normal eyes5.
When found in low concentration they don’t pose a great threat, but when concentrations increase a positive feedback is triggered. Increasing concentrations of TGF-? 2 increases fibroblasts concentration this results in fibroblast contraction leading to a bleb failure9. All these findings suggest that TGF-? plays an important role in the stimulation of subconjunctivital scarring and neutralising the effects of TGF-? 2 may reduce the scarring after glaucoma filtration surgery6. Using antibody phage display, CAT-152 was isolated and developed.
It is a monoclonal antibody that shows high affinity and specificity for the active form of TGF-? 26. In vivo demonstrations show that CAT-152 inhibits TGF-? 2 induced HTF proliferation and migration. Also subconjunctivital application of CAT-152 reduces subconjunctivital scarring. In 2001 a clinical trial was carried out on 24 patients undergoing glaucoma filtration surgery showed that patients who were given CAT-152 had a significant reduction in the IOP than the ones on placebo10.
It is proven that glaucoma filtration surgery significantly reduces IOP but the IOP in patients treated with CAT-152 was even lower10. A study was made on rabbits using CAT-152 alone in comparison with 5-FU after glaucoma filtration surgery to determine if the postoperative application of CAT-152 increases bleb survival. The study showed significant improvement in the rabbits treated with CAT-152 than the ones with 5-FU and no treatment [Fig 2]6. FIGURE 2: Bleb morphology at day 21 after glaucoma filtration surgery. shown per group.
Animals treated with CAT-152 (A) or 5-FU (B) or received no treatment (C). The figure shows that treatment with CAT-152 produced elevated, diffuse, fleshy looking blebs compared with the flat, scarred blebs in the 5-FU and control groups. Black arrows: bleb border; white arrow: cannula6. From all the studies and trials we can come to a conclusion that glaucoma filtration surgery does decrease the IOP. The postoperative complication of the surgery can be reduced using anti metabolites but with severe side effects in some cases.
Isolating the cause of the scarring gave us a deeper understanding into the mechanism involved and helped us identify a better treatment that had negligible side effects and reduced the IOP. Even though CAT-152 seemed to be working later studies showed that the results were inconsistent. This was due to the fact that the other growth factors which are not prominent in the eye but are still found in the eye, blood vessels etc, diminished the effects of CAT-152 as it only focussed on only one of the isomers of the growth factor; TGF- ? 2.
Further studies in the future may be able to isolate and produce a better treatment for the scarring and early bleb failure.
References: 1. David Edgar, Alicja Rudnicka. Glaucoma Identification & Co-management. Published 2007. ISBN: 9780750637824. 2. Relationship between Intraocular Pressure and Primary Open Angle Glaucoma among White and Black Americans. The Baltimore Eye Survey. Sommer A et al. Arch Opthalmol Vol 109, Aug 1991. Pg 1090 -1096. 3. http://www. privatehealth. co. uk/articles/september-2009/glaucoma-surgery-whats-involved/ 4. Cordorio et al. TGF-? 1, -? 2, and -?
3 In Vitro: Biphasic Effects on Tenon’s Fibroblast Contraction, Proliferation, and Migration. 5. Mead et al. Evaluation of Anti-TGF-? 2 Antibody as a New Postoperative Anti-scarring Agent in Glaucoma Surgery. 6. F. Grehn, R. Stamper. Essential of opthamology – Glaucoma. ISBN: 3540406085. 7. http://medical-dictionary. thefreedictionary. com/keratopathy 8. Lutty GA, Merges C, Threlkeld AB, Crone S, Mcleod DS. Heterogeneity in localization of isoforms of TGF-b in human retina, vitreous and choroid. Invest Ophthalmol Vis Sci. 1993;34:477–487. 9. ask shaz 10. http://www. bioportfolio. com/news/cat_1. htm.