Anti–Vascular Endothelial Growth Factor Therapy in Glaucoma Filtration Surgery

doi:10.1016/j.ajo.2011.03.013

American Journal of Ophthalmology

Volume 152, Issue 1, July 2011, Pages 10-15.e2

https://doi.org/10.1016/j.ajo.2011.03.013 Get rights and content

Purpose

To examine evidence supporting the use of vascular endothelial growth factor (VEGF) inhibition in controlling wound healing after glaucoma filtration surgery in primary open-angle glaucoma, to identify the optimum method of administration, and to clarify the potential position of anti-VEGF monoclonal antibodies in comparison with 5-fluorouracil and mitomycin C.

Design

Perspective based on an overview of evidence from current peer-reviewed literature.

Methods

Analysis of evidence from animal studies, in vitro studies, human studies, and from the use of anti-VEGF monoclonal antibodies in systemic disease.

Results

There is evidence that glaucoma patients have elevated levels of VEGF in the aqueous before filtration surgery, that this increases in animals after filtration surgery, and that both can be suppressed in animals by intraocular injection of bevacizumab. VEGF not only has a role in angiogenesis, but also has a direct action on fibroblast activity that may be modified directly at the time of filtration surgery.

Conclusions

There is evidence for a role for VEGF in wound healing after glaucoma filtration surgery. The optimum route of administration and dosing regimen of anti-VEGF antibodies and their positioning in comparison with 5-fluorouracil and mitomycin C are uncertain. There is some evidence that subconjunctival injection may produce sustained intraocular tissue levels. There is also evidence that bevacizumab may act in synergy with 5-fluorouracil. Although there are no direct comparative studies, it seems unlikely that bevacizumab alone will be as effective as mitomycin C, although bleb morphologic features may be better.

Section snippets

Background

Although trabeculectomy is an effective method of reducing the intraocular pressure (IOP) in primary open-angle glaucoma (POAG), current methods lack the high level of predictability that we expect from other types of ocular surgery, such as phacoemulsification. All types of glaucoma filtration surgery that function by draining aqueous to the sub-Tenon space, including trabeculectomy, some types of nonpenetrating surgery, and aqueous shunts, depend on external resistance created by wound

Anti–Vascular Endothelial Growth Factor Monoclonal Antibodies

Bevacizumab is a recombinant humanized monoclonal immunoglobulin (Ig) G1 antibody that binds to and inhibits the biologic activity of human VEGF in vitro and in vivo assay systems. Bevacizumab contains human framework regions and the complementarity-determining regions of a murine antibody that binds to VEGF. Bevacizumab has a molecular weight of 149 kD and is produced in the Chinese-hamster–ovary mammalian-cell expression system (Avastin full prescribing information; available at: //www.gene.com/gene/products/information/pdf/avastin-prescribing.pdf

Aqueous and Plasma Vascular Endothelial Growth Factor and Vascular Endothelial Growth Factor Receptors

Aqueous VEGF levels have been reported to be elevated consistently in eyes of POAG patients undergoing either cataract surgery13, 14 or trabeculectomy¹⁵ when compared with eyes without comorbidity undergoing cataract surgery. For example, in 1998, Tripathi and associates reported aqueous mean ± standard error of the mean VEGF concentrations of 0.257 ± 0.043 ng/mL for 20 eyes undergoing cataract surgery alone, 0.726 ± 0.204 ng/mL for 28 POAG eyes, and 29.276 ± 7.350 ng/mL for 12 eyes with

Animal Studies

Esson and associates, using a microarray technique, reported a large-scale gene expression analysis of bleb tissue biopsies from rats 2, 5, and 12 days after glaucoma filtration surgery.¹⁶ They found elevated VEGF gene expression as well as other cytokines in the postoperative bleb. Li and associates reported an increase in aqueous humor VEGF protein concentration after trabeculectomy in rabbits that did not returned to baseline after 30 days.¹⁵ This upregulation was suppressed partially for up

In Vitro Studies

Two in vitro studies confirm the direct effect of bevacizumab on human Tenon fibroblast proliferation. Li and associates reported that the addition of VEGF induced a significant increase in human (P = .04) and rabbit (P = .02) Tenon fibroblast proliferation in tissue culture.¹⁵ This was inhibited subsequently by administration of bevacizumab in a dose-dependent manner. O'Neill and associates demonstrated that in an in vitro model of wound healing, bevacizumab disrupts fibroblast proliferation,

Route of Administration (Pharmacokinetics)

The optimal route of administration of anti-VEGF drugs is still uncertain. In general, drugs injected into the subconjunctival space have two fates: (1) direct transscleral delivery into intraocular tissues, and (2) clearance via conjunctival blood and lymphatic flow. One might expect that subconjunctival delivery would lead to a short duration of action and would require repetitive injections. However, Ambati and associates showed that IgG antibodies have a relatively high scleral permeability.

Trabeculectomy in Patients

In addition to case reports in which anti-VEGF monoclonal antibodies have been used in adjunct to trabeculectomy,²⁶ at the time of writing there have been 2 pilot studies looking at anti-VEGF agents as wound modulators in trabeculectomy surgery. Grewal and associates reported a prospective interventional case series in which 1.25 mg bevacizumab was injected subconjunctivally in 12 patients at the end of trabeculectomy for POAG or chronic angle-closure glaucoma.²⁷ MMC and 5-FU were not used.

Bleb Rescue

There are a number of case reports of a beneficial effect of subconjunctival and topical bevacizumab in reducing bleb vascularity and needling with bevacizumab, but there are no published reports of comparative studies.32, 33, 34

Conclusions

The purpose of this perspective is to examine evidence supporting the use of VEGF inhibition in reducing fibroblastic activity after trabeculectomy, to identify the optimum method of administration, and to try to clarify the potential role of anti-VEGF monoclonal antibodies in glaucoma filtration surgery in comparison with MMC and 5-FU. The number of supporting publications is limited, and most have small sample sizes. Consequently, it is impossible to perform a full meta-analysis on this topic

Keith Barton completed medical school training at the Queen's University of Belfast, residency at Moorfields Eye Hospital, fellowship (in cornea) at Bascom Palmer Eye Institute, and since 1996 has been a consultant in the glaucoma service at Moorfields Eye Hospital, London, United Kingdom. He became clinical director of the glaucoma service in 2005. His chief clinical and research interests are in uveitic glaucoma, the surgical management of glaucoma and recently, glaucoma service delivery.

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Animal models and drug candidates for use in glaucoma filtration surgery: A systematic review
2022, Experimental Eye Research
Citation Excerpt :
The following drugs were excluded Losartan (Shi et al., 2017), Silver nanoparticles (Butler et al., 2013), Lovastatin (Park et al., 2016), Trastuzumab (Turgut et al., 2015), SB 202190 (Nassar et al., 2015), SB 431542 (Xiao et al., 2009), Doxycycline (Sen et al., 2010), Y-27632 (Honjo et al., 2007), Anti-PIGF antibody (Van Bergen et al., 2013a), TGF-beta antisense oligonucleotides (Cordeiro et al., 2003), Connexin43 (Deva et al., 2012), α-lipoic acid (Ekinci et al., 2014), Dimethylenastron (Luke et al., 2010), Anti-TGF-beta 2 antibody (Mead et al., 2003; Zhu et al., 2015), Sonepcizumab (Lukowski et al., 2013), P605 peptide (Avila et al., 2001), Human RAD50 (Yoon et al., 2004), Withaferin A (Bargagna-Mohan et al., 2013), Everolimus (Cinik et al., 2016), Minoxidil (Sharir, 1994), Rosmarinic acid (Ferreira Jde et al., 2015), Sunitinib (Eren et al., 2016), Aminoproprionitrile (Fourman, 1988), S-nitrosoglutathione (Tannous et al., 2000), Triamcinolone acetate (Rangel et al., 2018), AMA0526 (Van de Velde et al., 2015), Interferon alpha-2b (Xiong et al., 1999), 10-hydroxycamptothecin (Xia et al., 2014), 5-hydroxytryptamine(1 A) (Osborne et al., 2000), DNA topoisomerase II (Yamamoto et al., 2019), Monocyte chemoattractant protein-1 inhibitor (Chong et al., 2017), Halofuginone (Kasar et al., 2021), and Cytosine arabinoside (Al-Aswad et al., 1999), Forkhead domain inhibitory-6 (Lan et al., 2021). Many experimental drugs that may be beneficial for preventing the formation of fibrosis are currently being investigated such as bevacizumab (Hilgert et al., 2018; Hollanders et al., 2015; How et al., 2010; Mathew and Barton, 2011; Memarzadeh et al., 2009; Ozgonul et al., 2014; Van Bergen et al., 2015), veronistat (Kim et al., 2008; Sharma et al., 2016), and short interfering RNA (siRNA) (Seet et al., 2018; Ye et al., 2010) (see Table 2 for an extensive overview). While all drugs aim to inhibit a particular pathway or protein related to fibrosis not all drugs do this to the same extent.
Glaucoma, a degenerative disease of the optic nerve, is the leading cause of irreversible blindness worldwide. Currently, there is no curative treatment. The only proven treatment is lowering intraocular pressure (IOP), the most important risk factor. Glaucoma filtration surgery (GFS) can effectively lower IOP. However, approximately 10% of all surgeries fail yearly due to excessive wound healing, leading to fibrosis. GFS animal models are commonly used for the development of novel treatment modalities. The aim of the present review was to provide an overview of available animal models and anti-fibrotic drug candidates. MEDLINE and Embase were systematically searched. Manuscripts until September 1st^, 2021 were included. Studies that used animal models of GFS were included in this review. Additionally, the snowball method was used to identify other publications which had not been identified through the systematic search. Two hundred articles were included in this manuscript. Small rodents (e.g. mice and rats) are often used to study the fibrotic response after GFS and to test drug candidates. Due to their larger eyes, rabbits are better suited to develop medical devices. Novel drugs aim to inhibit specific pathways, e.g. through the use of modulators, monoclonal antibodies, aqueous suppressants or gene therapy. Although most newly studied drugs offer a higher safety profile compared to antimetabolites, their efficacy is in most cases lower when compared to MMC. Current literature on animal models and potential drug candidates for GFS were summarized in this review. Future research should focus on refining current animal models (for example through the induction of glaucoma prior to undertaking GFS) and standardizing animal research to ensure a higher reproducibility and reliability across different research groups. Lastly, novel therapies need to be further optimized, e.g. by conducting more research on the dosage, administration route, application frequency, the option of creating combination therapies, or the development of drug delivery systems for sustained release of anti-fibrotic medication.
Personalising surgical treatments for glaucoma patients
2021, Progress in Retinal and Eye Research
Surgical treatments for glaucoma have relied for decades on traditional filtering surgery such as trabeculectomy and, in more challenging cases, tubes. Antifibrotics were introduced to improve surgical success in patients at increased risk of failure but have been shown to be linked to a greater incidence of complications, some being potentially vision-threatening. As our understanding of glaucoma and its early diagnosis have improved, a more individualised management has been suggested. Recently the term “precision medicine” has emerged as a new concept of an individualised approach to disease management incorporating a wide range of individual data in the choice of therapeutic modalities. For glaucoma surgery, this involves evaluation of the right timing, individual risk factors, targeting the correct anatomical and functional outflow pathways and appropriate prevention of scarring. As a consequence, there is an obvious need for better knowledge of anatomical and functional pathways and for more individualised surgical approaches with new, less invasive and safer techniques allowing for earlier intervention. With the recent advent of minimally invasive glaucoma surgery (MIGS) a large number of novel devices have been introduced targeting potential new sites of the outflow pathway for lowering intraocular pressure (IOP). Their popularity is growing in view of the relative surgical simplicity and apparent lack of serious side effects. However, these new surgical techniques are still in an era of early experiences, short follow-up and lack of evidence of their superiority in safety and cost-effectiveness over the traditional methods. Each year several new devices are introduced while others are withdrawn from the market.
Glaucoma continues to be the primary cause of irreversible blindness worldwide and access to safe and efficacious treatment is a serious problem, particularly in the emerging world where the burden of glaucoma-related blindness is important and concerning. Early diagnosis, individualised treatment and, very importantly, safe surgical management should be the hallmarks of glaucoma treatment. However, there is still need for a better understanding of the disease, its onset and progression, the functional and structural elements of the outflow pathways in relation to the new devices as well as their long-term IOP-lowering efficacy and safety. This review discusses current knowledge and the future need for personalised glaucoma surgery.
Effects of mammalian target of rapamycin inhibitors on fibrosis after trabeculectomy
2021, Experimental Eye Research
Citation Excerpt :
However, these treatments often fail to maintain tissue health and can lead to thin-walled blebs with a risk for bleb leakage and infection; they do not facilitate the successful formation of glaucoma filtration blebs (CAT-152 0102 Trabeculectomy Study Group et al., 2007; Landers et al., 2012; Al et al., 2015). Various mediators (e.g., TGF-β, vascular endothelial growth factor, connective tissue growth factor, monocyte chemoattractant protein-1, and members of the metalloproteinase family) are involved in the pathogenesis of scarring after trabeculectomy (Cordeiro et al., 2000; Li et al., 2009; Mathew and Barton., 2011; Lei et al., 2016; Inoue et al., 2014; Wong et al., 2003; Browne et al., 2011). Among these growth factors, the levels of several factors (i.e., TGF-β, vascular endothelial growth factor, connective tissue growth factor, and monocyte chemoattractant protein-1) have been shown to enhance the aqueous humor levels in patients with primary open-angle glaucoma, exfoliation glaucoma, or neovascular glaucoma; thus, these factors may stimulate signaling pathways that lead to myofibroblast transdifferentiation of HCFs, monocyte-derived cell infiltration, and ECM remodeling after trabeculectomy(Cordeiro et al., 2000; Mathew and Barton., 2011; Lei et al., 2016; Inoue et al., 2014; Browne et al., 2011).
Glaucoma, the second leading cause of blindness worldwide, is characterized by aberrant elevations of intraocular pressure (IOP), which can damage the optic nerve. IOP reduction is the only effective therapy for prevention of visual impairment and blindness in both hypertensive and normotensive individuals, and in some cases, trabeculectomy is a major surgical procedure that can lower IOP in patients with glaucoma. No matter how surgical technique and postoperative care advances, excessive scarring and tissue fibrosis could result from increased human conjunctival fibroblast (HCF) proliferation and extracellular matrix (ECM) deposition of the subconjunctival tissue and scleral flaps would persist after trabeculectomy. And these issues are major impediments to IOP reduction and filtering of bleb formations, so the modulation of the factors which can induce fibrosis could used as a novel strategy to control scarring after trabeculectomy. In this study, we examined the effects of mammalian target of rapamycin (mTOR) inhibitors (rapamycin or Torin1) on the fibrotic response induced by transforming growth factor-beta 1 (TGF-β1) in cultured human conjunctival fibroblast (HCF) cells. The study also examined the effects of mTOR inhibitor on fibrosis after trabeculectomy in rabbit eyes. In in vitro studies, we stimulated HCFs with TGF-β1, and confirmed that the expression levels of fibronectin, collagen type I alpha 1 chain (COL1A1), and α-smooth muscle actin (SMA) were significantly upregulated in HCFs with TGF-β1, by means of quantitative real-time polymerase chain reaction and immunocytochemistry. And those TGF-β1-induced changes were significantly attenuated with mTOR inhibitors, rapamycin or Torin1. Additionally the migration rate of HCFs was examined under conditions of TGF-β1 induction, TGF-β1-induced changes were significantly attenuated with mTOR inhibitors. A rabbit model of trabeculectomy was examined in vivo, and the effects of topical mTOR inhibitor were also examined, and found that topical treatment with mTOR inhibitor significantly suppressed collagen deposition in rabbit eyes after trabeculectomy. These results have demonstrated that mTOR inhibitors may provide a novel treatment modality for reducing the fibrotic response in HCFs and improving bleb scarring after filtration surgery.
Conjunctival fibrosis following filtering glaucoma surgery
2016, Experimental Eye Research
Citation Excerpt :
A recent study reported VEGF-dependent TGF-β1 expression and myofibroblast transformation in a rabbit trabeculectomy model (Park et al., 2013). Current clinical data indicate that VEGF antagonists are not superior to antimetabolites (Pro et al., 2014) but may serve as adjuncts to improve outcome and reduce the need for secondary procedures (Freiberg et al., 2013; Mathew and Barton, 2011; Vandewalle et al., 2014; Xiong et al., 2014). Blockade of PLGF, another member of the VEGF family, has also shown beneficial effects in a mouse model of glaucoma surgery (Van Bergen et al., 2013a).
Despite advances in surgical technique and postoperative care, fibrosis remains the major impediment to a marked reduction of intraocular pressure without the need of additional medication (complete success) following filtering glaucoma surgery. Several aspects specific to filtering surgery may contribute to enhanced fibrosis. Changes in conjunctival tissue structure and composition due to preceding treatments as well as alterations in interstitial fluid flow and content due to aqueous humor efflux may act as important drivers of fibrosis. In light of these pathophysiological considerations, current and possible future strategies to control fibrosis following filtering glaucoma surgery are discussed.
Trabeculectomy
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Rashmi Mathew completed her undergraduate training at Guy's & St Thomas' School of Medicine, London, United Kingdom. She completed her internship at King's College Hospital, London, and has been a resident at Moorfields Eye Hospital since August 2008. She serves on the council for the Ophthalmology Section of the Royal Society of Medicine. Her research interests include wound healing and clinical risk in the health service. She is due to commence her glaucoma fellowship at Moorfields Eye Hospital from August 2011.

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PerspectiveAnti–Vascular Endothelial Growth Factor Therapy in Glaucoma Filtration Surgery

Purpose

Design

Methods

Results

Conclusions

Section snippets

Background

Anti–Vascular Endothelial Growth Factor Monoclonal Antibodies

Aqueous and Plasma Vascular Endothelial Growth Factor and Vascular Endothelial Growth Factor Receptors

Animal Studies

In Vitro Studies

Route of Administration (Pharmacokinetics)

Trabeculectomy in Patients

Bleb Rescue

Conclusions

Surv Ophthalmol

Exp Eye Res

Ophthalmology

Am J Ophthalmol

Lab Invest

Ophthalmology

Ophthalmology

Ophthalmology

Am J Ophthalmol

Ophthalmology

Late-onset bleb leaks after glaucoma filtering surgery

Arch Ophthalmol

Mitomycin C augmented glaucoma surgery: evolution of filtering bleb avascularity, transconjunctival oozing, and leaks

Br J Ophthalmol

Endophthalmitis after filtering surgery with mitomycin

Arch Ophthalmol

Vascular endothelial growth factor mediates angiogenic activity during the proliferative phase of wound healing

Am J Pathol

Increased vascular endothelial growth factor production in fibroblasts isolated from strictures in patients with Crohn's disease

Br J Surg

The biology of VEGF and its receptors

Nat Med

“Spontaneous,” delayed colon and rectal anastomotic complications associated with bevacizumab therapy

J Surg Oncol

Vascular endothelial growth factor is increased in aqueous humor of glaucomatous eyes

J Glaucoma

Perspective
Anti–Vascular Endothelial Growth Factor Therapy in Glaucoma Filtration Surgery