Ординатура / Офтальмология / Английские материалы / Ocular Therapeutics Eye on New Discoveries_Yorio, Clark, Wax_2007

Therapy aimed at blocking one or more pathways in the angiogenic process responsible for the growth and development of CNV has become the major focus for the treatment of macular degeneration at present. Triamcinolone acetonide, angiostatic steroids, cyclooxygenase-2 inhibitors, anti-oxidant therapies and agents targeting vascular endothelial growth factor (VEGF) target choroidal angiogenesis at different levels in an attempt to minimize or halt CNV development. Triamcinolone acetonide, a synthetic glucocorticoid, suppresses inflammation, affects ECM turnover and RPE responses, and downregulates VEGF. Clinical trials have shown that intravitreal administration of triamcinolone acetonide reduces the risks of severe visual loss, but more than 40% of patients had a higher risk of elevated IOP (Gillies et al., 2003; Jonas et al., 2003).The Anecortave Acetate Study Group demonstrated that a 15 mg posterior juxtascleral injection over the macula at 6 month intervals was statistically superior to placebo for three measures of clinical efficacy, without the elevated IOP observed with triamcinolone acetonide (D’Amico et al., 2003).

Recent specific anti-VEGF molecules include Pegaptanib, a pegylated RNA aptamer, an antisense oligonucleotide that acts like a high affinity anti-VEGF antibody (2002; Gragoudas et al., 2004), a monoclonal antibody fragment directed against VEGF (Krzystolik et al., 2002), a recombinant human anti-VEGF antibody against free VEGF, anti-VEGF receptor 2 (McMahon, 2000), the ribozyme, angiozyme, targeting VEGF mRNA (Weng and Usman, 2001), VEGF-specific antisense oligonucleotides (Bhisitkul et al., 2005), or siRNA (Reich et al., 2003). Recent large trials have shown the efficacy of Ranibizumab, a recombinant, humanized, monoclonal antibody Fab that neutralizes all active forms of vascular endothelial growth factor A. Ranibizumab is a FAB fragment derived from the same parent molecule as bevacizumab (Rosenfeld et al., 2006; Brown et al., 2006).

Bevacizunab (Avastin) is a humanized monoclonal antibody, and was the first commercially available angiogenesis inhibitor. It inhibits all isoforms of VEGF and is used for the treatment of colorectal cancer and both by both intravitreal and intravenous application in the treatment of AMD (Bashshur et al., 2006; Michels et al., 2005; Rosenfeld et al., 2005). No significant regional or systematic side effects were described in a 3 month follow-up study of intravitreal administered bevacizunab, and vital increase and decrease were observed in visual acuity and retinal thickness respectively (Rich et al., 2006). Although the primary target of therapy has been the neovascular process, secondary events and damage have facets similar to scarring and fibrosis. For instance, VEGF 165 evokes inflammatory responses which may contribute to a profibrotic process (Usui et al., 2004), and current VEGF antagonist therapies may affect these processes. Interestingly, treatment with infliximab, a monoclonal antibody targeting tumor necrosis factor, resulted in regression of membranes and improvement in visual acuity in patients in a small pilot study (Markomichelakis et al., 2005). Agents that interfere with the ECM invasion or remodeling may also be possible therapies. However, the MMP inhibitor, Prinomastat, failed to improve visual acuity when administered orally in a randomized, double-blind, placebo-controlled trial of CNV associated with AMD (Behrendt, 2004). Other agents with anti-angiogenic and antitumor effects are also being tested. A natural metabolite of estradiol – 2- methoxuestradiol (2ME2) – orally administered significantly decreased CNV in an in vivo induced CNV animal model (Funakoshi et al., 2006) (Figure 15.16).

J. Proliferative Vitreoretinopathy (PVR)

The incidence of PVR, a common complication of rhegmatogenous retinal detachment or severe ocular trauma (intraocular foreign body, penetration, perforation,

FIGURE 15.16 The use of antibody technology has had a dramatic effect on therapy for ARMD

FIGURE 15.17 Proliferative vitreoretinopathy – still the major cause of failure of retinal detachment surgery and an important cause of blindness in diabetic retinopathy

contusion, rupture), varies from 10 to 40% depending on the original disease. PVR represents an anomalous wound repair process and is characterized by the formation of epiretinal membranes and fibrocellular proliferations on the surface of the neuroretina (Figure 15.17). Crucial to the formation of periretinal contractile membranes are cellular attachment, migration, proliferation and deposition of extracellular matrix (ECM). Epiretinal membranes often contain numerous retinal pigment epithelial cells (RPE)

which readily undergo transdifferentiation, becoming more fibroblastor macrophagelike (Pastor et al., 2002).

Strategies to reduce the risk of PVR include surgical techniques, pharmacological adjuncts, and preventive measures. Surgical rates of anatomic success for PVR range from 60 to 80%, with rates lower for more severe stages of PVR (Pastor et al., 2002). Successful posterior reattachment rates of 77% have been achieved in silicone oil managed cases, slightly improved further by treatment with C3F8 gas tamponade (1992); the efficacy of perfluorohexyloctane (F6H8) as an admixture to silicone oil is the subject of an ongoing randomized multicentre clinical trial (HSO study, Cologne/ Germany). However, anatomical success is not always associated with functional improvement. Therefore, due to the complicated nature of PVR surgery and the uncertainty of improvement, an ongoing search is in progress for viable medical treatments that may prevent this intraocular wound healing response.

1. Antiproliferative agents

5-Flurouracil (5-FU), vincristine, doxorubicin, cisplatin, dectinomysin, bleomycin sulfate, etoposide, mitomycin-c, cytarabine, daunorubicin, adriamycin, 2 -benzoyloxy- cinnamaldehyde, and dexamethasone have all been investigated, with varying degrees of success. Daunorubicin treatment elicited a significant reduction in the number of reoperations required after rhegmatogeous retinal detachment surgery within 1 year. However, retinal reattachment rates at 6 months marginally failed to show a significant improvement (Wiedemann et al., 1998). Daunomycin does not improve functional outcome. Combination therapy targeting different aspects of the PVR process could provide a synergistic approach to prevention of PVR. Based on initial experimental studies in our laboratory (Khaw et al., 1992, 1993; Kon et al., 1998), an infusion of 5-FU in conjunction with low molecular weight heparin has been the subject of an initial two-center

UK clinical trial (Asaria et al., 2001). This was the first clinical study to show a significant reduction in the incidence of post-oper- ative PVR, which was significantly reduced in patients receiving 5-FU and heparin therapy (12.6% vs 26.4%). There appeared to be a reduction in the reoperation rates resulting from PVR in high risk primary surgery patients without PVR. However, in patients with established PVR, a second multicenter clinical trial demonstrated no significant difference in the success of the primary or secondary outcome measures or the rates of complication (Charteris et al., 2004), suggesting more effective agents are required for established disease. So far cytostatic drugs have been applied intraoperatively as an additive to the vitrectomy infusion fluid. The long-term requirement of treatment and narrow therapeutic window of drugs in use limit the control of PVR. Several sustained release delivery systems such as liposome encapsulation of daunomycin (Shinohara et al., 2003), 5-FU delivery via microspheres (Herrero-Vanrell and Refojo, 2001), scleral plugs (Yasukawa et al., 2001), and biodegradable implant polymers in combination with naproxen (Cardillo et al., 2004) have begun to be explored. In addition, sustained dissipation of 5-FU has been observed in silicone oil (Jolimaitre et al., 2003).

2. Growth factor modulators

A recent study has proposed a possible mechanism for the development of fibrosis in PVR. In this study, it has been found that TGF-β (which exists in increased levels in the vitreous of patients with PVR) can promote the expression of the platelet derived growth factor (PDGF) from RPE cells. The PDGF was shown to activate human choroids fibroblasts (HCHF) that express PDGF receptor α in high levels, which then proliferate and migrate, and produce ECM molecules, causing contraction, fibrosis and the development of fibrotic membranes characteristic of the PVR pathology (Nagineni et al., 2005). It has also been supported that PDGF may have an autocrine effect in the proliferation

of RPE. As PDGF seems to play a crucial role in the pathogenesis of PVR, its inhibition has already become the aim of many studies. The aptimers are nucleic acid-based macromolecules with similar function to the monoclonal antibodies as regards the affinity and specificity that they target proteins. ARC126 and ARC127 are capable of recognizing, binding and blocking PDGF-β and their effects have been tested in animal models, where significant reduction of ERM formation has been described, supporting the potential use of aptamers for the treatment of PVR in humans (Akiyama et al., 2006).

The role of p38 mitogen activated protein kinase (MAPK) was tested in a human retinal pigment epithelial cell line (ARPE-19) for its possible involvement in the induction of fibrogenic reaction. TGF-β2 was used to activate p38MAPK and SB 201290 inhibitor of p38 MAPK to test the effect of the p38MAPK blockage in ARPE-19 cells. P38MAPK is believed to trigger the transcription of Smad 2/3, facilitate the phosphorylation and activation of Smad 3 and subsequently the formation of Smad 3/4 complex, important for the development of fibrotic reaction; it has been shown that the Smad 3 signaling pathway is important for the epithelial–mesenchymal transition of the RPE cells that occurs in retinal fibrosis, and inhibition of Smad3 indicates reduction of RPE fibrotic reaction (Saika et al., 2004b). Inhibition of p38MAPK with SB202190 had a negative effect in ARPE-19 migration and the development of fibrosis, as well as in the production of fibronectin but not of collagen I. Additionally, adenoviral gene transfer in an in vivo PVR animal model with intravitreal application of dominant negative p38MAPK for the inhibition of p38MAPK revealed reduced fibrotic reaction of the RPE cells after post-retinal detachment. Due to these results, the inhibition of p38MAPK has been proposed as a possible future target in PVR therapeutic approach (Saika et al., 2005). Apart from the inhibition of p38MAPK, the activation of caspase 3 (promotes cellular apoptosis

in ERMs) and the inhibition of proliferative cell nuclear antigen (PCNA) (critical cell cycle division factor) have been suggested to have a potential therapeutic effect in PVR as well (Zhang et al., 2005; Mandava et al., 2002). Another study has proposed that the use of a cyclic integrin antagonist that blocks both ανβ3 and ανβ5 integrins may have a beneficial application in vivo, as in in vitro experiments they managed to inhibit RPE attachment to fibronectin, laminin and collagen IV, and migration and invasion that happen during PVR development (Hoffmann et al., 2005).

3. Modulators of cellular motility and matrix remodeling and contraction

Remodeling of the ECM as part of the contractile ERM is an important component of the abnormal wound healing response in PVR. Matrix metalloproteinases (MMPs) actively control this remodeling process by modulating cellular attachment and migration at the neuroretinal surface. Prinomastat (AG3340), which targets a broad spectrum of MMPs, has been the subject of several preclinical studies. In a murine model of oxygen-induced retinal neovascularization, prinomastat significantly inhibited formation of new blood vessels via inhibition of vessel growth (Garcia et al., 2002). Ilomastat, another broad spectrum MMP inhibitor, significantly inhibits collagen contraction by RPE cells (Sheridan et al., 2001), so it appears that these agents may have significant promise in the inhibition of PVR.

IV. THE FUTURE: FROM REPAIR

TO REGENERATION

BOX 15.1

Significant advances have been made in developing new treatments and refining existing treatments for the prevention of scarring after disease, trauma or

surgical intervention. The advent of new technologies, in addition to traditional chemical drugs such as dendrimers, antibodies, aptamers, ribozymes, gene therapy with viral vectors, and RNA interference, opens the door to a whole new generation of therapies to prevent fibrosis in the eye. The ability to control fibrotic processes in the eye offers many tantalizing prospects, including prevention of corneal blindness from scarring to “20/5 vision” with perfect corneal wound healing after wavefront refractive surgery, prevention of PCO to fully accommodative lens implants, 100% success of glaucoma surgery with pressure around 10mmHg associated with 5% progression over a decade, to no failure of retinal detachment surgery and minimal visual loss from age related macular degeneration. Finally, most exciting is the prospect that neutralizing the fibrotic response to disease and injury will allow us to revert to the “fetal” mode when regeneration is the “normal” process, as shown in the recent report which demonstrated that induction of bcl-2 gene expression together with down regulation of gliosis results in axonal regeneration in mice (Cho et al., 2005) (Figure 15.18).

FIGURE 15.18 Group of progenitor cells derived from adult retina – modulation of scarring may facilitate the regeneration of ocular tissues

V. SUMMARY

The cellular and molecular processes of wound healing play a part in either the pathogenesis or treatment failure of virtually all the blinding diseases in the world today. Furthermore, formation of nonfunctional scar tissue rather than healthy regenerated tissue means that the aging eye cannot reverse degenerative changes that occur with age. The use of non-specific anticancer agents has revolutionized glaucoma surgery by preventing scarring, and has found use in many other parts of the eye including the cornea and the retina, but may have potentially severe side effects. Simple changes in the surgical technique of application have considerably reduced the complications. However, increased understanding of the basic processes of healing and scar formation is enabling the development of a new generation of more specific antiscarring agents. Ultimately, this may lead, in conjunction with cellular therapy for regeneration of damaged ocular tissues, to retention or even restoration of visual function.

VI. ACKNOWLEDGMENTS

The authors acknowledge the support of the Wellcome Trust, Medical Research Council, Fight for Sight, Guide Dogs for the Blind, Moorfields Trustees, the Eranda Trust, the Daily Telegraph appeal, the Haymans Trust, the Ron and Liora Moskovitz Foundation, the Michael and Ilse Katz Foundation, and the Helen Hamlyn Trust in memory of Paul Hamlyn. Supported by funding from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology.

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