July 2010




Accelerated healing with Avastin

by Matt Young EyeWorld Contributing Editor

Anti-VEGF molecule binds VEGF, preventing VEGF action at endothelial receptor Source: Karl Brasse, M.D.; EyeLand Design Network

Novel uses of bevacizumab (Avastin, Genentech, South San Francisco, Calif.) are emerging beyond the retinal realm. One in particular involves the use of bevacizumab to accelerate corneal wound healing after a chemical burn. “This study shows that subconjunctival application of the anti-VEGF agent, bevacizumab, is useful for the inhibition of corneal NV [neovascularization] and for accelerating the regeneration of epithelial basement membrane,” according to study co-author Koonja Lee, Ph.D., associate professor, department of optometry, Eulji University, Daejeon, South Korea. The study was published online in December 2009 in Biochemistry and Molecular Biology Reports. Through this research, Dr. Lee not only explained theoretically why bevacizumab is so useful in this regard—not an easy task given the complex nature of corneal NV—but also presented evidence suggesting bevacizumab could work for such purposes when used at the proper time intervals.

Comprehensive analysis

Dr. Lee analyzed three groups of mouse corneas subjected to alkali burn injury via application stick soaked in 0.5 N NaOH. Group 1 served as the control, treated with saline. Group 2 received subconjunctival injection of bevacizumab one hour after injury. Group 3 received the same injection one hour after injury, as well as four days after injury. The injury was intense to group 1 and was not alleviated by the saline. “After removal of the alkali-immersed application stick from the eye, the injured central corneal stroma appeared opaque with a distinct edematous margin,” Dr. Lee noted. “The opaqueness continued to increase following the alkali burn, reaching an average of grade 2.5 by post-operative day 7. On day 3, the onset of peripheral NV extended from the limbus toward the central cornea, continuing to grow new vessels until day 7 (average of grade 3.5).”

Bevacizumab, meanwhile, made a difference. “Group 2 received a subconjunctival injection of bevacizumab at 1 hr and showed scarce corneal NV and moderate opacity at day 7,” Dr. Lee reported. “Group 3 received bevacizumab 1 hr and 4 days after alkali injury. There was no NV (average of grade 0.3) and central corneal opacity was mild (average of grade 0.9) by day 7.”

The result was significant for group 3. “In group 3, injection of bevacizumab significantly lowered neovascularization and improved corneal transparency,” Dr. Lee reported. “Immunostaining analysis demonstrated a reduction in CD31, αά–SMA and TGF-ß2 levels in stroma compared to group 1. These results indicate that bevacizumab may be useful in reducing neovascularization and improving corneal transparency following corneal alkali burn injury by accelerating regeneration of the basement membrane.”

Inhibiting corneal neovascularization

After alkali burn injury, VEGF stimulates corneal NV, which incites opacification. Therefore, one possible treatment could involve the competitive binding and inhibition of VEGF with a specific, neutralizing anti-VEGF antibody, Dr. Lee noted.

In this study, the anti-VEGF agent was bevacizumab. “Our results demonstrate that the epithelium and stroma of alkali-injured cornea expressed TGF–ß2 7 days post-injury,” Dr. Lee noted. “Bevacizumab-treated cornea showed that TGF–ß2 expression was confined to the epithelia and was suppressed by bevacizumab treatment in the corneal stroma. Since TGF–ß2 normally inhibits the growth of epithelial cells, its suppression by bevacizumab would increase epithelial cells proliferation, thereby enhancing reepithelialization as seen in our cornea model.”

Bevacizumab also interacted helpfully with the basement membrane to restore vision. “Bevacizumab treatment rapidly recovered the integrity of the basement membrane after alkali burn injury and prevented interaction between the epithelium and stroma, which in turn promotes stromal cell activation,” Dr. Lee concluded. “The subconjunctival injection of bevacizumab plays an important role in regenerating the basement membrane in the cornea after alkali burn injury by creating a physical barrier to TGF–ß2. It also plays a critical role in maintaining corneal homeostasis and minimizing fibrotic repair.”

Francis S. Mah, M.D., co-medical director, Charles T. Campbell Ophthalmic Microbiology Laboratory, University of Pittsburgh School of Medicine, Pittsburgh, called the use of bevacizumab for corneal wound healing “very interesting.” From a simple corneal abrasion to severe alkali burns, it could work, he said. Even in combination with such advanced surface epithelial removal techniques—such as Epi-LASIK—controlling healing to a degree with bevacizumab could prove useful. It could also be helpful with more serious conditions such as corneal transplants, he said. “It’s nice to modulate healing,” Dr. Mah said. “In certain circumstances you want more aggressive healing. Other times you want more controlled healing.” If the wrong kind of healing occurs after LASIK, Dr. Mah said, myopic regression could result. “So yes, it could be used in a variety of different corneal healing scenarios,” Dr. Mah said. “However, it’s not the easiest to study the effect of such agents on abrasions.” Overall, Dr. Mah said improving corneal healing with such an agent would be helpful in the areas of refractive surgery, recurrent erosions, and even dry eye.

Editors’ note: Dr. Lee reported no financial interests related to this study. Dr. Mah has no financial interests related to his comments.

Contact information

Lee: 82-31-740-7182, kjl@eulji.ac.kr
Mah: 412-647-2211, mahfs@upmc.edu

Accelerated healing with Avastin Accelerated healing with Avastin
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