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`Scientists discover why cornea is transparent | EurekAlert!
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`https://www.eurekalert.org/news-releases/652982
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`NEWS RELEA SE 17-JU L-2006
`Scientists discover why cornea is transparent
`and free of blood vessels, allowing vision
`Resu lts hold promise for treatments of eye d isease and cancer
`Peer-Reviewed Pub l ication
`SCHEPENS EYE RESEARCH INSTITUTE
`Boston , MA - - Scientists at the Harvard Department of Ophthalmology's Schepens Eye Research Institute
`and Massachusetts Eye and Ear Inrmary (MEEI) are the rst to learn why the cornea, the clear window of
`the eye, is free of b lood vessels- -a un ique phenomenon that makes vision possib le. The key, say the
`researchers, is the unexpected presence of large amounts of the protein VEGFR-3 (vascu lar endothel ial
`growth factor receptor-3) on the top ep ithel ial layer of normal healthy corneas. Accord ing to their nd ings,
`VEGFR-3 halts ang iogenesis (b lood vessel growth ) by acting as a "sink" to b ind or neutral ize the growth
`factors sent by the body to stimu late the growth of b lood vessels. The cornea has long been known to have
`the remarkab le and unusual property of not having b lood vessels, but the exact reasons for th is had
`remained unknown .
`These resu lts, pub l ished in the Ju ly 25, 2006 issue of the Proceed ings of the National Academy of Sciences
`and in the Ju ly 17 on l ine ed ition , not on ly solve a profound scientic mystery, but also hold great promise
`for preventing and curing b l ind ing eye d isease and i l lnesses such as cancer, in wh ich b lood vessels grow
`abnormal ly and uncontrol lab ly, since th is phenomenon , present in the cornea normal ly, can be used
`therapeutical ly in other tissues.
`"Th is is a very sign icant d iscovery," says Dr. Reza Dana, Sen ior Scientist at the Schepens Eye Research
`Institute, head of the Cornea Service at the Massachusetts Eye and Ear Inrmary, and an associate
`professor at Harvard Med ical School , and the sen ior author and principal investigator of the study. "A clear
`cornea is essential for vision . Without the ab i l ity to maintain a b lood -vessel - free cornea, our vision wou ld
`be sign icantly impaired ," he says, add ing that clear, vessel - free corneas are vital to any an imal that needs
`a h igh level of visual acu ity to survive.
`The cornea, one of on ly a few tissues in the body that actively keep themselves vessel - free (the other is
`carti lage), is the th in transparent tissue that covers the front of the eye. It is the clarity of the cornea that
`al lows l ight to pass onto the retina and from there to the brain for interpretation . When the cornea is
`clouded by in jury, infection or abnormal b lood vessel growth , vision is severely impaired , i f not destroyed .
`Scientists have been wrestl ing with the "clarity" puzz le for many decades. And , wh i le some previous
`stud ies have revealed smal l clues, none have pointed to one major mechan ism, unti l th is study.
`In most other tissues of the body, b lood vessel growth or ang iogenesis occurs in response to a need for
`increased b lood ow to heal an in jured or infected area. The immune system sends in growth factors such
`as vascu lar endothel ial growth factor (VEGF) to b ind with a protein receptor cal led VEGFR-2 on b lood
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`7/15/22, 9:42 AM
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`Scientists discover why cornea is transparent | EurekAlert!
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`https://www.eurekalert.org/news-releases/652982
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`2/3
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`Eye Therapies Exhibit 2177, 2 of 3
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`vessels to trigger vessel growth . Three forms of VEGF- -A, C, and D- -b ind with th is receptor. Two of them, C
`and D also b ind with VEGFR-3, wh ich is usual ly found on cel ls l in ing lymphatic vessels, to stimu late the
`growth of lymphatic vessels.
`Dana's team began to suspect the involvement of VEGFR-3 in stopp ing b lood growth in corneas when they
`noticed unexpected ly that large amounts of the protein seemed to exist natural ly on healthy corneal
`ep ithel ium, a previously unknown location for the receptor. Dana and h is team were already aware from
`cl in ical experience that the ep ithel ium most l ikely p layed a role in suppressing b lood vessel growth on the
`cornea, having witnessed b lood vessels develop on corneas stripped of their ep ithel ial layers.
`They began to theorize that the large amounts of VEGFR-3, in th is new, non-vascu lar location , might be
`attracting and sucking up al l the C and D VEGF growth factors, thereby b locking them from b ind ing with
`VEGFR-2. And , because th is b ind ing took p lace in a non-vascu lar setting , the growth factors were
`neutral ized .
`To test their theory, the team conducted a series of experiments.
`Using corneal tissue from mice, the team d id the fol lowing .
`They conducted chemical analyses that demonstrated that VEFGR-3 and the gene that expressed it were
`indeed present on the corneal ep ithel ium. Next, in two separate experiments, they compared corneas with
`and without ep ithel ial layers that were in jured . They found that on ly the corneas without ep ithel ial layers
`developed b lood vessels, imp l icating the role of the ep ithel ium in suppressing b lood vessel growth To
`further prove their theory, they added a VEGFR-3 substitute to corneas stripped of their ep ithel ial layers
`and found that vessel growth continued to be suppressed , rep lacing the normal anti -ang iogen ic role of the
`ep ithel ium. Final ly they exposed intact corneas to an agent that b locked VEGFR-3 and found that b lood
`vessels began to grow, formal ly demonstrating that the corneal ep ithel ium is key to suppression of b lood
`vessels and that the key mechan ism is expression of VEGFR-3.
`"The resu lts from th is series of tests, conrmed our bel ief that the presence of VEGFR-3 is the major factor
`in preventing b lood vessel formation in the cornea," says Dana, who says that the d iscovery wi l l have a far
`reach ing impact on the development of new therap ies for eye and other d iseases.
`"Drugs designed to man ipu late the levels of th is protein cou ld heal corneas that have undergone severe
`trauma or help shrink tumors fed by rap id ly growing abnormal b lood vessels," he says. " In fact, the next
`step in our work is exactly th is."
`###
`Other authors of the study include: Claus Cursiefen* +, Lu Chen*, Magal i Saint-Gen iez*, Pedram Hamrah*,
`Yip ing Jin*, Saad ia Rash id*, Bron islaw Pytowski**, Kris Persaud**, Yan Wu**, J. Wayne Strei lein*†, Reza
`Dana* ++ ,
`*The Schepens Eye Research Institute and Massachusetts Eye and Ear Inrmary, Dept. of Ophthalmology,
`Harvard Med ical School , Boston , MA; +Dept. of Ophthalmology, Friedrich-Alexander Un iversity Erlangen-
`Nürnberg , Erlangen , Germany; **ImClone Systems, Inc., New York; †Dr. J. Wayne Strei lein deceased March
`

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`7/15/22, 9:42 AM
`
`Scientists discover why cornea is transparent | EurekAlert!
`
`https://www.eurekalert.org/news-releases/652982
`
`3/3
`
`Eye Therapies Exhibit 2177, 3 of 3
`Slayback v. Eye Therapies - IPR2022-00142
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`15 th 2004.
`About the Massachusetts Eye and Ear Inrmary,
`http ://www.meei .harvard .edu . : The Massachusetts Eye and Ear Inrmary, an independent specialty
`hosp ital , is an international center for treatment and research and a teach ing hosp ital of Harvard Med ical
`School .
`Schepens Eye Research Institute is an al iate of Harvard Med ical School and he largest independent eye
`research institute in the world . For add itional information , go to http ://www.theschepens.org/.
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