Hindawi Publishing Corporation
`Journal of Ophthalmology
`Volume 2015,Article ID 892043, 2 pages
`http://dx.doi.org/10.1155/2015/892043
`
`Editorial
`
`Ocular Angiogenesis
`
`Hindawi
`
`JulianaL. Dreyfuss,'” Ricardo J. Giordano,’ and Caio V. Regatieri*”
`
`'DepartmentofHealth Informatics, Federal University ofSao Paulo, Paulista School ofMedicine, 04023-062 Sao Paulo, SP, Brazil
`?DepartmentofBiochemistry, Federal University ofSao Paulo, Paulista School ofMedicine, 04039-032 Sao Paulo, SP, Brazil
`3DepartmentofBiochemistry, University ofSao Paulo, 05508-000 Sao Paulo, SP, Brazil
`‘Department ofOphthalmology, Federal University ofSao Paulo, Paulista SchoolofMedicine, 04023-062 Sao Paulo, SP, Brazil
`*Department ofOphthalmology, Tufts University School ofMedicine, Boston, MA 02111, USA
`
`Correspondenceshould be addressed to Juliana L. Dreyfuss; jdreyfuss@unifesp.br
`
`Received 22 June 2015; Accepted 5 July 2015
`
`Copyright © 2015 Juliana L. Dreyfuss et al. This is an open access article distributed under the Creative Commons Attribution
`License, which permits unrestricted use, distribution, and reproduction in any medium,provided the original work is properly
`cited.
`
`This special issue showsthe continuingefforts to understand
`the molecular biology and the development of newtreat-
`ments and diagnostic tools for ocular angiogenesis. In this
`issue we bring novel research and discuss challenges in devel-
`oping therapeutics for ocular neovascular diseases, angio-
`genesis andits role in ocular diseases, and the mechanisms
`leading to progressive vessel dysfunction and blindness.
`This issue shows papers describing clinical and experi-
`mental studies of ocular angiogenesis (OA), showing advan-
`ces in molecular biology and newinsights into retinal, cor-
`neal, and choroidal neovascularization and imaging tech-
`niques, besides current concepts in the treatment of ocular
`angiogenesis. This special issue promotes new ideas, inspires
`discussion of the concepts presented in the issue, increases
`the understanding of mechanisms that control the dynamic
`process of angiogenesis in the eye, and brings together the
`available information of new types of treatments.
`Angiogenesis has fundamental importancein disease and
`health.It is the formation ofnew bloodvessels from preexist-
`ing vasculature. Angiogenesis is a complex process constitut-
`ing multiple steps. Extracellular matrix degrading enzymes
`secreted by activated endothelial cells degrade the basement
`membrane, allowing the migration andproliferation ofthese
`cells, resulting in the formation of solid endothelial cell
`capillary tubes. Pathologic angiogenesis in the eye can lead to
`severe visual impairment. The ocular angiogenesis can occur
`in retina, choroid, and cornea. The ocular angiogenesis is
`
`related to a broad spectrum of disorders such as wet age-
`related macular degeneration (AMD), diabetic retinopathy,
`retinal artery or vein occlusion, retinopathy of prematurity
`(ROP), neovascular glaucoma, and corneal neovasculariza-
`tion secondary to infectious or inflammatory processes.
`Ocular neovascularization is an intricate process con-
`trolled by myriad angiogenic agents such as growth factors,
`cytokines, and extracellular matrix components. Angiogen-
`esis is regulated by a balance between endogenous proan-
`giogenic and antiangiogenic factors. And the diseases where
`ocular angiogenesis occurs require disruption of such bal-
`ance; thus, the angiogenic switch must be turned “on” for
`neovascularization progression.
`The proangiogenic growth factors implicated in patho-
`logic vessel formation in ocular diseasesarefibroblast growth
`factor (FGF), platelet-derived endothelial growth factor
`(PDGF), and vascular endothelial growth factor (VEGF),
`among others. The antiangiogenic factors are pigment epi-
`thelium-derived factor (PEDF), endostatin, and thrombo-
`spondin, amongothers. Identification of these angiogenesis
`regulators has enabled the developmentof novel therapeutic
`approachesfor many ocular disorders.
`Recent clinical studies regarding the intravitreal injection
`ofmonoclonal antibodies anti-VEGF(ranibizumab andbeva-
`cizumab) have shown excellent results in the treatment of
`degenerative and vascular chorioretinal diseases. Diagnostic
`imaging tools have played an increasingly importantrole in
`eye carein recentyears.
`
`Exhibit 2179
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`Page 01 of 03
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`Mylan v. Regeneron, IPR2021-00881
`
`U.S. Pat. 9,254,338, Exhibit 2179
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`Exhibit 2179
`Page 01 of 03
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`2
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`Journal of Ophthalmology
`
`receptor APJ) from apoptosis due to chemical hypoxia
`induced in rat retinal pericytes. The study performed by L.
`Lytvynchuk et al. shows the antiproliferative, apoptotic, and
`autophagic activity of anti-VEGFs on fibroblasts cultures.
`These effects upon fibroblasts may explain the cellular
`response and the etiology of choroidal neovascularization
`involution after treatment with anti-VEGFs.
`This special issue additionally presents very interesting
`clinical studies. R. Mastropasqua et al. reveal that optical
`coherence tomography-angiography is a noninvasive dyeless
`method to image the retinal microcirculation; the images
`provided distinct vascular patterns for different diseases. It
`provides detailed images of retinal vascular plexuses and
`quantitative data of pathologic structures. P. Calvo et al.
`analyzed the visual outcome in 51 patients with wet age-
`related macular degeneration depending on the number
`of ranibizumab injections after 3 years of follow-up. The
`best outcomes were found in stable wet AMD patients that
`received ≥ 7 ranibizumab intravitreal injections in 3 years.
`Following the same treatment modality for wet AMD, anti-
`VEGF therapy using ranibizumab, A. Garc´ıa-Layana et al.
`compile data showing the comparison of different regimens
`of intravitreal injections and their outcomes. Finally, but not
`less interestingly, S. D. Nicoara et al. show the outcomes of
`bevacizumab treatment of retinopathy of prematurity. They
`recorded no complications subsequent to the intravitreal
`injections of bevacizumab with no late retinal detachment.
`In addition the study shows a very high ROP regression rate
`after one intravitreal bevacizumab injection.
`We expect that the present volume on ocular angiogenesis
`may provide useful information to understand the mech-
`anisms and new therapies and diagnostic tools for ocular
`angiogenesis to the readers.
`
`Juliana L. Dreyfuss
`Ricardo J. Giordano
`Caio V. Regatieri
`
`Advances in fundus imaging make assessment of periph-
`eral neovascularization in many chorioretinal diseases possi-
`ble, such as diabetic retinopathy and retinal vein occlusion.
`The technology has unveiled new insights into the role of
`peripheral pathology in retinal vascular, degenerative, and
`inflammatory diseases.
`Additionally, new techniques in optical coherence tomog-
`raphy have improved the axial image resolution and image
`acquisition and the ability to allow the detection of individual
`retinal layers and lesion components. With spectral domain
`it is possible to identify retinal new vessels in wet age-related
`macular degeneration using OCT angiography. The next step
`will be the swept source OCT development, which will make
`the blood flow measurements possible. The study by W. Chen
`et al. investigates the aqueous levels of pigment epithelium-
`derived factor (PEDF) and macular choroidal thickness
`in individuals with high myopia. The authors noticed a
`significant correlation between aqueous PEDF levels and
`macular choroidal thickness in patients without angiogenesis
`but no association with the group of patients with patho-
`logical angiogenesis. It would be interesting to expand these
`association studies to include vascular endothelial growth
`factor and assess whether the balance between VEGF and
`PEDF levels could predict disease progression and resistance
`to anti-VEGF therapy. Another study by S. Rusnak et al. shows
`that the concentrations of IL-6, TGF-𝛽1, and VEGF correlate
`with the severity of proliferative diabetic retinopathy and
`were particularly high in patients with refractive neovascular
`glaucoma. IL-6 is a multifunctional cytokine with pro- and
`anti-inflammatory properties and TGF-𝛽1 is an interesting
`therapeutic target for ocular angiogenesis. Their results rein-
`force these findings and also suggest that, in patients with
`neovascular glaucoma refractory to treatment, IL-6 and TGF-
`𝛽1 may have a potential use in patient stratification and in
`determining personalized medical needs.
`The mechanisms and new experimental treatments for
`corneal neovascularization are investigated and presented in
`this issue. K. Tomoyose et al. show that the loss of TRP vanil-
`loid subtype 1 (TRPV1), the capsaicin receptor, did not affect
`VEGF-dependent neovascularization in cell culture. On the
`other hand, lack of TRPV1 inhibited neovascularization in
`mouse corneal stroma following cauterization. The study
`performed by J. Yoshida et al. shows the inhibition of corneal
`neovascularization by subconjunctival injection of Fc-endos-
`tatin in rabbit corneas. The endostatin is an angiogenesis
`inhibitor, a fragment of collagen XVIII, and the Fc-endostatin
`was developed by fusing endostatin to the Fc region of an
`IgG molecule. The subconjunctival injection of this antian-
`giogenic molecule showed to be efficient and safe in rabbit
`model.
`The role of stromal cells in angiogenesis is also addressed
`in this special issue. The role of molecules in pericytes and
`anti-VEGF therapy in fibroblasts is shown in this issue. Per-
`icytes are contractile cells that interact with endothelial cells
`stabilizing the newly formed vessel. These cells modulate vas-
`cular permeability and blood flow and can regulate angiogen-
`esis modulating endothelial proliferation, differentiation, and
`migration. The study by L. Chen et al. shows the protective
`effect of apelin (an endogenous ligand of G protein-coupled
`
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