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  • Optical coherence tomography angiography is another promisin


    Optical coherence tomography angiography is another promising method for the assessment of corneal neovascularization. This relatively new modality is not yet widely used in part because of current limitations in the definition of images produced, lack of functional information, and inability to detect vessels without red cell flow. In vivo confocal microscopy has been used to visualize presumed lymph vessels in a case of corneal transplantation, and a novel non-invasive in vivo technique for the quantification of leukocyte rolling and extravasation at sites of inflammation in human patients has been reported. More recently, in vivo confocal microscopy has been used to demonstrate acellular perfusion of ghost vessels, intravascular cellular traffic, and corneal lymphatic new vessels. The emerging in vivo confocal microscopy and optical coherence tomography angiography techniques have the advantage of being noninvasive, but refinement of these imaging techniques is still needed. Regardless of the modalities used, further development of a standardized measurement procedure is still necessary to allow consensus in measuring and comparing efficacy of new treatments for corneal neovascularization.
    Current treatments of corneal neovascularization
    Gene delivery to the cornea Gene therapy refers to the transfer of nucleic acids into gamma-Glu-Cys using viral and nonviral vectors to correct cellular dysfunction or restore cellular function.188, 192 As such, gene therapy is a type of molecular medicine that targets the underlying molecular basis of disease. Compared to drug- or antibody-based treatments for corneal neovascularization that only provide short-term benefits and require repeated applications, a gene-based approach offers targeted treatments providing long-term therapeutic correction.149, 185, 188 The cornea has properties that make it an attractive target for gene-based manipulations: relative immune privilege and ease of access.130, 149, 185, 188 Corneal transparency allows live tracking of labeled molecules in animal studies.149, 185 The cornea is easily accessible to administer gene therapy reagents, and the ability to maintain the cornea in culture for several weeks permits ex vivo gene therapy approaches.185, 215 A variety of vectors have been used for gene-based therapies for corneal angiogenesis, including viral vectors, lipid-based vectors, nanoparticles, polymers, or naked plasmid–each with their own advantages and limitations.109, 56 Viral-based vectors are well established and effective, but can induce immune responses, whereas nonviral delivery methods are less likely to induce an immune response, but only produce short-term gene expression.102, 274, 56 These vectors are normally delivered to the cornea by subconjunctival, intrastromal, or intracameral injection.188, 228 In some cases, topical application or ex vivo incubation of cornea buttons were also employed.215, 70
    Target genes and therapeutic application Our increasing understanding of the mechanisms underlying angiogenic privilege in the cornea has facilitated the development of gene therapy approaches for corneal neovascularization (Table 1). Two therapeutic approaches are described: either transgenic expression of an antiangiogenic factor or inactivation of a proangiogenic factor via gene silencing.
    Conclusion Corneal neovascularization is a vision-impairing condition and a leading risk factor for corneal graft rejection. Current therapeutic options may be associated with significant side effects and have limited efficacy and a short duration of action. The immune-privileged nature and accessibility of the cornea makes it an attractive target for gene therapy, an alternative to pharmacological treatment that could provide nontoxic and long-term benefits. Additionally, progress of gene therapy to the cornea can be monitored visually and using several imaging modalities. Gene therapy seems to be effective in animal studies, although safety issues arising from the vectors and transgenic overexpression may limit clinical utility. In addition, the mode of delivery requires further refinement. The success of gene therapy seen in some animal studies is accomplished by early and frequent administration, which is far from ideal for treating ongoing corneal neovascularization. As clinical trials of GS-101 have recently approached the phase III stage, the first noninvasive gene therapy that can provide a sustained antiangiogenic effect is about to be applied clinically. With more target genes and biocompatible vectors being developed, more studies are needed to develop safe gene therapy that can not only prevent, but also regress, ongoing corneal neovascularization without the need for frequent and invasive administration. Failing this approach, using ex vivo incubation of the donor cornea button with therapeutic genes has been successful experimentally in both animal and human models to limit postcorneal transplant angiogenesis. Clinically, this may be a novel and safe approach to treat donor button in eye banks before transplantation into a high-risk vascularized corneal bed.195, 85