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VEGFR2 Trafficking by KIF13B Is a Novel Therapeutic Target for Wet Age-Related Macular Degeneration
journal contributionposted on 2022-11-15, 23:35 authored by Stephen B Waters, Christopher Zhou, Tara Nguyen, Ruth Zelkha, Hyun Lee, Andrius KazlauskasAndrius Kazlauskas, Mark RosenblattMark Rosenblatt, Asrar MalikAsrar Malik, Kaori YamadaKaori Yamada
Purpose: Vascular endothelial growth factor (VEGF) and its receptor VEGFR2 are promising therapeutic targets for wet age-related macular degeneration (AMD). As a topically applicable option, we developed the peptide KAI to selectively interfere with VEGFR2 trafficking to the cell surface where it receives VEGF. This study sought to determine the efficacy of KAI in the mouse model of choroidal neovascularization (CNV). Methods: The specificity of KAI was tested by surface plasmon resonance. The drug delivery was analyzed by cryosection and the ELISA after treatment of KAI eyedrop to the mouse eyes. For the laser-induced CNV model, mice with laser-induced ruptures in Bruch's membrane received daily treatment of KAI eyedrop or control peptide. The other groups of mice received intravitreal injection of anti-VEGF or IgG control. After two weeks, CNV was quantified and compared. Results: First, we showed the specificity and high affinity of KAI to VEGFR2. Next, biodistribution revealed successful delivery of KAI eyedrop to the back of the mouse eyes. KAI significantly reduced the disease progression in laser-induced CNV. The comparison with current therapy suggests that KAI eyedrop is as effective as current therapy to prevent CNV in wet AMD. Moreover, the genetic deletion of a kinesin KIF13B, which mediates VEGFR2 trafficking to the cell surface, confirmed the pivotal role of KIF13B in disease progression of wet AMD and neovascularization from choroidal vessels. Conclusions: Taken together, pharmacologic inhibition and genetic deletion complementarily suggest the therapeutic possibility of targeting VEGFR2 trafficking to inhibit pathological angiogenesis in wet AMD.
Regulation of Angiogenesis through VEGFR2 Trafficking | Funder: National Institutes of Health (National Heart, Lung, and Blood Institute) | Grant ID: R56HL128342
Role of VEGFR2 trafficking in pathological angiogenesis in age related macular degeneration | Funder: National Institutes of Health (National Eye Institute) | Grant ID: R01EY029339
CitationWaters, S. B., Zhou, C., Nguyen, T., Zelkha, R., Lee, H., Kazlauskas, A., Rosenblatt, M. I., Malik, A. B.Yamada, K. H. (2021). VEGFR2 Trafficking by KIF13B Is a Novel Therapeutic Target for Wet Age-Related Macular Degeneration. Investigative Ophthalmology & Visual Science, 62(2), 5-5. https://doi.org/10.1167/iovs.62.2.5
PublisherAssociation for Research in Vision and Ophthalmology (ARVO)
CategoriesNo categories selected
NeurodegenerativeBiotechnologyEye Disease and Disorders of VisionAgingMacular Degeneration5.1 Pharmaceuticals2.1 Biological and endogenous factorsEyewet AMDangiogenesiseyedroptherapyVEGFR2Angiogenesis InhibitorsAnimalsChoroidDisease Models, AnimalKinesinsMembrane ProteinsMiceMice, Inbred C57BLMice, Mutant StrainsTissue DistributionVascular Endothelial Growth Factor AWet Macular DegenerationOphthalmology & OptometryBiological SciencesMedical and Health Sciences