VEGFR2 Trafficking by KIF13B Is a Novel Therapeutic Target for Wet Age-Related Macular Degeneration

Autor: Asrar B. Malik, Stephen B Waters, Ruth Zelkha, Mark I. Rosenblatt, Hyun Lee, Andrius Kazlauskas, Tara Nguyen, Christopher Zhou, Kaori H. Yamada
Rok vydání: 2022
Předmět:
Vascular Endothelial Growth Factor A
0301 basic medicine
Physiology and Pharmacology
genetic structures
Cell
Kinesins
Angiogenesis Inhibitors
Pharmacology
Neovascularization
Mice
angiogenesis
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
wet AMD
eyedrop
Animals
Medicine
Tissue Distribution
Receptor
Uncategorized
therapy
biology
Choroid
business.industry
Membrane Proteins
Kinase insert domain receptor
Macular degeneration
medicine.disease
Mice
Mutant Strains
eye diseases
Mice
Inbred C57BL
Vascular endothelial growth factor
Disease Models
Animal
VEGFR2
030104 developmental biology
medicine.anatomical_structure
Choroidal neovascularization
chemistry
Wet Macular Degeneration
biology.protein
sense organs
Antibody
medicine.symptom
business
030217 neurology & neurosurgery
Zdroj: Investigative Ophthalmology & Visual Science
DOI: 10.25417/uic.21235677
Popis: 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.
Databáze: OpenAIRE
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