Evaluation of CXCR4 inhibition in the prevention and intervention model of laser-induced choroidal neovascularization.
PURPOSE. Endothelial precursor cells (EPCs) derived from hematopoietic stem cells (HSCs) have been shown to contribute to choroidal neovascularization by signaling through the SDF-1/CXCR4 axis. In a prevention and treatment/intervention modality of the laser choroidal neovascularization (CNV) model, the efficacy of CXCR4 inhibition on reducing choroidal leakage and angiogenesis was evaluated. METHODS. CNV in rats was generated by focal rupture of Bruch's membrane with an 810-nm diode laser. In the prevention mode, a CXCR4 antagonist (AMD3100) was delivered via an osmotic pump 1 day after laser induction. In the intervention mode, AMD3100 delivery commenced 14 days after laser induction. Inhibition of CXCR4 was determined through leukocyte and SDF-1 actin polymerization blood biomarker assays. Leakage was assessed by fluorescein angiography, and CNV lesion size was quantified after isolectin B4 endothelial cell staining. SU14813, an anti-VEGFR, PDGFR-beta, KIT, and FLT3 inhibitor, was also assessed in an intervention study protocol. RESULTS. Inhibition of CXCR4 was demonstrated by an increase in the number of blood leukocytes, and diminished SDF-1 induced actin polymerization in whole blood. CNV leakage and neovascularization were inhibited when the dose regimen was initiated 1 day after laser-induced CNV induction. AMD3100 did not show efficacy when administered 14 days after lasering. Treatment with SU14813 significantly decreased CNV leakage and lesion size in an intervention modality. CONCLUSIONS. Inhibition of CXCR4 may be useful in preventing neovascularization but does not appear to have an effect on already established angiogenesis. A multiple receptor tyrosine kinase (RTK) inhibitor approach shows promise for the treatment of wet age-related macular degeneration.
Lee
Edwin
E
Department of Ocular Biology, Pfizer, Inc., San Diego, California, USA.
Rewolinski
David
D
D000199:Actins / Q000378:metabolism; D000818:Animals; D001596:Benzylamines; D016570:Bruch Membrane / Q000601:surgery; D002199:Capillary Permeability; D020256:Choroidal Neovascularization / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000080027:Cyclams; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D005451:Fluorescein Angiography; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D017075:Laser Coagulation; D007958:Leukocyte Count; D007964:Leukocytosis; D009025:Morpholines / Q000494:pharmacology; D051381:Rats; D011914:Rats, Inbred BN; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D057135:Wet Macular Degeneration / Q000188:drug therapy
C513935:5-((5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl)-N-(2-hydroxy-3-morpholin-4-ylpropyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide; D000199:Actins; D001596:Benzylamines; C486264:Cxcr4 protein, rat; D000080027:Cyclams; D006571:Heterocyclic Compounds; D007211:Indoles; D009025:Morpholines; D019718:Receptors, CXCR4; D020794:Receptor Protein-Tyrosine Kinases; C088327:plerixafor