title: Inhibition of choroidal and corneal pathologic neovascularization by Plgf1-de gene transfer.
abstract: OBJECTIVE
  Ocular neovascularization (NV), the primary cause of blindness, typically is treated via inhibition of VEGF-A activity. However, besides VEGF-A, other proteins of the same family, including VEGF-B and placental growth factor (PlGF, all together VEGFs), have a crucial role in the angiogenesis process. PlGF and VEGF, which form heterodimers if co-expressed, both are required for pathologic angiogenesis. We generated a PlGF1 variant, named PlGF1-DE, which is unable to bind and activate VEGFR-1, but retains the ability to form heterodimer. PlGF1-DE acts as dominant negative of VEGF-A and PlGF1wt through heterodimerization mechanism. The purpose of our study was to explore the therapeutic potential of Plgf1-de gene in choroid and cornea NV context.
  
  
  METHODS
  In the model of laser-induced choroidal neovascularization (CNV), Plgf1-de gene, and as control Plgf1wt, LacZ, or gfp genes, were delivered using adeno-associated virus (AAV) vector by subretinal injection 14 days before the injury. After 7 days CNV volume was assessed. Corneal NV was induced by scrape or suture procedures. Expression vectors for PlGF1wt or PlGF1-DE, and as control the empty vector pCDNA3, were injected in the mouse cornea after the vascularization insults. NV was evaluated with CD31 and LYVE-1 immunostaining.
  
  
  RESULTS
  The expression of Plgf1-de induced significant inhibition of choroidal and corneal NV by reducing VEGF-A homodimer production. Conversely, the delivery of Plgf1wt, despite induced similar reduction of VEGF-A production, did not affect NV.
  
  
  CONCLUSIONS
  Plgf1-de gene is a new therapeutic tool for the inhibition of VEGFs driven ocular NV.
authors.affiliation: Angiogenesis Lab, Institute of Genetics and Biophysics, CNR, Naples, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Tarallo
authors.forename: Sasha
authors.initials: S
authors.lastname: Bogdanovich
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hirano
authors.forename: Laura
authors.initials: L
authors.lastname: Tudisco
authors.forename: Lorena
authors.initials: L
authors.lastname: Zentilin
authors.forename: Mauro
authors.initials: M
authors.lastname: Giacca
authors.forename: Jayakrishna
authors.initials: J
authors.lastname: Ambati
authors.forename: Sandro
authors.initials: S
authors.lastname: De Falco
mesh_terms: D000818:Animals; D020256:Choroidal Neovascularization / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016510:Corneal Neovascularization / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D004596:Electroretinography; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression / Q000502:physiology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000072483:Placenta Growth Factor; D010957:Plasmids; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011257:Pregnancy Proteins / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000378:metabolism
chemical_list: C119248:LYVE1 protein, human; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011257:Pregnancy Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D033921:Vesicular Transport Proteins; D000072483:Placenta Growth Factor